Is BRAF mutation associated with lymph node metastasis in patients with papillary thyroid cancer

Many researchers have investigated the clinical role of V600E BRAF mutation in patients with papillary thyroid cancer (PTC). The BRAF mutation constitutively activates the RAS/RAF/mitogen-activated protein kinase signal transduction pathway and results in the malignant transformation of cells. This mutation is found in ≤70% of PTCs, is highly specific, and is easily detected in thyroid fine-needle aspirate biopsy samples.1 In recent years, there has been an increased focus in the literature on the prognostic value and the potential clinical role of BRAF mutation in patients with PTC.2,3 However, the true association of BRAF with poor clinicopathologic features, particularly, lymph node metastasis (LNM) that could affect the surgical approach to these patients, remains controversial. With the exception of 2 studies,4-6 the remaining studies, including one that we have co-authored, examining BRAF association with LNM do not include patients who have undergone routine central lymph node dissection (CLND).1,7 The largest study, by Basolo et al,8 as an example, examined 1,060 patients with PTC and found correlation with BRAF mutation and LMN. However, in this study, only tumors <2 cm were included and patients only underwent CLND if there were intraoperative abnormalities identified.8 By including only patients who underwent CLND and have likely more advanced disease and known lymph node status and, by excluding those who have not undergone CLND, there may exist potential bias by including only those patients with larger, more aggressive tumors and/or those who have clinically evident LNM at presentation. Additionally, many studies evaluate the association of BRAF with presence of LNM overall, rather than only central LNM. Many studies also report a significant association between the BRAF mutation and LNM on univariate analysis only.4,9,10 However, this significance is lost in the few studies that perform multivariate analysis, adjusting for all variables known to be associated with aggressive PTC (age, gender, extrathyroidal extension, multifocality, and PTC variants and size). Studies maintaining significance on multivariate analysis either adjust only for age and gender or do not specify adjusted variables. Table I includes the 2 studies that adjusted for a majority of variables known to be associated with aggressive features and none demonstrated an association of BRAF status with LMN.3,6,11 Table I Multivariable logistic regressions in the literature examining BRAF as a predictor of lymph node metastases, adjusting for variables associated with aggressive papillary thyroid cancer Despite the controversy that exists in the literature and conflicting reports, some have proposed that BRAF status should be incorporated into the surgical algorithmic management of patients with PTC with respect to extent of surgery, specifically, whether or not the patient should undergo a CLND.12 Additional multi-institutional studies in which the surgeons perform routine CLND and therefore include evaluable patients are needed to determine whether the measurement of BRAF status does or does not independently predict the presence of nodal metastases. In a small study, we therefore chose to examine whether BRAF mutation status is associated with LNM in patients with PTC by retrospectively examining consecutive patients who underwent routine CLND as part of an endocrine surgery practice, adjusting for confounding factors that included age, gender, tumor size, multifocality, PTC variant, and extrathyroidal extension.