Dr Guo Overviews the Management of Incidental Thyroid Nodules

Theresa Guo, MD, University of California, San Diego, discusses the management of incidental thyroid nodules, presented at the virtual 2022 Rare Cancer Series from Great Debates & Updates.

Incidental thyroid nodules are extremely common, Dr Guo said, and they are often asymptomatic. They may be identified incidentally on imaging studies, including carotid duplex ultrasound, CT scans of the neck or chest, cervical MRI, and PET imaging scan. Once thyroid nodules are identified, the goal is to differentiate between malignancy and benign disease, but the majority are benign.

Dr Guo then highlighted the epidemiology of thyroid nodules. The prevalence of thyroid nodules is difficult to estimate “because often they can be there without us looking,” she said.

Highlighting a study focused on the incidence of thyroid nodules in the general population detectable by ultrasound, Dr Guo said it was estimated that about 19-35% of patients will have thyroid nodules at any given time. Further, looking at autopsy reports, thyroid nodules exist in about 8-65% of the population at the time of biopsy, suggesting that most of the general patient population will develop thyroid nodules at some point in their lifetime.

Both thyroid nodules and thyroid cancer (TC) are increasing in incidence due to increased detection.

“As we do more imaging studies for our patient population, we are increasingly detecting these thyroid nodules and subsequently TC,” explained Dr Guo.

Evaluating the United States SEER database of papillary TC (PTC)—which is the most common thyroid malignancy—Dr Guo said there’s been an increase in the incidence of PTC in the US, primarily driven by small thyroid tumors less than 2 cm in size, while the incidence of larger tumors remains relatively stable.

The ability to detect more TC impacts clinical research, explained Dr Guo. The excellent prognosis of TC contributes to the fact that although the incidence of TC—especially PTC—is increasing, mortality rates have remained the same.

“One cautionary tale from Korea is that if we look more, we will find more,” mentioned Dr Guo.

In Korea, after offering routine screenings for TCs, the incidence of TC increased by nearly 10-fold, she said. Up to 90% of these patients underwent surgery, with 2/3receiving a total thyroidectomy.

“The question is, given the change in lack of mortality, did these patients need to undergo surgery, and are we potentially over treating some of these TCs,” asked Dr Guo. “Therefore, detecting and screening is a balance. We should keep this in mind, especially when we incidentally identify thyroid nodules.”

TC is usually indolent, Dr Guo said. PTC is the most common diagnosis, and has a 1-2% mortality rate at 20 years. The disease mortality rate for follicular thyroid carcinoma is more aggressive, with a 10-20% mortality rate at 20 years. When considering the low mortality rates in the context of other potential malignancies, Dr Guo said, most patients who have TC will not die from TC, but will die of other causes.

Notably, autopsy studies have demonstrated that 11-35% of patients who die from other causes will have a PTC present at the time of death, showing that untreated PTC may have no major untoward effect on patients. There are, however, some rare pathologies that are more aggressive, including anaplastic thyroid carcinoma and poorly differentiated thyroid carcinoma.

The risk for malignancy in thyroid nodules is generally quite low, Dr Guo said. About 5% of thyroid nodules will be positive for malignancy, most commonly PTC. The risk in a newly identified nodule declines with advancing age, so nodules in younger patients have a slightly higher risk. Other risk factors include family history, and a history of radiation (geographic or prior treatment). Notably, the size of a nodule does not contribute to risk of malignancy, so a larger nodule does not necessarily mean a higher risk for tumor, she said. Lastly, there are some characteristics on imaging that may be suspicious for a malignancy, including extra thyroidal extension, cervical lymphadenopathy, or PET avidity.

Dr Guo said PET avidity is important because it is encountered during routine PET scans. The incidence of PET avid thyroid nodules is estimated to be in 1- 4% of the population. In general, thyroid nodules have about a 5% risk for malignancy. For PET avid nodules, this risk is estimated to be 28% up to 74%. However, PET avidity should be correlated with concurrent thyroid nodule, confirmed by ultrasound. Also, thyroiditis can result in diffuse thyroid uptake without an associated nodule.

