32 chapter 2 next chapter) is most likely more useful. Sole RAS mutation analysis is not accurate in the preoperative setting. Although specificity is high, only two out of three RAS mutation positive indeterminate nodules are histopathologically malignant, evidently fewer than assumed and previously described in the ATA guidelines. Therefore, RAS mutation positive indeterminate thyroid nodules should be surgically managed with no more than hemithyroidectomy. Whether hemithyroidectomy is justified for RAS-mutated follicular adenomas as a precancerous lesion, is yet under debate. RET/PTC rearrangement Rearrangements of the RET proto-oncogene arise from the fusion of the 3’ end of RET to the 5’ regions of unrelated genes that are expressed in thyroid follicular cells. Proto-oncogene RET encodes for a transmembrane receptor with a tyrosine kinase domain; a RET/PTC rearrangement causes inappropriate overexpression of that domain. It activates the MAPK and PI3K/AKT pathways and stimulates malignant transition of the cell through BRAF [132, 133]. At least 12 different fusion variants have been detected until today, of which RET/PTC1 and RET/PTC3 are the most common. They have a well-known association with PTC. Cases of both rearrangements in a single lesion are also reported [42, 132, 134, 135]. RET/PTC rearrangements, especially RET/PTC3, occur more frequently in PTC in children or patients that were exposed to ionizing radiation and are clinically associated with the presence of lymph node metastases [42]. Worldwide variations in frequency of RET/PTC rearrangements exist, dependent on demographics and ethnicity. The RET/PTC rearrangement is present in 42% of PTC in Western populations with a predominance of RET/PTC1, and in 37% of PTC in Asian populations with a predominance of RET/PTC3. Without radiation exposure, in female PTC patients RET/PTC1 is predominant [136]. The rearrangements are also found in benign nodules, especially in patients that were exposed to ionizing irradiation [67, 135]. Alike RAS mutations, it is assumed to be an activating genetic alteration and it is argued that a histopathologically benign nodule with a RET/PTC rearrangement should be considered a precancerous lesion. RET/PTC rearrangements are seldom found in indeterminate nodules. In many studies, no RET/PTC translocation was found at all. Most studies investigated RET/PTC in light of a gene mutation panel and paid it no specific attention [60, 67, 69, 75, 76, 83, 87, 88, 93, 97, 99, 100, 102, 108, 114, 118, 134]. Only Guerra et al. solely investigated the RET/PTC rearrangement in 101 thyroid nodules of all cytological categories. In this Italian study, RET/PTC rearrangements were found in 18 of the 50 PTC (36%) using RT-PCR and Southern-Blot. All these RET/PTC-positive carcinomas were Thy4 or Thy5 nodules on cytology. Among the 24 Thy3 nodules, two nodules with a RET/PTC3 rearrangement were histopathologically benign [134]. Noteworthy, Sapio et al. detected two RET mutations during their RET/PTC assessments. In contrast to the RET/PTC translocation, RET point mutations are related to sporadic and familial MTC [83, 137]. Surgery confirmed histopathological MTC in the RET-mutated nodules [83].
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