BACKGROUND
Thyroid nodules are very common, occurring in up to 50% of individuals. Ultrasound is the best way to evaluate a nodule. Nodules that are concerning on ultrasound are then recommended to proceed to a biopsy. In up to 25% of biopsies, the results are indeterminate, meaning that the cells cannot be clearly identified as either normal or abnormal. These biopsies are usually then sent out for molecular analysis to determine if any gene mutations associated with cancer are present. If mutations are absent, the results are considered benign/not cancer. While the decision to send the patient to surgery if any mutation is present is the usual practice, there is a wide range of cancer risk depending on what mutation is identified.

Currently, most nodules containing RAS mutations are referred for surgery. However, this mutation is associated with ~50% risk of a low risk cancer or the pre-cancerous NIFTP. Thus, this makes RAS+ nodules excellent candidates for active surveillance, which is following nodules by ultrasound and proceeding with surgery only with significant growth of the nodule. This study studied the growth rate of RAS+ indeterminate nodules that are currently undergoing active surveillance and compare them with RAS+ indeterminate nodules that go immediately to surgery.

THE FULL ARTICLE TITLE
Sfreddo HJ, Koh ES, Zhao K, et al. RAS-mutated cytologically indeterminate thyroid nodules: Prevalence of malignancy and behavior under active surveillance. Thyroid. Epub 2024 Mar 28.

SUMMARY OF THE STUDY
This is a multicenter study performed on patients with RAS+ indeterminate nodules at Memorial Sloan Kettering, New York University Langone Medical Center, and Mount Sinai Health System. HRAS, NRAS, or KRAS gene mutations were identified via DNA-based sequencing assays (ThyroSeq v2-v3, CBL Path, Rye Brook, New York). At all sites, active surveillance was offered to patients with RAS+ nodules from 2010 to 2023 who met the following criteria: isolated RAS variant, nodule ≤4 cm and lacking high-risk features on ultrasound. The decision to undergo active surveillance versus immediate surgery was made via shared decision making between patient and physician.

The active surveillance group had ultrasound evaluation of the thyroid and lateral neck every 6 months for 2 years and then annually. Nodule growth was defined as an increase in nodule volume from baseline >72%. The immediate surgery group was comprised of RAS+ nodules that underwent diagnostic surgery at Memorial Sloan Kettering or New York University Langone Medical Center from 2016 to 2020.

The active surveillance group consisted of 63 nodules in 62 patients. The average nodule size was 1.7 cm, and 74.6% were between 1 and 3 cm. The majority of the patients were female (73.0%), were mainly White (63.5%), and had an average age at diagnosis of 46 years (40-67 years). In terms of molecular alterations, the most common was NRAS (50.8%), followed by KRAS (22.2%), HRAS (22.2%), and then RAS of unspecified subtype (4.8%). The average duration of observation while under active surveillance was 23 months. Growth was detected in 1.9% at 1 year, 15% at 2 years, 23% (95% CI, 12–44) at 3 years, and 28% at 4 and 5 years. The average doubling time for nodules that showed growth was 39 months. A total of 6 nodules underwent surgery after an average surveillance of 6.5 months, but only one of these nodules had the indication of growth, whereas the rest were resected based on patient or physician preference. Of the resected nodules, all but one had a diagnosis that was benign or noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) on pathology. No patient had spread of cancer into the neck our outside of the neck and there were no deaths from any cause. At the end of the study, 90.5% of patients continued with active surveillance.

The immediate surgery group consisted of 209 nodules. Surgical pathology revealed that 33% were cancer and 67% were benign, of which 35.4% were classified as NIFTP. Most cancerous nodules were ATA low-risk thyroid cancers (72.5%), 15 (21.7%) were ATA intermediate-risk thyroid cancer, and only 4 (5.8%) were ATA high-risk thyroid cancers. The most common cancer was follicular variant of papillary thyroid carcinoma.

WHAT ARE THE IMPLICATIONS OF THIS STUDY?
This study demonstrates that most RAS+ indeterminate nodules under active surveillance exhibited stability over time. The majority of RAS+ indeterminate that underwent immediate surgery were benign, and those that were cancer were mainly classified as ATA low-risk cancers. These is an important study to give both doctors and patients additional options to manage these low risk nodules.

— Pinar Smith, MD

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