Test Patterns: How Thyroid Nodule Tests Can Eliminate Needless Procedures

New research of genetic testing for thyroid nodules shows that they can make a substantial difference in patient outcomes, not to mention eliminating the need for unnecessary surgeries and biopsies. Then why aren’t more patients choosing to be tested?

Let’s face it: no one likes taking tests. Then again, no one particularly enjoys going under the knife either. For years, thyroid nodules have confounded patients and the physicians who treat them, but here in 2022, research is showing that commercially available molecular tests have been getting better and better at helping people avoid unnecessary diagnostic surgeries to determine a thyroid nodule’s malignancy. On the hierarchy of “Things People Wish to Avoid,” surgery outranks taking a test.

About 65% of people will be diagnosed with a thyroid nodule by the time they’re 60 years old. Each year, around 565,000 people with thyroid nodules undergo fine-needle aspiration (FNA) biopsies to determine whether those nodules are malignant. About a third of those biopsy results are indeterminate, and most of the patients with indeterminate nodules are directed or undergo diagnostic surgery, even though those surgeries reveal a benign nodule 70% to 80% of the time.

Toward the end of last year, a paper appeared in the Journal of the Endocrine Society, in which researchers looked at two genetic tests used to evaluate indeterminate thyroid nodules – Veracyte, Inc.’s Afirma Gene Expression Classifier (GEC) and the next-generation Afirma Genomic Sequencing Classifier (GSC). The GSC replaced the GEC in 2017, as it was able to perform all the functions of its predecessor, as well as test for gene mutations and more accurately identify benign Hurthle cells, which can be difficult to discern from cancer.  

The researchers, led by Whitney Goldner, MD, a professor in the Department of Internal Medicine, Division of Diabetes, Endocrinology, and Metabolism, at the University of Nebraska Medical Center in Omaha, write that the implementation of the GEC and subsequently the GSC resulted in higher benign call rates (BCR) and improved positive predictive value (PPV). However, not all patients undergo molecular testing to help them make the decision whether to have surgery.

“We started this study to evaluate the performance of molecular testing in the indeterminate thyroid nodules in our institution and compare it to previously published institutional studies,” Goldner and the study’s first author, Preethi Polavarapu, MBBS, a clinical fellow at the University of Nebraska Medical Center, tell Endocrine News. “Initially, we used Afirma GEC for testing, and then switched to GSC when it became available. We wanted to compare these two tests to each other as well as compare them to those that did not have molecular testing.”

Patient Hesitation to Testing?

For this study, Goldner and her team at the University of Nebraska Medical Center and researchers at the VA Nebraska-Western Iowa Health System retrospectively analyzed 468 cytologically indeterminate thyroid nodules from January 2013 to December 2019 to assess and compare how use of the Afirma GSC (n=124) and the original Afirma GEC (n=71) impacted patient care. The teams also evaluated patient and nodule characteristics of those who did not undergo molecular testing (n=273) to determine the impact of other variables on the evaluation and management of indeterminate thyroid nodules.

They found that the Afirma GSC identified 30% more nodules as benign compared to the GEC, and that use of the Afirma GSC resulted in 41% fewer surgeries compared to patients with no molecular testing (40% vs. 68%, respectively). Additionally, when surgery was performed, patients deemed “suspicious for cancer” by the Afirma GSC were 95% more likely to have cancer compared to those who had no molecular testing (39% vs. 20%, respectively).

Goldner and Polavarapu say they were surprised by the number of people who did not undergo genetic testing to aid in their decision making. “When we evaluated this further, we found that factors such as larger nodule size and constructive symptoms were more common in the ‘no molecular testing’ group and this group had higher rates of surgery,” they say. “It is possible that patients who already were planning to have surgery for these reasons declined molecular testing as it would not change clinical management.”

