INTRODUCTION
The widespread use of medical imaging has contributed to the increased incidence of thyroid nodules detected and incidental thyroid cancer diagnosed. [1] Studies suggest that the number of ultrasound guided fine needles aspirations (USFNAs) performed has doubled and the number of thyroid surgeries performed has increased by nearly 30% over the last decade. [1] Currently, USFNA is the standard diagnostic method for thyroid nodules. Although USFNA specimens are categorized according to the Bethesda classification, 24%-57% of thyroid USFNAs have an indeterminate result. [2-4] As a consequence, thyroid lobectomy is often performed for diagnostic and potentially therapeutic purposes. In roughly 60% of patients with indeterminate cytology, the thyroid nodule is benign. [4] In these patients, molecular testing of thyroid nodules has become an adjunct to USFNA biopsy to reduce the likelihood of unnecessary diagnostic surgery. [5]
Mutations that are uncovered with molecular testing of thyroid nodules, namely BRAF V600E or RAS-type mutations, can assist with uncovering the phenotype of the nodule (benign versus malignant) as well as whether the tumor may be an aggressive variant. Mutations of the BRAF V600E gene, found in 35-70% of papillary thyroid carcinomas (PTC), lead to the activation of BRAF kinase and chronically stimulate the MAPK signaling pathway. [7,8] The BRAF V600E mutation has been strongly associated with classic and tall cell variant of PTC. [8] This mutation has also been shown to correlate with aggressive tumor characteristics including multifocality, extrathyroidal extension, regional or distant metastases and an advanced tumor stage at presentation. [8-15] Moreover, studies have shown that BRAF V600E mutations are associated with tumor recurrence and poor prognosis. [14,15] Mutation in the three RAS genes (HRAS, KRAS, and NRAS) are found in follicular adenomas and follicular carcinomas, as well as in the follicular variant of PTC and more recently for non-invasive follicular neoplasm with papillary-like nuclear features (NIFTP). [7] RAS mutations result in permanent RAS activation which chronically stimulate the MAPK and PI3K/AKT signaling pathways. [7] They are associated follicular-patterned neoplasms, with less prominent nuclear features of PTC, more frequent encapsulation and a lower rate of lymph node metastases than those with BRAF V600E mutations. [16-18] According to a recent study, RAS mutations in malignant thyroid nodules, when isolated, are associated with low-risk features and a favorable prognosis. [16-18]
In this study, the association between Bethesda category and molecular mutation assessed with ThyroSeq V3 or ThyGeNEXT in patients with thyroid nodules undergoing thyroidectomy is explored to better tailor patient diagnosis and treatment.