Once a nodule is identified, she said, the next steps in work up are that all thyroid nodules should undergo an untrasound evaluation, which is the gold standard for evaluating thyroid. The ultrasound helps to determine whether there’s a need for fine needle aspiration (FNA) biopsy is needed for further workup. However, ultrasound characteristics can often help identify benign disease with no additional workup needed after the ultrasound if the nodule identified to be benign.

In terms of ultrasound characteristics, TCs are hypoechoic, however, most are still benign. Calcification is also an important feature.

Dr Guo said thyroid function studies should also be performed, including a TSH, which can help identify whether a patient has a “hot” nodule (secreting thyroid hormone), which are benign with a radionuclide scan. This workup can also detect thyroiditis.

Another thyroid function study includes the Thyroid Imaging Reporting and Data System, or TI-RADS. This is used to evaluate thyroid nodules under ultrasound, Dr Guo said. There are different criteria to determine the severity of the nodule, as well as determine the potential risk for malignancy. Considerations include composition (stick nodules versus solid nodules), echogenicity, shape (taller-than-wide nodules are more suspicious), margin, and echogenic foci. Nodules are evaluated from TI-RADS 1 (benign, < 2% risk for malignancy) to TI-RADS 5 (highly suspicious, 67-85% risk for malignancy).

If nodules undergo fine needle aspiration, then the Bethesda Classification is used. Notably, Dr Guo said, fine needle aspiration should always be performed under ultrasound guidance to confirm biopsy of the target nodule. Nodules are classified from I to VI.

• Class I is non-diagnostic or unsatisfactory, has a 10% incidence rate, a risk of malignancy between 1-4%, and is recommended for repeat biopsy.
• Class II is benign and happens in about 70% of nodules, has a risk of malignancy between 0-3%, and is recommended for ultrasound follow-up.
• Class III is atypia of undetermined significance (AUS) or follicular lesion of undetermined significance (FLUS). This is in about 12% of lesions, and the risk for malignancy is 5-15%. It is recommended to do repeat needle aspirations or molecular testing at this level.
• Class IV is follicular neoplasm or suspicious for follicular neoplasm, has a 3% incidence rate, and a 15-30% risk for malignancy, and a lobectomy is recommended.
• Class V is suspicious for malignancy, has a 2.6% incidence rate, a 60-75% risk for malignancy, and surgery is recommended.
• Class VI is malignant with a 4% incidence rate. The risk for malignancy is 97-99%, and surgery is also recommended.

Lastly, genomic classifier testing (Afirma and Thyroseq) can be ordered for indeterminate nodules, Dr Guo said, including Bethesda Class III and Class IV categories. These tests help differentiate high- versus low-risk lesions by using a combination of gene expression and mutation analysis to determine the risk for malignancy.

Dr Guo said once a diagnosis of TC is made, patients should see both an endocrinologist and surgeon. The mainstay of TC treatment is surgery, which may involve a lobectomy or total thyroidectomy, and may involve the removal of lymph nodes if any abnormalities are detected. Depending on the extend of the disease, patients may be recommended for adjuvant radioactive iodine (RAI). Aggressive poorly differentiated or anaplastic TC may require medical or radiation oncology.

Notably, there’s been an increase in the acceptance of active surveillance for well-differentiated small TCs, Dr Guo said, referring to a few Japanese trials that demonstrated the safety of observing small TCs, including papillary TC ≤1 cm. Overall, 90% of nodules did not increase in size at a mean follow-up of 5 years. The risk to develop nodal metastasis was 1.5% at 5 years, and 3.4% at 10 years.

“Ideal candidates for observation are older patients with smaller nodules, as the indolent nature of TC means that these patients may be unable to undergo surveillance and potentially avoid surgery,” Dr Guo said.

In summary, thyroid nodules are very common, and increasingly more are incidentally detected on imaging. Most thyroid nodules are benign; however, we do need to evaluate them for malignancy. PET avidity suggests an increased risk for malignancy, and once thyroid nodules are identified, workup should include ultrasound and possible fine needle aspiration biopsy and thyroid function studies. Once TC is diagnosed, the patient should see both an endocrinologist and surgeon, Dr Guo said.—Emily Bader