63 Diagnostic utility of molecular and imaging biomarkers 2 75% of the histopathologically benign lesions that were considered suspicious for malignancy on US, and 83% of the malignancies that were misdiagnosed as benign on US [255]. These results suggest that the existing TIRADS classification could be extended with tissue elasticity features. In unselected thyroid nodules this improved TIRADS sensitivity, but not specificity [278, 330]. The combination is a suitable topic for future research in indeterminate thyroid nodules. Major benefit is that the two techniques are individually inexpensive and obviously easily combined during one diagnostic procedure. Cost-effectiveness can be anticipated. Ultrasonography and mutation analysis US assessment was also reported in various studies on gene mutation analysis, presumably because US data were usually readily available in clinical studies at no additional costs and thus easily combined with results of more experimental techniques. Even though US assessment improved the diagnostic accuracy of both [18F]FDG-PET and elastosonography, combined use of ultrasound with the sensitive Afirma® GEC or specific BRAF mutation analysis demonstrated little additional diagnostic value [95]. Suspicious US features such as hypoechogenicity, presence of calcifications and hypervascularity were not predictors of malignancy in Afirma® GEC-positive nodules [182]. Also, as expected by their individual association to classic PTC, a positive BRAFV600E mutation was correlated to the presence of suspicious US features in unselected nodules, including hypoechogeneity and the presence of microcalcifications [67, 104, 116]. BRAF mutation less frequently occurred in thyroid nodules without suspicious US features [104, 116]. In Bethesda III and IV thyroid without suspicious US features the prevalence of the BRAF mutation was only 1.5% (1/67) in the study by Seo et al. – very low, particularly for a South Korean population – all while the malignancy rate was still 18% (12/67)[104]. Considering the negligible yield at additional costs, BRAF mutation analysis might not be contributory in indeterminate nodules without suspicious US features. An even lower yield from BRAF mutation analysis in US-unsuspicious nodules is presumed in populations with a lower general prevalence of BRAF mutations. Additionally, these results suggest a different US appearance of BRAF mutation-negative malignancies – or a different molecular profile of thyroid carcinoma without suspicious US features. RAS mutation analysis and assessment of the typical suspicious US features could be complementary in the differentiation of indeterminate thyroid nodules, as follicular-type thyroid carcinomas are associated with RAS mutations and infrequently showed the typically suspicious US features [41, 67, 231-234]. Combined assessment could improve diagnostic accuracy of either technique in indeterminate thyroid nodules, identifying papillary thyroid malignancies through classic suspicious US features and follicular-type carcinoma by RAS mutation analysis. However, challenges for clinical practice continue to exist in the imperfect specificity of RAS mutation analysis, and the interobserver variability and ambiguity of certain US features.
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