DISCUSSION
Our study shows that thyroid nodules with BRAF V600E mutations are strongly associated with Bethesda categories V and VI, whereas nodules with a RAS or EIF1AX mutation, copy number alteration or GEP are more commonly associated with Bethesda categories III and IV. Certain mutations within dominant thyroid nodules, specifically those with a BRAF V600E, TERT or RET mutation, were associated with thyroid cancer subtypes known to be more aggressive. An increasing number of studies have concluded that molecular testing of thyroid nodules has a significant diagnostic as well as prognostic value and can help improve management of patients. [19-25] Other studies, however, question the clinical utility and cost-benefit analysis of molecular testing. [20,24] The Afirma Gene Expression Classifier (Afirma®, Veracyte, Inc., South San Francisco, CA) measures mRNA transcript levels of 142 genes and has shown to have a high sensitivity of 91% and a moderate specificity of 68%. [18,22] ThyGeNEXT (ThyGeNEXT®, Interpace Diagnostics, PDI Inc, Parsippany, NJ) and ThyroSeq v3 (ThyroSeq® joint partnership between UPMC and CBLPath, Pittsburgh, PA) are two comprehensive tests, designed to improve the overall accuracy of molecular testing, with sensitivity of 89% and 94% and specificity of 85% and 82%, respectively. [20,24] The data regarding the clinical utility of molecular testing in patients with a Bethesda V and VI thyroid nodules remains unclear. [24-28] The value in molecular testing for such thyroid nodules lies not in the fact that this tool can predict malignancy. Further characterizing Bethesda V and VI thyroid nodules with molecular testing can identify patients with higher-risk disease (ex. presence of BRAF V600E, TERT) and may offer clinicians better perioperative patient counselling and prognostication.
The American Association of Endocrine Surgeons 2020 guidelines strongly recommend molecular testing as a diagnostic adjunct for cytologically indeterminate thyroid nodules if the information gained will affect clinical care. [20] Molecular testing may help clinicians with the management of thyroid nodules by identifying the nature of indeterminate lesions with mutations highly specific for malignancy such as BRAF V600E, RET or TERT, leading to improved diagnostic accuracy and potential reduction in the number of completion thyroidectomies performed. [22-24] Moreover, the extent of surgery performed on patients with a cytologic diagnosis of Bethesda category V or VI is related to the risk of recurrence and determined by the tumor size, radiographic features, presence of adenopathy and contralateral thyroid disease. [20] In this study, 44% of patients with a Bethesda category V or VI nodule harboured a BRAF V600E mutation. Given the relatively high prevalence of this mutation in Bethesda V/VI lesions, identifying this mutation can stratify patients into a distinct higher risk group. [8-15,22] Preoperative knowledge of a BRAF V600E mutation can help clinicians recognize patients with high risk thyroid nodule and potentially offer personalized patient counselling and treatment planning, even in nodules of smaller size. In the four patients with a less than 2 cm Bethesda III/IV thyroid nodule, identification of a BRAF V600E mutation preoperatively allowed for a total thyroidectomy with elective neck dissection to be performed. All 4 patients showed aggressive thyroid cancer features: 2 with central neck metastasis and 2 with solid or tall cell variants of papillary thyroid cancer.
The management of patients with thyroid nodules that are indeterminate on cytology often consists of a diagnostic lobectomy or active surveillance based on clinical factors including the nodule’s size, enlargement on ultrasound, suspicious ultrasound features, clinical and family history, history of radiation exposure, and patient’s preferences. [5,20, 25] Yip et al. show that molecular testing of thyroid nodules can also be useful in defining the extent of surgery for patients with low risk mutations to thyroid lobectomy. [24] Understanding that RAS-type mutations, which are shown to have a favorable prognosis when isolated, are commonly associated with Bethesda III and IV suggests that patients with an isolated RAS mutation may potentially be more conservatively treated with lobectomy. [25] The current results show that BRAF V600E mutations have been identified in 4.1% of indeterminate nodules which highlights the need for molecular testing to identify nodules of higher risk of malignancy. In this context, it may be warranted for the thyroid specialist to consider mutation testing analysis for specific higher-risk mutations such as BRAF V600E, TERT or RET as a means to preoperatively risk stratify patients. That being said, 128 patients did not have an identified molecular mutation with 64.6% proving to be malignant. In this subgroup of patients, only 12.6% of patients showed evidence of aggressive variants of thyroid cancer or central neck metastasis and is significantly lower in prevalence compared to patients with an identified molecular mutation. Additional understanding of thyroid carcinogenesis, presence of co-mutations and heterogeneity of nodules is needed to better allow clinicians to predict risk of malignancy and tumor aggressivity. [25]
Certain limitations to this study are related to the retrospective design and inclusion of patients undergoing molecular testing and thyroidectomy. By doing so, the overall prevalence of malignancy was elevated due to the selection of cases with more suspicious disease. Also, the indication for molecular profile testing was at the surgeon’s discretion. Expenses related to molecular profile testing of thyroid nodules is currently not covered in the Quebec health system; this may introduce a selection bias for patients who have the financial means to access it. Lastly, validation with larger prospectively collected data is needed to generalize results. That being said, the number of patients included and analyzed in this study offers a measure of diagnostic precision and clinical utility of using molecular test for thyroid nodules.