Clinical Thyroidology® for the Public

Summaries for the Public from recent articles in Clinical Thyroidology
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The risk of thyroid cancer is higher than previously thought when thyroid biopsies show uncertain results

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Thyroid surgery is a safe and effective procedure to remove growths in the thyroid that are, or might be, cancerous (thyroid cancer). Thyroid growths, or nodules, are very common, although the vast majority of these do not turn out to be cancerous (such nodules are called benign). In order to determine if a thyroid nodule is cancerous, doctors perform a simple and safe procedure called a thyroid biopsy, during which a very thin needle is used to collect cells from the inside of a thyroid nodule. These cells are then evaluated by a pathologist, who determines if these cells are cancerous. If cancerous cells are identified, a thyroid surgeon will perform thyroid surgery to remove at least the cancerous part of the thyroid.

The pathologist will sometimes not be able to tell for sure if the cells that come from a thyroid biopsy are cancerous – the cells don’t quite look like cancer but also don’t quite look benign. This is called an indeterminate biopsy. There are three types of indeterminate biopsies, called Bethesda 3, Bethesda 4 and Bethesda 5. The Bethesda 3 biopsy type is the least likely to be cancerous (the biopsy cells look almost benign) while the Bethesda 5 biopsy type is the most likely to be cancerous (the biopsy cells look almost cancerous). The chances that a thyroid cancer is actually present for each of type of indeterminate biopsy have been estimated previously. The risk of cancer for Bethesda 3 biopsies was thought to be about 12% (about one out of ten people having this biopsy will have a thyroid cancer), for Bethesda 4 biopsies, about 25% (about one out of four people having this biopsy will have a thyroid cancer) and for Bethesda 5 biopsies, about 52% (about half of people having this biopsy will have a thyroid cancer). Unfortunately, the only certain way to determine if an indeterminate thyroid biopsy is actually cancer is to surgically remove at least the part of the thyroid that contains the nodule that was biopsied. This allows the pathologist to study the entire thyroid nodule directly for the presence of cancer.

The authors of the research described here were interested in learning how accurate the previously reported risk of cancer is for each type of indeterminate biopsy. This information is very important, as it helps people for whom a thyroid biopsy is indeterminate understand their chance of having a thyroid cancer, which then helps them work with their doctors to choose their best treatment option.

Delman AM et al 2023 The national rate of malignancy among Bethesda III, IV, and V nodules is higher than expected: A NSQIP analysis. Surgery 173:645–652. PMID: 36229250.

The authors of this research used a large database that includes information from hospitals across the United States to study people who underwent thyroid surgery between 2016 and 2019. Using this information, the authors were able to determine how many people having a Bethesda 3, Bethesda 4 or Bethesda 5 thyroid biopsy actually had a thyroid cancer and then to compare this information to the previously reported cancer risk for each of these biopsy types. A total of 13,121 people were identified in the database. For each of these three biopsy categories, the authors found a higher risk of cancer than what was previously reported. For Bethesda 3 biopsies, the risk of cancer increased from 12% to 36.2%. For Bethesda 4 biopsies, the thyroid cancer risk increased from 25% to 36.6%. Last, for Bethesda 5 biopsies, the risk of thyroid cancer increased from 52.5% to 91.1%. The authors also found that younger people and men who have a Bethesda 3, Bethesda 4 or Bethesda 5 thyroid biopsy were more likely to have a thyroid cancer than were older people and women, respectively.

The ability to estimate the risk of thyroid cancer when a thyroid nodule is found is very important. If this risk is low, a person might decide to monitor their thyroid nodule, choosing to defer thyroid surgery unless the thyroid nodule becomes more suspicious over time. On the other hand, if the risk of thyroid cancer is high, the thyroid is usually removed surgically, so as to prevent the chance that a thyroid cancer, if present, could grow and spread. The findings described by these researchers indicate that the risk of thyroid cancer for Bethesda 3, Bethesda 4 or Bethesda 5 biopsies is significantly higher than previously thought. In light of this information, people who have one of these thyroid biopsy types might be more inclined to choose thyroid surgery over thyroid observation. Regardless, all people considering thyroid surgery should discuss the risks and benefits of surgery with their thyroid surgeon, so that they may make their own best possible treatment decisions.

— Syed Haider, MD, 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 fine needle aspiration biopsy (FNAB): 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) – Bethesda 3) or when the diagnosis is a follicular or hurthle cell lesion (Bethesda 4). 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.

Suspicious thyroid biopsy: this happens when there are atypical cytological features suggestive of, but not diagnostic for malignancy (Bethesda 5). Surgical removal of the nodule is required for a definitive diagnosis.