139 Diagnostic utility of molecular and imaging biomarkers 2 PAX8/PPARγ rearrangement Our systematic literature search yielded 13 studies that investigated the PAX8/PPARγ rearrangement in a total of 2,290 thyroid nodules with indeterminate cytology [60, 69, 75, 76, 87, 93, 97, 99, 100, 114, 118, 147, 351]. Baseline characteristics of these studies are presented (Table 17). In most studies the PAX8/PPARγ analysis was part of a gene mutation panel. One prospective study solely studied the PAX8/PPARγ rearrangement [147]. In the 2,290 indeterminate thyroid nodules from all included studies, the PAX8/PPARγ rearrangement was found in 32 (1.4%). Three studies reported no positive tests [76, 87, 93]. Although they are both rare, in the studies included in the current review, PAX8/ PPARγ translocation was reported more often than RET/PTC rearrangement (1.4% (32/2,290) versus 0.66% (17/2,581), p=0.01, Pearson χ2). Meta-analysis was performed. Seventy-five cases (3.3%) had a nondiagnostic molecular test result and were excluded from our analysis. Of the indeterminate thyroid nodules with a conclusive molecular result, histopathology was available in 76.6% (1,696/2,215), including 31 (97%) of the PAX8/PPARγ-positive nodules. Twenty-three of these nodules were diagnosed as thyroid carcinoma: 12 FVPTC, six FTC and five unspecified subtypes (Table 18). Visual analysis of the forest plots suggests little between-study variance; I2 is 32.5% for sensitivity and 68.6% for specificity. Estimated pooled sensitivity, specificity, positive and negative LR are 5.9% (95% CI: 3.8%-9.0%), 99.7% (95% CI: 98.1%-100%), 19.44 (95% CI: 3.17-119.27), and 0.94 (95% CI: 0.92-0.97), respectively (Table 19, Figure 20). The AUC is 0.12 (95% CI: 0.10-0.15) (Figure 21). For a given prevalence of malignancy of 15%, 25% or 40%, these results correspond to an estimated PPV and NPV of 77.4% (95% CI: 35.9%-95.5%) and 85.7% (95% CI: 85.4%-86.0%), 86.6% (95% CI: 51.4%-97.5%) and 76.1% (95% CI: 75.6%-76.5%), or 92.8% (95% CI: 67.9%-98.8%) and 61.4% (95% CI: 60.7%-62.0%), respectively (Figure 22). Table 18. Cytological PAX8/PPARγ rearrangement status in histopathologically confirmed malignancies PAX8/PPARγ positive malignancies, ni PAX8/PPARγ negative malignancies, ni PTC FVPTC FTC FTC-OV MTC mPTC other n.s. PTC FVPTC FTC FTC-OV MTC mPTC other n.s. French 2008 1 1 2 2 1 Cantara 2010 7 Nikiforov 2011 3 15 66 9 Mancini 2012 2 7 Ohori 2013 6 1 6 90 3 5 2 1 Beaudenon-Huibregtse 2014 11 5 1 Eszlinger 2014 (1) 2 2 2 16 Eszlinger 2014 (2) 1 4 4 Nikiforov 2014 4 35 Eszlinger 2015 7 11 21 5 1 Giovanella 2015 1 3 2 4 5 1 Nikiforov 2015 1 21 Valderrabano 2016 2 1 11 2 1 1 1 TOTAL 0126 0 0 0 0 55818961172 1 563 FTC: follicular thyroid carcinoma. FTC-OV: FTC, oncocytic variant (Hürthle cell carcinoma). FVPTC: papillary thyroid carcinoma, follicular variant. mPTC: papillary thyroid microcarcinoma. MTC: medullary thyroid carcinoma. n.s.: not specified. PTC: papillary thyroid carcinoma.
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