22 chapter 2 Abstract Indeterminate thyroid cytology (Bethesda III and IV) corresponds to follicular-patterned benign and malignant lesions, which are particularly difficult to differentiate on cytology alone. As approximately 25% of these nodules harbour malignancy, diagnostic hemithyroidectomy is still custom. However, advanced preoperative diagnostics are rapidly evolving. This review provides an overview of additional molecular and imaging diagnostics for indeterminate thyroid nodules in a pre-operative clinical setting, including considerations regarding costeffectiveness, availability, and feasibility of combining techniques. Addressed diagnostics include gene mutation analysis, microRNA, immunocytochemistry, ultrasonography, elastosonography, CT, [99mTc]Tc-MIBI scintigraphy, [18F]FDG-PET and diffusion-weighted MRI. The best rule-out tests for malignancy were the Afirma® GEC and [18F]FDG-PET. The most accurate rule-in test was sole BRAF mutation analysis. No diagnostic had both near-perfect sensitivity and specificity, and estimated cost-effectiveness. Molecular techniques are rapidly advancing. However, given the currently available techniques a multimodality stepwise approach likely offers the most accurate diagnosis, sequentially applying one sensitive rule-out test and one specific rulein test. Geographical variations in cytology (e.g., Hürthle cell neoplasms) and tumour genetics strongly influence local test performance and clinical utility. Multidisciplinary collaboration and implementation studies can aid the local decision for one or more eligible diagnostics.
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