Outcomes of Patients with RAS-Positive Bethesda III and IV Cytology Thyroid Nodules

Routine resection of all RAS-positive nodules may result in overtreatment for up to 50% of patients. We evaluated the management strategy and outcomes of RAS-positive nodules.

Following implementation of reflexive ThyroSPEC^TM molecular testing (MT) for all Bethesda III and IV thyroid nodules in July 2020, we identified patients with isolated RAS mutations between July 30, 2020, and September 30, 2024, using an institutional prospective thyroid nodule database. Patients were categorized by management strategy: surgery versus surveillance. Exclusion criteria included: absence of ultrasound (US) within 12 months prior to MT, incomplete post-MT management data, comutations with RAS, initial lobectomy before MT, concomitant fine-needle aspiration-proven papillary thyroid carcinomas or metastatic lymph nodes, and presence of contralateral high-risk nodules. This study represents a retrospective analysis of institutional registry data from a single health care region.

Among 203 patients with RAS-positive nodules (175 Bethesda III, 28 Bethesda IV), 126 (62%) underwent surgery and 77 (38%) were under surveillance (median follow-up: 24 months, interquartile range 14-37). Final pathology in surgery group revealed malignancy in 43 (34%), with 8 (19%) 2025 American Thyroid Association (ATA) intermediate-high or high risk, 57 (45%) benign lesions, and 26 (21%) neoplasms of uncertain or very low malignant potential. Surgical patients were younger (45 vs. 53 years, p = 0.001) with larger nodules (maximum diameter 2.9 vs. 2.5 cm, volume 6.2 vs. 3.8 cm³, p < 0.05 for both). Bethesda III nodules were more frequently managed with surveillance than surgery (95% vs. 81%, p = 0.010). Nuclear atypia was more frequent in malignant versus benign resected nodules (70% vs. 40%, p = 0.007). Seven patients crossed over to surgery during surveillance due to patient preference, nodule growth, or symptoms; two had malignant pathology (both ATA low-intermediate risk). Nodule stability was evaluated in 48 surveillance patients with at least one post-MT US and minimum 1-year follow-up. Using a threshold of 50%, 3/48 (6%) exhibited growth, with a 2% cumulative incidence of growth at 2 years.

Isolated RAS mutation alone may not uniformly mandate surgery. Active surveillance represents a viable and safe alternative to surgery in appropriately selected patients with RAS-positive nodules, though further long-term data are needed.