339 Quantitative classification and radiomics of [18F]FDG-PET/CT 5 Introduction An accurate diagnostic workup of cytologically indeterminate thyroid nodules is crucial to prevent futile diagnostic surgeries for benign nodules as well as to ensure timely diagnosis of malignant or borderline tumours. Including cytology with atypia of undetermined significance or follicular lesions of undetermined significance (Bethesda III, AUS/FLUS) and cytology suspicious for a follicular neoplasm (Bethesda IV, FN/SFN) or Hürthle cell neoplasm (Bethesda IV, HCN/SHCN), indeterminate thyroid nodules have an approximate 25% risk of malignancy [18, 464, 500]. Our recent randomised controlled trial showed that visual assessment of [18F]-2-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography ([18F]FDG-PET/CT) reliably rules out thyroid malignancy in [18F] FDG-negative indeterminate nodules, with a reported 94% sensitivity and 31% benign call rate (i.e., fraction of negative tests). As such, [18F]FDG-PET/CT-driven management resulted in an oncologically safe 40% reduction in futile diagnostic surgeries for benign nodules. With a limited 40% specificity, visual [18F]FDG-PET/CT assessment increased the post-test risk of malignancy but appeared unable to fully risk-stratify the approximately two-thirds visually [18F]FDG-positive nodules [501]. These results validated the findings from previously published, smaller, non-randomised studies [37, 39, 40, 59, 309, 462, 485, 502]. Part of this limited specificity is explained by the proportion of HCN/SHCN cytology, which varied from 21% to 52% in previous PET/CT studies including 23% in our trial [37, 309, 501]. Hürthle cell neoplasms, defined as tumours composed of >75% Hürthle cells, constitute an extraordinary subgroup: following the abundance of mitochondria in their oxyphilic follicular-derived cells, nearly all of these neoplasms are strongly [18F]FDG-positive [480, 501, 503, 504]. As such, visual [18F]FDGPET/CT assessment cannot differentiate between benign and malignant Hürthle cell nodules. We previously advocated that a visual [18F]FDG-PET/CT-driven diagnostic workup should be limited to non-Hürthle cell Bethesda III/IV nodules to optimize therapeutic yield [501]. The risk of malignancy in nodules with HCN/SHCN cytology appears lower than in FN/SFN cytology, but Hürthle cell carcinomas typically show more aggressive behaviour and less favourable prognosis than their nononcocytic follicular counterparts [503, 504]. This underlines the currently unmet need for an accurate diagnostic workup for this subgroup. Several studies have reported the quantitative assessment of [18F]FDG-PET/CT images using the standardised uptake value (SUV, g/mL) of the indeterminate thyroid nodule, most frequently reported as the maximum SUV (SUVmax) [25, 39, 40, 462, 485]. A higher SUVmax was generally reported in thyroid malignancies than in benign lesions [37, 59, 309, 502]. Threshold analysis using a SUVmax cut-off of 5 g/mL resulted in 42%-80% sensitivity and 41%-91% specificity to detect malignancy [39, 309, 485]. To the best of our knowledge, there is no evidence on the quantitative assessment of [18F] FDG-PET/CT in Hürthle cell nodules.
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