THE ROLE OF MOLECULAR MARKERS IN THE THERAPEUTIC MANAGEMENT OF THYROID NODULES WITH INDETERMINATE CYTOLOGY (BETHESDA III AND IV)

Abstract

Thyroid cancer is the most common malignant neoplasm of the endocrine system, with an estimated 16,450 new cases per year in Brazil during the 2026–2028 triennium. Fine-needle aspiration biopsy (FNAB) is the primary initial diagnostic method for the cytological evaluation of suspicious thyroid nodules. However, approximately 25% of cases result in indeterminate cytology and are classified as Bethesda categories III (atypia of undetermined significance) and IV (follicular neoplasm). This study is an integrative literature review that aims to examine the role of molecular markers, particularly BRAF V600E and RAS mutations, as well as RET/PTC rearrangements, in defining the treatment of patients with thyroid nodules classified as Bethesda III and IV. The literature search was conducted in the PubMed, SciELO, and Virtual Health Library (VHL) databases, including studies published between 2017 and 2025. The results showed that second-generation molecular panels, such as ThyroSeq v3, Afirma GSC, and ThyGenX/ThyraMIR, have high negative predictive value and can reduce the number of unnecessary surgeries. The BRAF V600E mutation is associated with greater tumor aggressiveness and helps determine the extent of surgery, whereas mutations in the RAS gene family are generally associated with low- or intermediate-risk tumors, making it possible to consider active surveillance in selected cases. It is concluded that molecular markers represent a significant advance in the personalized management of indeterminate thyroid nodules, although their widespread use remains limited in the Brazilian setting.