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Repeated biopsies of thyroid nodules to perform molecular testing reduces need for thyroid surgery

CTFP October 2021

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Thyroid nodules are very common and, for the most part, develop for unknown reasons. The concern about any nodule is whether the nodule is cancerous. Only a small fraction (<6%) of thyroid nodules will turn out to be cancers. The American Thyroid Association has published guidelines as to which nodules are recommended to be evaluated for cancer, which requires a biopsy of the nodule.

Overall, ~5% of biopsies identify a cancer (papillary thyroid cancer) and 80-85% are benign (non-cancerous). However, 10-15% are indeterminate, which means that the cells are not either clearly abnormal or clearly normal. Because of this uncertainty, people who have indeterminate thyroid biopsies often undergo surgery to remove at least part of the thyroid to make sure that cancer is not present. Alternatively, the cells obtained in an indeterminate biopsy can be sent out for further analysis using molecular marker testing. If the molecular markers are positive, surgery is recommended. If they are negative, the nodule is considered benign. Molecular marker testing is an important clinical tool to provide additional cancer risk assessment, but it is expensive and their best use remains an area of ongoing study. It is unclear whether molecular testing should be used reflexively to test all categories of indeterminate nodules.

In this study, the authors analyze a unique clinical group of patients in whom repeat biopsy was obtained prior to molecular testing in almost all cases to evaluate the implications of performing a repeat biopsy before molecular diagnostic testing indeterminate nodules.

Nishino M et al 2021 Repeat fine needle aspiration cytology refines the selection of thyroid nodules for Afirma gene expression classifier testing. Thyroid. Epub 2021 Apr 3. PMID: 33813868.

All of the patients included in this study not only had an indeterminate thyroid nodule biopsy, but all had a second biopsy to confirm the initial indeterminate result. Patients were 25 to 90 years of age and 80% of patients were female. A total of 370 nodules were included and all of these also had molecular marker testing using Afirma™. The study authors then went back and asked how many of the 370 indeterminate nodules actually benefited from Afirma™ testing.

Of the 370 nodules that were indeterminate with the first biopsy, the Afirma™ results were 148 suspicious and 222 negative (benign). A total of 182 second biopsies returned a different cytology result with the repeat biopsy (133 benign, 49 insufficient) and were considered low risk. The Afirma™ results were suspicious in 61 (33.2%) of these nodules. These 61 suspicious nodules were subsequently removed by surgery and revealed 4 cancers and 3 per-cancerous results (NFTP). Of the 188 nodules that were indeterminate on both biopsies, 87 were suspicious (46.3%) and 16 ended up being cancers with 12 pre-cancers (NFTP). Overall, if the decision was made to perform Afirma testing only if both biopsies were indeterminate, the number of tests would decrease by ~50% and result in missing 4 cancers. However, these 4 cancers were 20% of the total number of cancers in the entire group. Thus, the more nodules tested with Afirma™, the more cancers identified and the more surgeries were performed.

These data show that repeating a biopsy after an indeterminate result and testing with Afirma™ only if there were 2 inderminate results would decrease the number of Afirma™ tests by ~50%, decrease surgery by ~33% and miss 20% of the cancers. More data is needed to evaluate whether the missed cancers could otherwise be identified. These data are important in the evaluation as to the best use of these molecular maker tests. Further, repeating this study with other molecular marker tests may be helpful to provide both the patient and the physician with the best data to make the best decision for treatment of inderminate nodules.

— Sarah R. Kaslow, MD, MPH and Jason D. Prescott MD PhD


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 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% of 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™.

Noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP): a new term has been used to describe a type of papillary thyroid cancer which is non-invasive. These cancers behave less aggressively than typical papillary thyroid cancer and have been shown to have low risk for recurrence and low risk for spread outside of the thyroid.