29 Diagnostic utility of molecular and imaging biomarkers 2 BRAF mutation analysis has been extensively studied as a rule-in test for thyroid carcinoma. The BRAF mutation is superior to other mutations in its oftentimes 100% specificity – a positive mutation could prevent two-stage surgery for an indeterminate thyroid nodule [60, 67-69, 73-76, 79-114]. Even though the BRAF mutation was found in a majority of PTC in a number of studies, the prevalence of the BRAF mutation in indeterminate cytology ranged from 0% to 48% in individual studies [82, 84, 86, 97, 103, 108]. Reported sensitivities were therefore heterogeneous and generally poor, ranging from 0% to 83% [67, 72, 77, 84]. Other types of thyroid carcinoma occurring in indeterminate nodules, including FTC, FVPTC and Hürthle cell carcinoma (oncocytic variant of follicular thyroid carcinoma, FTC-OV), were respectively never or infrequently BRAF mutation-positive [69, 75, 76, 80, 88, 95, 114]. Predominated by follicular type carcinoma, the BRAF mutation rarely occurs in Bethesda IV cytology [67, 69, 75, 79, 88, 90, 92, 95, 97, 98, 101, 103, 104, 108, 111-118]. Likely contributors to the observed heterogeneity are known global variations in the occurrence rates of PTC and BRAF mutations. In South Korea, where iodine consumption is high, 90% to 95% of thyroid cancers are PTC. More specifically, the proportion of BRAF -mutated PTC is very high: rates of 80% to more than 90% are reported [72, 84, 115]. Consequently, BRAFV600E mutation analysis might have both high specificity and high sensitivity in these populations. Studies with higher sensitivities were more often of South Korean origin and frequently demonstrated sensitivity above 40%, with the prevalence of BRAF mutations reported as high as 30% to 48%. [72, 77, 84, 85, 111, 119-121]. Conversely, the majority of studies with sensitivity below 10% were conducted in Western countries (USA, Europe or Canada), with some studies reporting no BRAF mutations at all [60, 69, 75, 83, 86, 90, 94-97, 99, 100, 103, 107, 108, 114, 118]. Some South Korean studies based surgical decision-making on the result of the BRAF mutation analysis: surgery was relatively less often performed in BRAF mutation-negative indeterminate nodules [72, 77, 116, 121]. Such a surgical management strategy is not oncologically safe for Western countries (e.g. Europa or Northern America), where 80% to 90% of thyroid carcinomas are PTC and reported rates of BRAF-mutated PTC vary from 30% to 40% [72, 84, 115]. Moreover, even though the true sensitivity of BRAF mutation analysis is presumably high in South Korea for the mentioned epidemiological reasons, the conservative management of BRAF mutation-negative nodules likely magnified test sensitivity by underestimating the rate of BRAF-negative malignant nodules in these studies. Altogether we estimate that approximately one in five South Korean patients would benefit from BRAF mutation analysis, opposite mere one in 25 patients from other countries. BRAF mutation in papillary microcarcinoma Papillary microcarcinoma (mPTC) have lower BRAF mutation rates [91, 96, 101, 106, 111, 114, 122]. The ATA guidelines are reserved with regard to the recommended clinical management of positive BRAF mutation in mPTC, as its relation to extrathyroidal spread and positive lymph node metastases is not as clear as in larger thyroid carcinoma. Although there are studies that associate mPTC to factors of poorer prognosis, the 2015 guidelines recommend that BRAF-mutated mPTC are treated as low-risk malignancies [17, 73].
RkJQdWJsaXNoZXIy MTk4NDMw