33 Diagnostic utility of molecular and imaging biomarkers 2 Even though previous histological studies undeniably associated RET/PTC1 and RET/PTC3 rearrangements to PTC, the low prevalence of the rearrangement in indeterminate cytology is a major downside. Testing exclusively for this genetic alteration in indeterminate nodules is not advantageous, even if issues regarding the number of tested variants and sensitivity of molecular techniques are overcome. The 2015 ATA guidelines only advise RET/PTC testing in context of a gene mutation panel [17]. PAX8/PPARy rearrangement The PAX8/PPARγ rearrangement arises from a fusion of the promoter and 5’-coding portion of the thyroid-specific transcription factor PAX8 gene to the gene of the nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ) [138, 139]. The role of the product of this translocation – the PAX8/PPARγ fusion protein – is not yet understood, as the DNA binding sites of both original proteins are uniquely preserved in the fusion [139]. In the normal thyroid, transcription factor PAX8 is involved in differentiation of thyrocytes and regulation of the expression of thyroid-specific genes encoding thyroperoxidase, thyroglobulin and the sodium/iodide symporter [140]. Nuclear receptor PPARγ has multiple presumed functions, including involvement in the regulation of lipid metabolism, adipogenesis and insulin sensitivity [139, 141]. The chromosomal translocation PAX8/PPARγ was first discovered in – and traditionally associated with – FTC and follicular adenoma [138]. It is reported in 30% to 45% of FTC and in up to 33% of follicular adenoma [88, 142-144]. However, several studies have also uncovered varying amounts of FVPTC carrying the translocation, with published rates up to 38% [142, 145, 146]. It has not been reported in benign or malignant Hürthle cell neoplasms [143, 147]. PAX8/PPARγ is often related to well-differentiated malignancies with a relatively favourable prognosis. Capsular and vascular invasion are reported to a lesser extent in FTCs with a PAX8/PPARγ rearrangement than in RAS-mutated tumours [143]. Widely invasive features are not reported. PAX8/ PPARγ-mutated FVPTC are mostly encapsulated, following an indolent clinical course with minimal disease recurrence despite the presence of some capsular and vascular invasion at presentation [143-145]. In contrast to the BRAF, RAS and RET/PTC genetic alterations in thyroid carcinoma, the PAX8/PPARγ rearrangement does not involve the RAS-RAF-MAPK pathway. Nikiforova et al. hypothesized that oncogenesis of follicular-type tumours likely takes place through two different molecular pathways: a RAS-mutation driven and PAX8/PPARγ rearrangement driven pathway [143]. Similar to the RET/PTC rearrangement, the PAX8/PPARγ rearrangement rarely occurred in indeterminate thyroid cytology. Approximately two-thirds of the indeterminate nodules carrying the rearrangement were histopathologically malignant, most often FVPTC or FTC [60, 69, 75, 76, 87, 93, 97, 99, 100, 108, 114, 118, 147]. False-positive results corresponded to follicular adenomas [99, 100, 108]. Similar to RAS mutations, histopathologically benign PAX8/PPARγ-mutated nodules are likely premalignant lesions, or pre-invasive FTC. Eszlinger et al. observed a microfollicular morphological
RkJQdWJsaXNoZXIy MTk4NDMw