213 Diagnostic utility of molecular and imaging biomarkers 2 Imaging biomarkers Ultrasound Our systematic literature search resulted in 56 suitable articles, in total including 6,692 indeterminate thyroid nodules (Table 50). The average malignancy rate was 27.0% (1,809/6,692) Of the 1,809 malignancies, 639 were PTC (35.3%), 285 FVPTC (15.8%), 240 FTC (13.3%), 39 FTC-OV (2.2%), 11 MTC (0.6%), and 37 other type of malignancy (2.0%). Diagnostic accuracy results for individual US characteristics in indeterminate thyroid nodules were available from 43 of the included studies. We performed meta-analyses for ten US characteristics that are well established as suspicious for thyroid malignancy: singularity of the nodule, a solid appearance, (marked) hypoechogenicity, nodule diameter larger than 4 cm, a taller-than-wide shape in transverse view, absence of hypoechoic halo, irregular margins, increased central vascularization, microcalcifications, and macrocalcifications, reporting the number of studies that contributed to the pooled results per US characteristic (Table 51, Figure 66, Figure 67, Figure 68). For the group of indeterminate thyroid nodules as a whole, the sensitivities of all suspicious US features are rather limited: the highest estimated pooled sensitivity is obtained for a solid appearance as opposed to varying degrees of cystic content (83.7%, 95% CI: 77.7%-88.3%). The specificities ranged from moderate to good, with the highest pooled estimates found for a taller-than-wide shape (91.3%, 95% CI: 85.2%-95.0%), presence of irregular margins (89.5%, 95% CI: 84.2%-93.1%) and presence of microcalcifications (86.6%, 95% CI: 81.3%-90.6%). Clinically useful test results – presence of these characteristics – occurred in 20.4% (435/2,129), 26.2% (1,041/3,969) and 21.8% (878/4,027) of the indeterminate thyroid nodules, respectively (Figure 66, Figure 67 and Table 51). Ultrasound assessment of Bethesda III nodules Twelve studies provided results for 1,679 Bethesda III nodules [68, 236, 237, 239, 243, 244, 252, 253, 262, 269, 277, 279]. The average malignancy rate in this group was 34.2% (575/1,679), including 163 PTC (28.3%), 23 FVPTC (4.0%), six FTC (1.0%), one FTC-OV (0.2%), three other thyroid malignancies (0.5%) and 379 unreported malignant subtypes (65.9%). In Bethesda III nodules, a solid US appearance demonstrates a very good estimated pooled sensitivity of 90.4% (95% CI: 87.1%-93.0%), with a potentially useful negative test result in 16.2% (246/1,518) of nodules. The sensitivity of a taller-than-wide shape (43.5%, 95% CI: 37.5%-49.8%) and presence of irregular margins (58.5%, 95% CI: 47.9%-68.5%) are also higher in Bethesda III nodules than in the entire indeterminate group, although not up to clinically useful performance rates. The most specific US characteristics are a taller-than-wide shape (87.1%, 95% CI: 79.0%-92.3%) and microcalcifications (86.0%, 95% CI: 75.0%-92.6%). Both are less specific than in the general indeterminate population. An irregular margin is not specific in Bethesda III nodules (Figure 66, Figure 67 and Table 52).
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