482 chapter 12 Molecular landscape Considering the genetic alterations observed during all MD (n=130, Figure 2), 61 (47%) nodules were MD positive (Table 6, Supplementary Table 5). Isolated RAS sequence variations were most frequently reported in 22 of 130 (17%) nodules, followed by 5 (4%) suspicious GH type CNA plus a TP53 mutation, four (3%) suspicious GH type CNA, three (2%) EIF1AX and three (2%) PTEN mutations, and three (2%) PAX8/ PPARγ gene fusions (Table 6). Fifteen (12%) nodules carried alterations with a high risk of malignancy. Concordance was 63% (82/130) between MD and [18F]FDG-PET/CT (Table 5). No borderline or malignant tumours were both MD negative and [18F]FDG negative. Two MD+/[18F]FDG- nodules were morphologically difficult-to-diagnose thyroid neoplasms that were only considered malignant after external consultation and/or MD were performed during histopathological review (Table 7). As previously described in greater detail, the MD result was decisive for their malignant diagnosis and consequent true-positive MD and false-negative [18F]FDG-PET/CT result [501]. Seven other MD+/ [18F]FDG- (i.e., false-positive/true-negative) nodules included four follicular adenomas and three nodules that were considered benign on ultrasound follow-up, all with intermediate-risk molecular Table 5. Concordance between MD and [18F]FDG-PET/CT Histopathology MD [18F]FDG-PET/CT Malignant/ borderline Benign ROM, % (95% CI) MD on cytology (n=115), assuming nodules under active surveillance are benign (a priori ROM 26%) MD and [18F]FDG-PET/CT concordant (n=72) - - 1 29 3 (0-17) + + 22 20 52 (36-68) MD and [18F]FDG-PET/CT discordant (n=43) + - 1 6 14 (0-58) - + 6 30 17 (6-33) MD on cytology and histopathology (n=130), assuming nodules under active surveillance are benign (a priori ROM 26%) MD and [18F]FDG-PET/CT concordant (n=82) - - 0 30 0 (0-12) + + 27 25 52 (38-66) MD and [18F]FDG-PET/CT discordant (n=48) + - 2 7 22 (3-60) - + 5 34 13 (4-27) CI, confidence interval; [18F]FDG, 2-[18F]fluoro-2-deoxy-D-glucose; [18F]FDG-PET/CT, positron emission tomography/computed tomography using [18F]FDG; MD, molecular diagnostics; n, number; ROM, rate of malignancy, defined as rate of malignancy or borderline tumour.
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