BRAF V600E Mutation Independently Predicts Central Compartment Lymph Node Metastasis in Patients with Papillary Thyroid Cancer

Howell et al. examine a very timely question regarding the utility of measuring BRAF mutation status in papillary thyroid cancer (PTC) specimens to determine if it can be used to predict the presence or absence of lymph node metastases. The premise is that its measurement could potentially guide the surgical management of patients with PTC; i.e., to determine whether a prophylactic central lymph node dissection (CLND) should be performed. This is a very well-written study that nicely captures the common clinical dilemma faced by endocrine surgeons and also is comprehensive in the interpretation of its results. It is generally accepted that patients with PTC who have clinically detectable lymph node metastases either on physical examination or by ultrasound should undergo a lymph node dissection. Whether to perform a prophylactic CLND for PTC remains debatable; some authors claim that there is no advantage in terms of decreased local recurrence and improved survival, whereas others claim advantages regarding both. Because of this controversy, some authors have proposed that BRAF may confer a more aggressive phenotype and its measurement could then help to guide the surgeon in terms of whether or not to perform a prophylactic CLND. Conversely, other authors have documented no correlation with BRAF mutation and aggressive features of PTC, including the case in point, namely, the presence of lymph node metastases. The literature is replete with studies that include only patients who had therapeutic and not routine prophylactic CLND, patients who had lymph nodes removed only incidentally, or patients who had no lymph nodes removed; none of these groups of patients would therefore be evaluable in terms of determining whether BRAF status is truly associated with CLN metastases. Two studies have included only patients who have undergone routine CLND and both found that BRAF mutation predicted metastatic disease only in patients who had a PTC that was less than 1 cm in size; there was no association for larger tumors. Howell et al. initially identified 274 patients who were operated on for PTC at the University of Pittsburgh in 2010 and from this group studied 156 (57 %) patients who had both lymph nodes resected and BRAF testing. In their study, therapeutic CLND was performed for patients who had evidence of metastatic disease either on ultrasonography or at the time of surgery. A prophylactic CLND was performed for patients who had a diagnosis of PTC or a positive BRAF mutation. If PTC was not diagnosed preoperatively, the lymph nodes were assessed with visual and tactile inspection and patients ‘‘had nonanatomic resection of immediate perithyroidal central compartment lymph nodes if no suspicious lymphadenopathy was identified.’’ Incidentally, we know from others’ work that intraoperative assessment of lymph nodes is generally unreliable. In the study by Howell et al. 29 (19 %) had a therapeutic CLND, 85 (54 %) had a prophylactic CLND, and 42 (27 %) had incidental central lymph nodes resected. In the entire group of 156, 37 % had evidence of metastatic disease and 46 % were BRAF mutation-positive. They found that BRAF mutation was associated with lymph node metastases both in univariate analysis and multivariable logistic regression. The sensitivity was noted to be 62 % and the specificity was 63 %; the positive and negative predictive values were 50 and 74 %, respectively. The study by Howell et al. includes patients who have undergone some sort of lymph node removal. It excludes, however, more than 40 %, because they did not have a Society of Surgical Oncology 2012