Lisanne de Koster

530 Appendices Summary The incidence of both thyroid nodules as well as differentiated thyroid carcinoma is rising due to the increased use of sensitive imaging techniques. Yet, the general risk of malignancy in thyroid nodules remains low (i.e., <10%). This calls for an accurate diagnostic workup, which classically consists of ultrasound assessment and fine-needle aspiration cytology (FNAC) with application of the Bethesda classification. In cytologically indeterminate nodules (i.e., Bethesda III and IV), diagnostic thyroid surgery would traditionally subsequently be advised to obtain a definitive diagnosis. To aid the malignancy risk stratification prior to surgery and avoid unbeneficial patient management by more accurately ruling-in and/or ruling-out malignancy, various ancillary diagnostics can currently be considered, including but not limited to molecular diagnostics (MD) and [18F]FDG-PET/CT. When evaluating advanced diagnostic strategies, focussing on clinical utility (i.e., the extent to which the use of a diagnostic test improves health outcomes relative to its current best alternative) and societal efficacy rather than merely assessing a tests’ diagnostic accuracy will result in a higher level of evidence, similar to the standardized, incremental phases in therapeutic (drug) research. In line with current trends towards de-escalating management strategies for thyroid nodules and differentiated thyroid carcinoma, the aim of this thesis was to optimize the diagnostic workup of cytologically indeterminate thyroid nodules (Bethesda classification III and IV) and reduce unbeneficial patient management, including unbeneficial diagnostic tests as well as futile diagnostic thyroid surgeries, in order to benefit the individual patient as well as our health care system from a societal perspective. Part I. Prologue Part I of this thesis reviewed the available additional diagnostics for cytologically indeterminate thyroid nodules, including their test characteristics, advantages and disadvantages, and any available clinical utility data. Chapter 2 provided a comprehensive, systematic review of the literature, comprising the entire spectrum of available molecular and imaging biomarkers. In this comprehensive overview, we covered MD including gene mutation analysis, microRNA, and immunocytochemistry, conventional imaging techniques including ultrasonography, elastosonography and CT, and molecular imaging techniques including [99mTc]Tc-MIBI scintigraphy, [18F]FDG-PET and diffusion-weighted MRI. The diagnostic accuracy of each test in a pre-operative clinical setting was discussed, including considerations regarding cost-effectiveness, availability, and feasibility of combining techniques. Based on the literature that was available at the time of the writing of this review, the best rule-out tests for thyroid malignancy were the Afirma® GEC and [18F]FDG-PET(/CT). The most accurate rule-

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