Clinical Thyroidology® for the Public
Summaries for the Public from recent articles in Clinical Thyroidology
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THYROID NODULES
How often are thyroid nodules with indeterminate results and negative molecular testing actually cancer?
BACKGROUND
Thyroid nodules are very common. Up to 50% of individuals that have any imaging test of the neck will be found to have a thyroid nodule. The concern of any thyroid nodule is whether it is a thyroid cancer. To evaluate this, a thyroid biopsy can be performed. While most biopsies show that the nodule is benign (not cancerous), sometimes, the results are unclear. This is called “indeterminate cytology” and usually means more testing or even surgery is needed to find out if it’s cancer. There are 2 categories of indeterminate nodules: Bethesda III (Atypia of unknown significance, AUS, or follicular lesion of unknown significance, FLUS) and Bethesda IV (Follicular lesion or Hurtle cell lestion).
New genetic tests on the cells removed during a biopsy, like ThyroSeq v3, can help doctors decide if surgery is necessary by checking for cancer-related gene changes. Many nodules come back with negative results on this test, meaning no gene changes linked to cancer were found. These nodules are then considered benign.
This study looked at how often these indeterminate nodules with negative results on genetic tests are benign and how many actually turn out to be cancer. They also looked at how best to follow these nodules over time,
THE FULL ARTICLE TITLE
Nachum S, et al. Thyroid nodules with indeterminate cytology and negative molecular profile: prevalence of malignancy and practice paradigms for surveillance. Thyroid 2025;35(3):265-273; doi: 10.1089/ thy.2024.0455. PMID: 39874551.
SUMMARY OF THE STUDY
Doctors reviewed records from 556 people with thyroid nodules that had indeterminate biopsy results (called Bethesda III or IV) and tested negative on the ThyroSeq v3 genetic test. These nodules were grouped based on the kind of negative result they got: 1) Negative, 2) Currently Negative, or 3) Negative but Limited. Researchers looked at what kind of follow-up these patients had, who needed surgery, and which nodules turned out to be cancer.
Overall, 75 patients (13.5%) had surgery. Of these, 15 nodules were cancer and 2 were low-risk cancers. Nodules called “Currently Negative” or “Negative but Limited” were more likely to be operated on than those simply called “Negative.” Cancer risk in these 3 categories were: Negative: 2–18%, Currently Negative: 7–30%, Negative but Limited: 7–33%. Nodules labeled Bethesda IV had higher cancer risk than Bethesda III, even if their molecular test was negative. Most patients were followed without surgery, often with ultrasound, and few needed a second biopsy.
WHAT ARE THE IMPLICATIONS OF THIS STUDY?
Even when genetic tests are negative, the type of negative result and biopsy category matter. Some patients may still need close follow-up, especially those with Bethesda IV or less certain negative results. This study helps patients and doctors make better decisions about follow-up care. Not all nodules with negative genetic tests are the same, so the follow-up plan should be tailored based on the test subtype and biopsy findings. Most of these nodules can be watched safely with regular check-ups and imaging, instead of surgery.
— Maria Brito, MD, ECNU
ATA RESOURCES
Thyroid Nodules: https://www.thyroid.org/thyroid-nodules/
Fine Needle Aspiration Biopsy of Thyroid Nodules: https://www.thyroid.org/fna-thyroid-nodules/
Thyroid Cancer (Papillary and Follicular): https://www.thyroid.org/thyroid-cancer/
ABBREVIATIONS & DEFINITIONS
Thyroid Nodule: an abnormal growth of thyroid cells that forms a lump within the thyroid. While most thyroid nodules are non-cancerous (Benign), ~5% are cancerous.
Thyroid Ultrasound: a common imaging test used to evaluate the structure of the thyroid gland. Ultrasound uses soundwaves to create a picture of the structure of the thyroid gland and accurately identify and characterize nodules within the thyroid. Ultrasound is also frequently used to guide the needle into a nodule during a thyroid nodule biopsy.
Thyroid Biopsy: a simple procedure that is done in the doctor’s office to determine if a thyroid nodule is benign (non-cancerous) or cancer. The doctor uses a very thin needle to withdraw cells from the thyroid nodule. Patients usually return home or to work after the biopsy without any ill effects.
Indeterminate Thyroid Biopsy: this happens a few atypical cells are seen but not enough to be abnormal (atypia of unknown significance (AUS) or follicular lesion of unknown significance (FLUS)) or when the diagnosis is a follicular or hurthle cell lesion. Follicular and hurthle cells are normal cells found in the thyroid. Current analysis of thyroid biopsy results cannot differentiate between follicular or hurthle cell cancer from noncancerous adenomas. This occurs in 15-20% biopsies and often results in the need for surgery to remove the nodule.
Molecular Markers: genes and microRNAs that are expressed in benign or cancerous cells. Molecular markers can be used in thyroid biopsy specimens to either to diagnose cancer or to determine that the nodule is benign. The two most common molecular marker tests are the Afirma™ Gene Expression Classifier and Thyroseq™.
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