34 chapter 2 growth pattern in two of the PAX8/PPARγ-positive follicular adenoma, supporting this hypothesis [99]. Still, PAX8/PPARγ rearrangement is a rare rearrangement associated with (encapsulated) follicular tumours. Similar to RET/PTC rearrangements, the PAX8/PPARγ rearrangement should only be assessed in indeterminate thyroid nodules in combination with more frequently occurring genetic alterations in a gene mutation panel. Other genetic alterations hTERT The enzyme human telomerase is involved in the maintenance of the chromosomes’ telomeres, which are essential for cell life and proliferation. The catalytic subunit of telomerase is human telomerase reverse transcription (hTERT). In normal thyroid cells, it is inactive. Inappropriate reactivation is associated with malignancy and inflammatory thyroid disease [148]. hTERT promotor mutations were previously observed in both PTC and FTC, sometimes together with a BRAF mutation. The mutation is strongly correlated to mortality in differentiated thyroid carcinoma [149]. hTERT gene expression is potentially accurate in the preoperative differentiation of indeterminate nodules, with 57% to 88% sensitivity and 75% to 85% specificity demonstrated in two small clinical series of cytological follicular neoplasms [150, 151]. TRK The tyrosine receptor kinase (TRK) rearrangement arises from a translocation of the NTRK1 gene, which is normally expressed in the central and peripheral nervous system and involved in cell differentiation. The TRK rearrangement is associated with PTC and presumably with an adverse prognosis, although evidence is limited [152]. In feasibility studies in indeterminate thyroid cytology, not a single TRK rearrangement has been detected – it is most likely not a useful marker [83, 87, 88]. HMGA2 Proteins high mobility group AT-hook (HMGA) 1 and 2 regulate the structure and function of chromatin. Normally only expressed during embryogenesis, the overexpression of HMGA in adult tissues is associated with malignancy [153]. Lappinga et al. demonstrated that HMGA2 could be a promising additional biomarker. Using ROC curve analysis, a >5.9-fold HMGA2 overexpression had 76% sensitivity and 98% specificity in SFN/FN nodules [154]. To date no other studies attempted to validate these results. Galectin-3 and CD44v6 One Croatian study used RT-PCR to investigate the simultaneous expression of galectin-3 and CD44v6, two molecular biomarkers better known for their application in immunohistochemistry of their expression products [155]. CD44v6 normally functions as the cell-surface receptor for
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