Histopathologic and Clinical Features of Bethesda III-VI Nodules Harboring Isolated RAS Mutations

Although thyroid tumors possessing isolated RAS mutations are generally considered to be indolent, the oncologic outcomes of tumors evaluated with comprehensive molecular testing have not been well characterized.

We performed a retrospective cohort study of 368 consecutive patients with Bethesda III-VI thyroid nodules at a single institution (2016-2021) who underwent molecular testing with ThyroSeq v3. Patients with isolated RAS mutations were identified, and those with isolated BRAF V600E-mutated cancers were used as comparators. Outcomes of interest included rate of malignancy, high-risk histopathologic features, and structural disease recurrence.

A total of 50 patients (14%) had an isolated RAS-mutated nodule, of whom 41 underwent surgery (median age, 43 years; female, 83%). The malignancy rate on final pathology was 46%, whereas 32% of patients had noninvasive follicular thyroid neoplasm with papillary-like nuclear features and 22% had benign histopathology. In comparison, the isolated BRAF-mutated cohort (86 [24%] patients; median age, 45 years; female, 68%) had a 100% rate of malignancy. Only 2 (11%) of the isolated RAS patients with malignant histopathology had lymph node metastasis, compared with 34 (39%) of the BRAF cohort (P = .016). Over a median follow-up of 5 years, no patients with isolated RAS mutations had a structural recurrence compared with 5 patients (6%) in the isolated BRAF cohort.

Bethesda III-VI thyroid nodules with isolated RAS mutations have a low rate of aggressive histopathologic features and are unlikely to recur. Thyroid lobectomy may be sufficient treatment for these tumors.