Clinical and Molecular Predictors of Malignancy in a Series of 585 RAS-positive Thyroid Nodules with Surgical Outcome

Abstract Context RAS mutations are detected in a wide spectrum of thyroid tumors and when found on FNA biopsy, surgery is typically indicated. Objective To identify clinical and molecular predictors of malignancy or non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) in a consecutive series of RAS-positive thyroid nodules with known surgical outcome. Methods We performed a single institution retrospective analysis of a consecutive series of RAS-positive thyroid nodules detected using ThyroSeqv3 and with either histopathology or ≥1 year follow-up ultrasound (2018-2024). Results Totally, 585 RAS positive nodules with surgical pathology and 55 non-resected nodules were identified. After surgery 140/585 (24%) of nodules were benign, 149/585 (25%) NIFTP, and 296/585 (51%) cancer. The rate of cancer/NIFTP was lower in nodules with isolated KRAS mutations (34%) compared to isolated NRAS (74%) or HRAS (81%) (p<0.0001). The presence of copy number alterations (CNA) (OR 12, p=0.02), nodule size on ultrasound (OR 1.3, p=0.003) and higher Bethesda classification (IV, V or VI) were associated with cancer/NIFTP on multivariable analysis. On median follow-up of 2.5 years (IQR 1.2-4), persistent/recurrent disease occurred in 19/272 (7%) patients with a cancer diagnosis and was more likely with concurrent high-risk mutations (14/28, 50%) vs without (5/244, 2%), p<0.0001, with an even lower rate among isolated RAS cancers (1/133, 0.8%). After median 2.3 years (IQR 1.5-4.5), 6/55 nodules (11%) had significant growth. Conclusions In this large series of RAS-positive tumors molecular and clinical factors predicted cancer. In isolated RAS-positive tumors, the rate of recurrent/persistent disease was very low with low rates of significant growth in non-resected nodules, suggesting that these nodules may be managed with lobectomy, and in select cases, even non-surgically.