RAS-Mutated Cytologically Indeterminate Thyroid Nodules: Prevalence of Malignancy and Behavior Under Active Surveillance

Abstract

Background: Genomic profiling is now available for risk stratification of cytologically indeterminate thyroid nodules (ITNs). Mutations in RAS genes (HRAS, NRAS, KRAS) are found in both benign and malignant thyroid nodules, although isolated RAS mutations are rarely associated with aggressive tumors. Because the long-term behavior of RAS-mutant ITNs is not well understood, most undergo immediate surgery. In this multicenter retrospective cohort study, we characterize tumor growth kinetics of RAS-mutant ITNs followed with active surveillance (AS) using serial ultrasound (US) scans and examine the histopathologic diagnoses of those surgically resected. Methods: US and histopathologic data were analyzed retrospectively from two cohorts: (1) RAS-mutant ITNs managed with AS at three institutions (2010-2023) and (2) RAS-mutant ITNs managed with immediate surgery at two institutions (2016-2020). AS cohort subjects had ≥3 months of follow-up and two or more US scans. Cumulative incidence of nodule growth was determined by the Kaplan-Meier method and growth by ≥72% change in tumor volume. Pathological diagnoses for the immediate surgery cohort were analyzed separately. Results: Sixty-two patients with 63 RAS-mutated ITNs under AS had a median diameter of 1.7 cm (interquartile range [IQR] 1.2-2.6) at time of diagnosis. During a median AS period of 23 months (IQR 9.5-53.5 months), growth was observed in 12 of 63 nodules (19.0%), with a cumulative incidence of 1.9% (1 year), 23.0% (3 years), and 28.0% (5 years). Most nodules (81.0%) demonstrated stability. Surgery was ultimately performed in 6 nodules, of which 1 (16.7%) was malignant. In the cohort of 209 RAS-mutant ITNs triaged to immediate surgery, 33% were malignant (23.9% American Thyroid Association [ATA] low-risk cancers, 7.2% ATA intermediate-risk, and 1.9% ATA high-risk. During a median follow-up of 6.9 (IQR 4.4-7.1) years, there were no disease-specific deaths in these patients. Conclusions: We describe the behavior of RAS-mutant ITNs under AS and find that most demonstrate stability over time. Of the resected RAS-mutant nodules, most were benign; of the cancers, most were ATA low-risk. Immediate surgical resection of all RAS-mutant ITNs appears to be a low-value practice. Further research is needed to help define cases most appropriate for AS or immediate surgery.

Keywords: RAS gene mutation; ThyroSeq; active surveillance; cytologically indeterminate thyroid nodules; thyroid nodules.

FIG. 1.

Patient selection process for active surveillance cohort and diagnostic surgery cohort.

FIG. 2.

Cumulative incidence of nodule growth. In this figure, nodule growth was defined as >72% change in volume from baseline measurement.

FIG. 3.

Percent change in tumor volume during active surveillance for each patient.

FIG. 4.

Percent change in volume of individual RAS-mutated nodules from baseline as determined by thyroid ultrasound scans (n = 63). Tumor growth was defined as >72% change in volume at any point during active surveillance (orange lines: n = 12) and included nodules that subsequently regressed (n = 2).

FIG. 5.

Surgical pathology of RAS-mutant thyroid nodules triaged to surgery. Benign or nonmalignant entities made up the majority (67.0%, n = 140) of the resected RAS-mutant indeterminate thyroid nodules, while cancer was found in 33.0% (n = 69). Of the carcinomas, 78% were ATA low-risk cancers. Follicular nodular disease, previously known as nodular hyperplasia; Oncocytic adenoma, previously known as Hürthle cell adenoma; Hashimoto's thyroiditis, described as chronic lymphocytic thyroiditis; Oncocytic cell carcinoma, previously known as Hürthle cell carcinoma. ATA, American Thyroid Association; FVPTC, follicular variant of papillary thyroid cancer; HGDTC, high-grade differentiated thyroid carcinoma; NIFTP, noninvasive follicular thyroid neoplasm with papillary-like nuclear features; PDTC, poorly differentiated thyroid cancer; PTC, papillary thyroid carcinoma.