150 chapter 2 Regardless of the high specificity of combined BRAF and RAS mutation testing, results of the individual studies were heterogeneous with regard to the occurrence rate of BRAF and RAS mutations. First of all, it is noteworthy that a significantly lower rate of BRAF mutations (3.9% (130/3,351)) was reported in the 19 studies included in the current meta-analysis than in the remaining 32 studies that were also included in the meta-analysis for single BRAF mutation (13.0% (364/2,805), p<0.0001, Pearson χ2). As discussed in the previous chapter on BRAF mutation analysis, evident geographical variations in mutation profiles and histopathology exist, most likely explaining this difference. Combined BRAF/RAS mutation analysis in Bethesda III nodules Seven of the included studies reported on the performance of combined BRAF/RAS mutation analysis in a total of 1,559 Bethesda III nodules. There were 182 (11.7%) mutation-positive nodules: 88 BRAF and 94 RAS positive. Of the 187 (12%) malignancies, 132 carried a BRAF or RAS mutation: 54 of the 62 reported PTC (87%), 49 of the 75 FVPTC (65%), 1 of 4 FTC (25%) and 28 of the 45 unspecified carcinomas (62%). I2 is 77.7% for sensitivity and 85.1% for specificity. Estimated pooled sensitivity, specificity, positive and negative LR are 65.0% (95% CI: 48.4%-78.6%), 97.1% (95% CI: 88.5%-99.3%), 22.2 (95% CI: 6.37-77.27), and 0.36 (95% CI: 0.24-0.55), respectively (Table 23, Figure 26). The AUC is 0.88 (95% CI: 0.85-0.91) (Figure 27). Combined BRAF/RAS mutation analysis in Bethesda IV nodules Nine studies reported on 1,105 Bethesda IV nodules. As expected from the previous chapters of the current review, the RAS mutation predominated in this group: of the 162 (14.7%) mutations identified in this group, 140 (86.4%) were RAS mutations and only 22 (14%) were BRAF mutations. This distribution significantly differed between Bethesda III and IV (Pearson chi-squared, p<0.0001). Combined BRAF/ RAS mutation analysis correctly distinguished 126 of the 293 malignancies, including 16 of 30 PTC (53%), 78 of 170 FVPTC (46%), 10 of 27 FTC (37%), 1 of 10 FTC-OV (10%), 1 of 2 MTC (50%), no mPTC, 4 of 6 other (67%) and 26 of the 47 unspecified thyroid carcinomas (55%). I2 is 47.4% for sensitivity and 45.2% for specificity. Estimated pooled sensitivity, specificity, positive and negative LR are 46.0% (95% CI: 37.1%-55.2%), 96.4% (95% CI: 94.0%-97.8%), 12.7 (95% CI: 7.41-21.76), and 0.56 (95% CI: 0.47-0.66), respectively (Table 24, Figure 28). The AUC is 0.88 (95% CI: 0.85-0.91) (Figure 29). Best-case and worst-case scenarios Hypothetical best-case and worst-case scenarios were constructed to overcome the 32.8% (1,073/3,272) missing histopathology in nodules with a conclusive BRAF/RAS mutation analysis, including 50 mutation-positive nodules (13 BRAF-positive and 37 RAS-positive) and 1,023 mutationnegative nodules. In the best-case scenario, the estimated pooled sensitivity, specificity, positive and negative LR would be 51.1% (95% CI: 41.2%-61.0%), 96.7% (95% CI: 94.6%-98.0%), 15.61 (95% CI: 8.33-29.24) and 0.51 (95% CI: 0.41-0.63), respectively. In the worst-case scenario, the estimated pooled sensitivity, specificity, positive and negative LR would be 26.5% (95% CI: 16.8%-39.1%), 92.0% (95% CI: 84.4%-96.0%), 3.29 (95% CI: 1.28-8.47) and 0.80 (95% CI: 0.66-0.96), respectively (Figure 4).
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