The teams also found that time to surgery was longest with the GEC and lowest with no molecular testing. Goldner and Polavarapu explain that patients who chose not to get tested had already made the decision to have surgery, so they’re able to proceed directly to the operating room. “When GEC was initially offered, it was only offered at our institution AFTER someone had already had an indeterminate thyroid nodule biopsy,” they say. “This required a second clinical visit and repeat biopsy, usually at least one month after the first biopsy. In the later years of GEC and with all of GSC, we collected samples for reflex molecular testing in the event of an indeterminate thyroid nodule biopsy, which eliminated the need for a second biopsy, which shortened the decision-making time and allowed patients to go to surgery sooner.”

Surgeons Versus Endocrinologists

The authors of the JES paper also looked at other factors that might have played into whether a patient would opt for diagnostic surgery, evaluating the differences between those in the “no molecular testing” cohort who did and did not have surgery. “Unlike the comparison between groups for or against molecular testing, among those who did not undergo molecular testing, there was a difference between those who underwent surgery and those who did not regarding ultrasound TIRADS score and cytology,” the authors write. “Those who underwent surgery had higher TIRADS scores and were more likely to have Bethesda IV (FN or HCN) cytologic diagnosis.”

Polavarapu et al, also point out that type of provider predicted whether someone would choose the surgical route. Forty-one percent of patients who saw an endocrinologist did not undergo surgery, while 62% of patients who saw a surgeon chose to have surgery. Patients who saw a provider other than an endocrinologist or surgeon were more likely to avoid surgery, the authors write.

And while those numbers may speak to a provider’s level of expertise either way, Goldner and Polavarapu say they did not look at those reasons specifically, and that’s a topic that warrants further exploration. “It is possible that patients who already had an indication for surgery presented to the surgeons directly, instead of starting with the endocrinologists,” they say.

A Decade of Upgrades

Progressive improvements have been made to these commercially available tests over the past 10 years; the GEC had already demonstrated reduced rates of unnecessary surgeries and its replacement, the GSC, improved on those numbers. Goldner and Polavarapu say they are happy to see that their results were in line with previously published data and that patients appreciate that molecular tests are improving and reducing the need for unnecessary surgeries. “Thyroid nodules are extremely common and to send everyone with indeterminate thyroid nodules to surgeries will lead to unnecessary surgeries,” they say. “Hence, it is very important to predict accurate malignancy risk to guide long term management.” 

Goldner and Polavarapu say that the differences between groups with and without molecular testing proved interesting, and those differences may require further study. “Further studies are needed to understand the practical application of these molecular markers preoperatively in cytologically indeterminate thyroid nodules as not all patients opt for the use molecular testing for further evaluation in this clinical scenario,” the authors write in the Conclusion.

For Goldner and Polavarapu, it will be important to further evaluate which patients need molecular testing to guide clinical decision making.  “Is molecular testing needed for every individual,” they ask, “or is there any subset of individuals who are best suitable for molecular testing?”

“Our analysis showed a significant improvement in the benign call rate with the Afirma GSC as compared to no molecular testing, as well as a significant increase in confirmed malignancies among those patients who did go to surgery when utilizing the test.”

Whitney Goldner, MD, professor, Department of Internal Medicine, Division of Diabetes, Endocrinology, and Metabolism, University of Nebraska Medical Center, Omaha, Neb.

Indeed, further studies may speak to the need for personalized care but for now, this study reinforces the clinical utility of molecular testing to reduce unnecessary surgeries in patients with indeterminate thyroid nodule cytology, as compared to the use of no molecular testing.

“Our analysis showed a significant improvement in the benign call rate with the Afirma GSC as compared to no molecular testing, as well as a significant increase in confirmed malignancies among those patients who did go to surgery when utilizing the test,” Goldner says. “Additionally, the test demonstrated high sensitivity and [negative predictive value], and we saw enhanced specificity and PPV with the GSC test as compared to the GEC, which is all consistent with prior studies. Overall, these results demonstrate the value and accuracy of GSC testing in the diagnostic management of cytologically indeterminate thyroid nodules.”

Bagley is the senior editor of Endocrine News. He researched, compiled, and wrote the 2021 Progress Report in the December issue.