36 chapter 2 are unknown, but the authors hypothesized that the two types have subtle histopathological differences. The colloid-rich thyroid carcinomas likely more often develop through the well-known mutations included in the miRInform® thyroid test, whereas mutations that elicit colloid-poor thyroid carcinoma are yet unknown [75]. Simultaneously with the American miRInform® studies, five European studies independently investigated whether a panel of the same 7 genes could reliably be assessed using different methods [76, 93, 99, 100, 108]. In three separate studies, Eszlinger et al. demonstrated that testing was also feasible on routine air-dried FNAC samples from indeterminate thyroid nodules. Over the course of these studies, sensitivity of this method improved from 18% to 49% and specificity from 86% to 93%, respectively. The use of air-dried FNAC samples for mutation analysis could advance the implementation of mutation analysis in daily practice, as specific storage conditions of fresh FNAC samples for mutation analysis are no longer required [76, 99, 100]. Mancini et al. showed that high-resolution melting (HRM) analysis is an accurate screening method for the seven genetic alterations, with 56% sensitivity and 90% specificity. HRM is a post-PCR procedure that does not require significant additional resources. This could reserve the costlier direct sequencing procedures solely for samples with abnormal HRM results, thereby reducing the overall costs of mutation analysis [93]. Overall, reported sensitivities and specificities of a 7-gene mutation panel in indeterminate thyroid nodules ranges from 18% to 69% and 86% to 99%, respectively [61, 75, 99]. It is an adequate diagnostic tool with a high rule-in capacity in indeterminate nodules. Test performance was similar in Bethesda III and Bethesda IV nodules, although the latter more frequently had a positive test result based on the higher prevalence of RAS mutations [69, 97]. Due to the common RAS mutations, PPV of the 7-gene mutation panel never exceeds 90% in a range of realistic 15% to 40% prevalence of malignancy. As such it is debatable whether a positive test warrants immediate single-stage total thyroidectomy. It translates into an inappropriate overtreatment in a significant number of patients with a positive test but benign final histology at higher risk of surgical complications and all requiring lifelong levothyroxine supplementation. Deliberate surgical decision-making should consider the underlying positive mutation rather than mere the positive test itself. The limited size of the seven-gene gene mutation panel keeps the costs per test low compared to other, larger molecular panels. Reported prices of the 7-gene mutation panel all concern the commercial miRInform® thyroid (or ThyGenX® Thyroid Oncogene Panel) and range between $425 and $1,700 [158, 159]. Implementation of miRInform® testing for indeterminate nodules theoretically resulted in a 20% cost reduction in the USA: the prevented two-step surgical procedures would outweigh the added expenses for miRInform® testing and increased number of total thyroidectomies – including those for nodules with a false-positive test [158]. In a European setting, treatment and hospitalization costs are generally lower and miRInform® would most likely not be cost-effective [53]. However, these cost-effectiveness studies both adopted the unequalled
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