BRAF testing and thyroid FNA

Fine-needle aspiration biopsy (FNAB) is considered the most accurate and cost-effective method available for evaluating thyroid nodules. However, the utility of thyroid FNAB is limited by the prevalence of indeterminate diagnoses (the atypia of undetermined significance/follicular lesion of undetermined significance [AUS/ FLUS], follicular neoplasm/suspicious for follicular neoplasm [FN/SFN], and suspicious for malignancy categories in the Bethesda System for Reporting Thyroid Cytopathology), which can be assigned to up to 30% of an institution’s thyroid FNAB specimens. These indeterminate aspirates represent a gray zone for clinical management, which can range from repeat thyroid FNAB to total thyroidectomy. In the United States, approximately 75,000 surgeries are performed each year for thyroid nodules with indeterminate cytology, and a large majority (70%-80%) of these patients do not have a clinically significant thyroid cancer on histological followup. Moreover, there is substantial interobserver and intraobserver variability among cytopathologists in the use of the Bethesda indeterminate diagnostic categories and in the subsequent histopathologic evaluation of the corresponding thyroid nodules. As knowledge of the molecular landscape of thyroid neoplasia has expanded, extensive resources have been devoted to applying molecular testing to the problem of appropriate management for patients with indeterminate thyroid FNAB diagnoses. One aspect that has received particular attention in recent years is the potential role of BRAF mutation testing. The oncogenic role of the BRAF gene in neoplasia was first recognized in 2002 when similar activating mutations of this gene were discovered in several human cancers, predominantly malignant melanoma (MM) and papillary thyroid carcinoma (PTC), for which BRAF acts as a driver of tumor progression. Interestingly, patients with either PTC or MM have an increased risk of developing the other cancer as a second primary neoplasm, and this suggests an associated genetic predisposition. Over the past decade, numerous studies have expanded our understanding of BRAF gene mutations as a critical diagnostic, prognostic, and predictive biomarker for many cancers. A recent PubMed search using the keywords BRAF and thyroid cancer retrieved 1168 publications between 2003 and 2015, including 758 with cytology as an additional keyword. In this commentary, we examine the various applications for BRAF mutation testing in thyroid FNAB specimens. Rather than a general, basic review, this article is meant to be a specialized update on the use of BRAF testing for thyroid FNAB.