General discussion 499 13 imaging of small lesions (by reducing the partial volume effect, among others), although one may also advocate that the improved spatial resolution may increase the number of false-positive findings [25]. Following the results of the EfFECTS trial, [18F]FDG-PET/CT meets the ATA’s rule-out criterium for an ideal rule-out test, as do some commercial molecular classifiers with similar sensitivity. These MD panels appear to outperform [18F]FDG-PET/CT on specificity and benign call rate [490, 696, 697]. Reproducibility of the diagnostic accuracy parameters can be questioned for both diagnostics by the results of some single outlier studies [309, 693, 696, 723]. Implementation of [18F]FDG-PET/CT for indeterminate thyroid nodules in the upcoming versions of the Dutch and ATA thyroid guidelines is still pending the valuation of the studies in this thesis by the respective guideline committees. In the United States, with wide accessibility to several commercial molecular tests, MD has taken a firm position in daily practice over the past decade, despite its still debated cost-effectiveness [25, 495, 496, 579, 719, 724]. Adding the rather conservative American point of view regarding the use of ionizing radiation, it seems unlikely that [18F]FDG-PET/CT will be considered more than a suitable runner-up. In the Netherlands, however, [18F]FDG-PET/CT is widely available and recently validated oncologically safe and cost-effective by the results of the EfFECTS trial [28, 501]. MD, on the other hand, is still under development and has limited availability besides the next generation sequencing (NGS) panels that we used in our study at the Leiden University Medical Center and that require further clinical validation studies in their current setup [695, 725]. We therefore expect that in the upcoming revision of the Dutch guidelines, which is expected later in 2024, [18F]FDG-PET/CT may be recommended as a rule-out test for Bethesda III and IV nodules. At the time of the writing of this thesis, new versions of the ETA and French thyroid guidelines have recently been published. Although the cards are stacked in favour of MD, crucial limitations are recognized as well. According to the 2023 European Thyroid Association (ETA) clinical practice guidelines for thyroid nodule management, MD may be considered for cytologically indeterminate thyroid nodules, if available (Strength of recommendation: 1 [strong]; quality of evidence: moderate) [15]. The French SFE-AFCE-SFMN 2022 Consensus on the management of thyroid nodules recognizes the performance and potential clinical impact of the highly accurate commercially available molecular tests, but questions the high costs and lack of clinical validation studies of these panels in the French setting, too. By also acknowledging that more limited (i.e., 7-gene) molecular panels have insufficient performance for clinical practice, they hit the nail on the head regarding the current limitations of MD in Europe: the molecular panels with the highest negative predictive value (NPV) to accurately exclude malignancy are unavailable, too expensive, and not validated in a European setting; 7-gene MD panels are more widely available and affordable but lack oncologically safe rule-out capacities [492, 493]. Thus, no currently available molecular panel may thick all boxes in a European setting.
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