BACKGROUND
Thyroid nodules are common, being seen on ultrasound in more than 50% of individuals over the age of 60. However, only 5 to 10% of these nodules are cancerous. Thyroid nodule biopsy can help to determine whether the nodule is benign or a cancer in 70-80% of cases. The remaining 20-30% of thyroid nodules are called indeterminate, meaning the cells are neither entirely normal nor abnormal, so a clear diagnosis cannot be made based on these results. Based on the Bethesda scoring system for thyroid nodules, indeterminate nodules are scored as Bethesda 3 or 4, where the cancer risk ranges from 13-34%. Further, Bethesda 5 nodules, which are suspicious for cancer, carry a cancer risk up to 83%.

More recently, molecular marker tests of the biopsy samples have been developed to further identify the cancer risk of thyroid nodules scored Bethesda 3, 4 or 5. If a molecular marker is negative, the nodule is considered to be benign. Certain molecular markers can also predict an aggressive cancer behavior and help chose the best surgical management. In addition, personalized treatment options for advanced thyroid cancer have been developed that target specific molecular markers. The aim of this study was to evaluate the molecular profile of thyroid nodules classified as Bethesda 3-5 by using comprehensive molecular marker testing.

THE FULL ARTICLE TITLE
Chiosea S et al. 2023 Molecular profiling of 50,734 Bethesda III-VI thyroid nodules by ThyroSeq v3: Implications for personalized management. J Clin Endocrinol Metab. Epub 2023 Apr 18. PMID: 37071871.

SUMMARY OF THE STUDY
This is a study of 50,734 thyroid biopsy samples with cytology in the Bethesda 3-5 categories which were further analyzed using the ThyroSeq v3 assay at the University of Pittsburgh Medical Center from January 2018 to May 2021. The samples were collected from 1102 different practice sites as part of routine clinical care.

The average patient age was 58 years, 75% of the patients being women. The ThyroSeq v3 assay evaluates 112 molecular markers. The positive samples, which have a higher probability of being cancer, were then further divided into three groups based on their risk of aggressive behavior using the ThyroSeq Cancer Risk Classifier: low risk, intermediate risk and high risk.

Among the 50,734 samples, 65% were negative for molecular markers, 0.2% were positive for medullary thyroid cancer, 0.6% were positive for parathyroid cells, and 34% were positive for follicular thyroid cancer. Thus, based on the molecular markers, 71% of the Bethesda class 3 and 52% of the Bethesda class 4 biopsies were benign. Of the 32% of biopsies that were positive for molecular markers, Bethesda classes 3 and 4 biopsies showed predominantly low risk, RAS-like alterations which can be seen in benign nodules, while Bethesda class 5 biopsies showed mainly the cancer marker BRAF V600E–like alterations and fusions. A total of 70% of the positive samples had a low-risk profile, while 6% had a high-risk profile for aggressive behavior, more frequently seen in the Bethesda 5 biopsies.

WHAT ARE THE IMPLICATIONS OF THIS STUDY?
In this large group, 2/3 of the Bethesda class 3 and 4 thyroid nodule biopsies showed no molecular alterations when using the ThyroSeq v3 molecular test. This is clinically important, since the patients with a negative molecular test can avoid undergoing surgery for cancer diagnosis. Specific cancer markers, including BRAF and TERT mutations, were detected in the majority of Bethesda 5 biopsies, while low risk mutations were mainly seen in the Bethesda 3 and 4 biopsies. This information can be used to evaluate the cancer aggressiveness and prescribe personalized treatment in advanced thyroid cancer that targets specific genetic alterations.

— Alina Gavrila, MD, MMSC

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