49 Diagnostic utility of molecular and imaging biomarkers 2 Clinical validation studies of existing ICC markers are ongoing. Meanwhile, new markers are also playing the field, searching for the interfaces between mutation analysis of highly specific oncogenic driver mutations and accessible ICC techniques. For example, Leslie et al. investigated ICC of the BRAFV600E mutation using the mutation specific antibody VE1 in a small series of thyroid FNAC samples. Concordance between ICC and conventional BRAFV600E mutation analysis was 85%. All samples that were BRAFV600E positive by either method were confirmed as BRAFV600E positive PTC on histopathology. Of the eight included indeterminate thyroid nodules, seven were histopathologically malignant and BRAFV600E mutation was detected in two nodules: one by both methods, one only by molecular analysis. The BRAFV600E specific antibody (VE1) stain was much weaker in cytology than in histology. Moreover, costs of the VE1 antibody are currently high and optimization of methodology is warranted. Yet, Leslie et al. demonstrated that BRAFV600E mutation analysis using ICC is a promising alternative to mutation analysis [117]. If future studies could validate these results in larger cohorts of indeterminate thyroid nodules and detect reliable immunomarkers for other oncogenic driver mutations, this technique unites the strengths of gene mutation analysis and immunocytochemistry in one technique, though likely at lower costs. In general, ICC is a widely available and relatively inexpensive technique with a reasonable diagnostic accuracy. Many immunomarkers seem to have a pronounced association with PTC. Galectin-3 and HBME-1 were most frequently investigated, but their specificities and sensitivities seem to fall short of justifying ICC-based surgical decision making. Diagnostic accuracy of their combined use seems promising, yet current evidence is limited. Prospective validation trials are warranted to confirm the diagnostic potential of ICC, including validation of thresholds for stain positivity, panels of multiple immunostains and other methodology. Conventional imaging Ultrasound Ultrasound (US) is one of the principal steps in the initial work-up of thyroid nodules. It is cheap, fast, non-invasive and globally available, but accurate assessment strongly depends on operator experience [229]. Multiple meta-analyses showed that well-known US features such as nodule hypoechogenicity, microcalcifications, irregular margins (including microlobulated or ill-defined margins), and a taller-than-wide shape raise the suspicion for thyroid malignancy and are mostly associated with PTC [229, 230]. Nonetheless, no single US feature is sufficiently sensitive nor specific to accurately identify a malignant nodule in an unselected population [229]. Certain combinations of US features, however, may offer accurate closure. The current ATA guidelines now include a flowchart recommending FNAC dependent on nodule size and various combinations of US characteristics
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