202 chapter 2 HBME-1 Meta-analysis was performed of the seven studies that performed ICC using HBME-1 and presented separate results for this marker, including 419 indeterminate thyroid nodules [203, 212, 214, 217-219, 224]. A positive HBME-1 stain was found in 38.9% (163/419) nodules, and the average prevalence of malignancy was 39.9% (167/419). I2 is 37.2% for sensitivity and 40.3% for specificity, suggesting no overt between-study heterogeneity. The estimated pooled sensitivity, specificity, positive LR and negative LR are 80.2% (95% CI: 68.7%-88.2%), 88.1% (95% CI: 81.9%-92.4%), 6.77 (95% CI: 4.4610.27) and 0.22 (95% CI: 0.14-0.36), respectively. The AUC is 0.92 (95% CI: 0.89-0.94) (Table 46, Figure 56 and Figure 57). For a given prevalence of malignancy of 15%, 25% or 40%, these results correspond to an estimated PPV and NPV of 54.4% (95% CI: 44.0%-64.5%) and 96.2% (95% CI: 94.0%-97.6%), 69.3% (95% CI: 59.8%-77.4%) and 93.0% (95% CI: 89.2%-95.6%), or 81.9% (95% CI: 74.8%-87.3%) and 87.0% (95% CI: 80.5%-91.5%), respectively (Figure 58). Subgroup analyses for Bethesda III and IV nodules could not be performed. Best-case and worst-case scenarios include results for eight additional thyroid nodules for which no histopathology was available (Figure 4). Cytokeratin 19 Pooling of the results from the three studies using a random effects model demonstrates an estimated pooled sensitivity, specificity, positive and negative LR of 78% (95% CI: 70%-87%), 91% (95% CI: 81%-100%), 6.07 (95% CI: 3.18-11.57) and 0.26 (95% CI: 0.17-0.38), respectively ((Table 47 and Figure 59). For a given prevalence of malignancy of 15%, 25% or 40%, these results correspond to an estimated PPV and NPV of 51.7% (95% CI: 35.9%-67.1%) and 95.6% (95% CI: 93.7%-97.1%), 66.9% (95% CI: 51.5%-79.4%) and 92.0% (95% CI: 88.8%-94.6%), or 80.2% (95% CI: 67.9%-88.5%) and 85.2% (95% CI: 79.8%-89.8%), respectively. Altogether, CK-19 seems less accurate to diagnose malignancy in indeterminate thyroid nodules than galectin-3 and HBME-1, although literature is rather limited. CK-19 is likely only clinically useful in combination with other immunomarkers. Combined use of ICC markers Unfortunately, few studies investigated the same combination of ICC markers in a similar way in indeterminate thyroid nodules. We performed a meta-analysis of the four studies that investigated the combination of galectin-3 and HBME-1, including 263 indeterminate thyroid nodules. The average malignancy rate was 47.5% (125/263). Zhang et al. provided inconsistent summarized patient data in their article; we therefore recalculated these data from their presented sensitivities and specificities [203]. There were two possible methods of interpretation of the combination of stains: either the
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