The implications of molecular alterations in cytologically benign thyroid nodules.

Background

Ablation of benign thyroid nodules has gained clinical favor. However, reliably excluding malignancy remains a diagnostic challenge. We assessed the frequency and spectrum of molecular abnormalities in cytologically benign nodules.

Methods

This retrospective cohort study of national and institutional cohorts reviewed nodules with cytologically benign fine-needle aspiration results referred for next-generation sequencing-based molecular testing (2017-2024). Frequency/type of molecular abnormalities, histopathology, and clinical variables predictive of positive molecular testing were evaluated.

Results

Among 825 cases in the national cohort, 121 (15%) tested positive, including 97 (80%) for low-risk RAS/RAS-like alterations, 19 (16%) for intermediate-risk BRAF V600E and BRAF V600E-like alterations, and 5 (4%) for high-risk molecular profiles including TERT and TP53. Twenty-four nodules with intermediate- or high-risk molecular alterations represented 20% of cytologically benign molecular testing-positive nodules and 3% of all nodules. Among 36 patients with surgical outcomes, 16 (44%) nodules were malignant, and 3 (8%) were noninvasive follicular thyroid neoplasm with papillary-like nuclear features. Among 38 cases in the institutional cohort, 11 (29%) tested positive, 7 (64%) carried low-risk, 2 (18%) carried intermediate-risk, and 2 (18%) carried high-risk alterations. Intermediate- or high-risk alterations were present in 36% of nodules with positive molecular testing and 11% of all nodules. Age <55 years (odds ratio, 13.4) and history of nodule growth (odds ratio, 13.6) were independent predictors of positive molecular testing. Of 9 molecular testing-positive nodules managed with surgery, 4 (44%) were malignant.

Conclusion

Among thyroid nodules with benign cytology referred for molecular testing, 3%-11% demonstrated intermediate- or high-risk alterations. Considering this molecular heterogeneity, further investigation of clinicopathologic factors is warranted to inform nonoperative or preablation molecular risk stratification and ensure accurate exclusion of malignancy.