Prognostic Assessment of BRAF Mutation in Preoperative Thyroid Fine-Needle Aspiration Specimens

Rita Abi-Raad, MD; Manju L. Prasad, MD; Jingwei Zheng, MD; Pei Hui, MD, PhD; Berrin Ustun, MD; Kevin Schofield, CT(ASCP); Guoping Cai, MD; Adebowale J. Adeniran, MD


Am J Clin Pathol. 2021;156(1):100-108. 

In This Article

Abstract and Introduction


Objectives: We investigate the potential role of BRAF testing in guiding surgical intervention in papillary thyroid carcinoma (PTC).

Methods: Thyroid fine-needle aspiration (FNA) cases with available BRAF result and follow-up thyroidectomy for PTC were included in the study. Cytology and surgical diagnoses were correlated with BRAF status.

Results: There were 151 cases of thyroid FNA specimens with BRAF testing (70 mutant and 81 wild-type BRAF) and histologically confirmed unilateral, unifocal PTCs. There were no differences in age, sex, tumor size, or lymphovascular invasion on thyroidectomy specimens between mutant and wild-type BRAF cases. BRAF mutation was significantly associated with cytology diagnosis (P < .001), PTC subtype (P < .001), extrathyroidal extension (ETE) (P = .006), and higher tumor (T) stage (P = .04). However, an analysis within the histologic subtypes of PTC revealed no significant association between BRAF mutation and ETE or higher T stage. There was also no difference in central (P = .847) or lateral (p = 1) neck lymph node (LN) metastasis.

Conclusions: BRAF mutation identified in thyroid FNA specimens correlates with histologic subtypes but is not an independent factor for predicting PTC biological behavior and should not be used to guide the extent of LN dissection.


Thyroid cancer is the most prevalent malignancy of the endocrine system, with papillary thyroid carcinoma (PTC) being the most common type. Its incidence is on the rise, mostly due to increased detection of small PTC.[1] Surgery is still the treatment of choice, but surgical modalities have varied over the years. While the American Thyroid Association (ATA)[2] had recommended total thyroidectomy for PTC nodules larger than 1 cm in 2009, the guidelines were revised in 2015 to unilateral lobectomy for single nodules less than 4 cm in size.[2] Lobectomy, as the treatment of choice, is appealing as in some cases it would prevent hypothyroidism, hypoparathyroidism, and bilateral recurrent laryngeal nerve damage but might not be sufficient, and reoperation of the thyroid gland can increase the risk of severe complications and could be a waste of medical resources.[2,3] The extent of neck lymph node dissection is also controversial. Nodal involvement is thought to be predictive of persistence or recurrence of PTC,[4–6] prompting the ATA to recommend therapeutic central neck dissection if clinical evidence of lymph node involvement is identified before or at the time of initial surgery.[2] Management of subclinical nodal disease, estimated at over 60% of node-positive PTC,[7] however, remains debatable. Suboptimal initial surgical management would result in persistent/recurrent PTC with subsequent mortality and morbidity. Reoperation in the central neck is associated with increased risk of surgical complications, including recurrent laryngeal nerve injury,[3,8] and repetitive radioactive iodine treatments for the disease may predispose the patient to the development of secondary malignant neoplasms. Thus, it is crucial to tailor initial surgical management according to patterns of tumor behavior. The ability to predict which tumors are at higher risk for local recurrence and stratify patients with PTC into different risk categories preoperatively could allow for optimization of the initial surgical procedure, such as the extent of thyroidectomy and lymph node dissection.

BRAF V600E somatic mutation (referred to as BRAF) is the transversion mutation in exon 15 of the gene, involving the substitution of thymine with adenine (T1799A), which leads to a coding change in amino acid 600 from valine to glutamate. This oncogenic mutation results in continued activation of the mitogen-activated protein-kinase signaling pathway, leading to uncontrolled cell proliferation.[9,10]BRAF mutation is the most common genetic alteration in PTC and has been reported in approximately 40% to 60% of sporadic PTCs.[9,10] In primary thyroid neoplasms, BRAF mutation is highly specific for PTC and has been reported at all stages of progression, including microcarcinomas, as well as poorly differentiated and anaplastic carcinomas arising in a background of papillary carcinomas.[11–14] In addition to preoperative cytologic evaluation of thyroid nodules, fine-needle aspiration (FNA) specimens can be used for preoperative BRAF mutation testing. Because of the specificity of BRAF mutation for PTC, total thyroidectomy has been recommended for patients with thyroid nodules harboring BRAF upon detection in the FNA sample.[11,15] Although BRAF gene mutation has a definitive diagnostic role, its prognostic value remains inconclusive. Traditionally, this mutation has been linked with clinicopathologic characteristics that relate to tumor progression and recurrence[13,14,16–20] and has therefore been advocated as a powerful tool to characterize individual cases, improve risk stratification, and determine the extent of initial surgery for PTC. Other studies have, however, concluded that BRAF mutation is not related to the prognosis of PTC, thereby discouraging the use of this marker for the purposes of prognostication and management.[21–26] Whether or not BRAF mutation is of prognostic significance is not yet fully established. Given the inconsistency of data and the disproven role of BRAF on tumor recurrence, the ATA has recommended against using BRAF testing to decide on prophylactic central neck dissection. We aimed to review the association between BRAF mutation and clinicopathologic features to determine whether preoperative BRAF testing on FNA can be used to guide extent of surgery when deciding surgical management of patients with PTC.