64 chapter 2 Immunocytochemistry and mutation analysis In histopathology samples, certain genetic alterations were correlated to positive staining for specific immunomarkers: PAX8/PPARγ rearrangement was associated with galectin-3 reactivity, and RAS point mutation with HBME-1 [143]. Only one study investigated this combination of techniques in indeterminate thyroid cytology. Although no significant correlation was demonstrated between positive BRAFV600E mutation and galectin-3 overexpression – benefitting possible complementary use – no additional diagnostic value was demonstrated either [82]. MicroRNA and mutation analysis Combined microRNA expression profiling and mutation analysis could accurately aid diagnosis and prognosis of thyroid malignancy. Distinct microRNAs have been related to oncogenic mutations. For example, miR-221, miR-222 and miR-146b were more overexpressed in BRAF- and RAS-mutated PTC. High expression of miR-187 was associated with RET/PTC rearrangement [186, 331]. The first step towards diagnostic integration of the two techniques was taken by Labourier et al., who tested the commercially developed 10-microRNA thyroid classifier ThyraMIR™ simultaneously with the miRInform® thyroid [61]. The ThyraMIR™ was designed to increase the sensitivity of the miRInform® without affecting its specificity. Combined use demonstrated 89% sensitivity and 85% specificity [61]. A recent decision analytics model for Bethesda III and IV nodules estimated that combined miRInform® and ThyraMIR™ testing was cost-effective, reducing the rate of unnecessary surgery (diagnostic hemithyroidectomy as well as two-step thyroidectomies) from 88% to 20% and saving $1,384 per patient in the first year of treatment or $3,170 per avoided surgery. However, it is not described how the economic consequences of the 15% missed malignancies are accounted for in this model [178]. The economic as well as medical-ethical consequences of such a high number of missed malignancies question the current clinical utility of this combination of expensive techniques. In brief, the combined or sequential use of multiple diagnostics in indeterminate thyroid nodules was infrequently studied. Regrettably, the available studies also mostly remained within their own field of expertise: comparing tests either within the domain of pathological (molecular) techniques or within the domain of imaging. Although a sequential combination of a sensitive and an uncorrelated specific test might bring the solution that this clinical issue has been waiting for, the most accurate combination of tests cannot reliably be determined yet.
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