Repeat Testing of Indeterminate Thyroid Nodules ‘Useless’?

Thyroid nodules initially diagnosed on fine needle aspiration (FNA) cytology to be indeterminate rarely have a change in management after repeat FNA, suggesting little benefit in repeat testing of the nodule, with the exception of a few higher-risk subgroups, such as younger adults, new research concluded.

“Our study demonstrated that fine needle aspiration cytology repetition is useless for most cases, hence it should only be considered for young adults having nodules with ultrasound-suspicious characteristics,” reported the authors in the study, published in the Journal of Endocrinological Investigation.

“Furthermore, a 10-year follow-up for indeterminate thyroid nodules is safe enough rather than a long-life follow-up,” they added.

In clinical practice, up to 30% of thyroid nodules are estimated to be indeterminate, and while molecular testing, commonly used in the United States, can better identify which nodules are benign, the tests are not as widely used in Europe and elsewhere, where costs can be high, hence follow-up FNA testing and other measures may be more relied upon.

However, with studies showing only a small percentage of indeterminate nodules turn out to be malignant, the usefulness of potentially burdensome, life-long repeat FNA testing has been subject to debate.

To further investigate, first author Tommaso Piticchio, PhD, of Garibaldi Nesima Hospital, University of Catania, Catania, Italy, and colleagues evaluated data on 506 patients at two centers in Italy who were diagnosed with indeterminate thyroid nodules based on FNA between January 2015 and April 2024.

The patients median age was 56 years, 82% were women, and the median maximum diameter of nodules biopsied for the first time was 18 mm (range 14-24 mm).

Of the nodules, 21.4% were iso-anechoic, 44.2% isoechoic, and 34.4% hypoechoic. Calcifications were reported in 7.4% of cases, including 6.2% representing macrocalcifications, and 1.2% microcalcifications. Nodule margins were irregular in 3.1% of cases.

With a median time to a repeat FNA of 18 months (range 11-40 months), nodules had a median increase in diameter of 1 mm between the first and second FNA.

Overall, 216 cases (42.7%) had repeat FNA results that differed from the first FNA, however, the change for nearly all was from indeterminate to benign.

The repeat FNA resulted in a change in management in only 30 cases (5.9%; P = .036).

Of the remaining 476 follow-up cases, over a median follow-up of 80 months (range 4-300 months), 20 patients required surgery and of those, 16 were found to be benign and only 4 had malignant pathology, all occurring within the first 8 years of observation.

The malignant cases occurred among those ranging from 19-38 years, with a median diagnosis at 49 months.

“In most cases, repeating FNA was not helpful to improve the clinical management of indeterminate thyroid nodules,” the authors concluded.

Overall, on a multivariate analysis, key factors associated with a change in management included age (odds ratio [OR], 0.97; P = .04), margins (OR, 5.6; P = .004) and echogenicity (hypoechoic vs isoechoic [OR, 5.2; P = .002], hypoechoic vs iso-anechoic [OR, 5.9; P = .02]).

Based on the findings, “we propose to consider repeat FNA only for young adult patients, up to a maximum of 55 years and/or having nodules with suspicious ultrasound characteristics,” the authors suggested.

“In this category, repeat FNA should be performed after at least 3-6 months to allow inflammation and tissue repair recovery occurring after the first FNA, since the risk of malignancy of the repeat FNA does not change over time, as demonstrated by regression analyses,” they added.

Overall, among those receiving an FNA diagnosis of indeterminate or benign, “the estimated cumulative risk of event (ie, diagnosis of thyroid carcinoma after surgery) was very low and the mean overall time from the first observation of the nodule to event was very long,” the authors added.

Guideline Recommendations

The findings are consistent with research indicating that only a small percentage (5%-15%) of indeterminate nodules turn out to be malignant, however, the American Thyroid Association and European Thyroid Association recommend repeat FNA in those cases.

Typically, the repeat FNA is recommended within 6-12 months after the first FNA, whereas research is lacking on the effects of delayed FNA repetition on patient prognosis in terms of the risk for nodule malignancy.

The current findings support “the need for a shorter and less strict follow-up of patients with indeterminate thyroid nodules,” the authors concluded. “We suggest reducing frequency of follow-up after 10 years of observation and, in turn, it would be reasonable to stop follow-up in patients aged over 70 years.”

Patient Preference, an Important Consideration

Commenting on the study, Matthew Ettleson, MD, of the Section of Endocrinology, Diabetes and Metabolism, The University of Chicago, Chicago, agreed that the findings indicate that “if there will be an indication for surgery, it will emerge within the first 10 years of monitoring. Therefore, monitoring over 10 years in middle-aged and older adults is a reasonable conclusion from their data.”

He noted, however, the limitation that the results reflect the study’s specific population, and malignancy rates could vary in other populations as well as between pathologists and institutions.

“It is valuable for centers that do many FNAs to track their own outcomes so they can accurately convey malignancy risk to [their patient population],” Ettleson said.

There is also the important issue the psychological burden of an indeterminate diagnosis on patients, he noted.

“These decisions are complicated and should take into account patient preference,” Ettleson underscored.

“Patients’ risk tolerance will vary. When molecular testing is not available, repeat FNA does not often change management, but offering patients reassurance with a benign follow-up may help their peace of mind,” he said.

Even when molecular testing is available, “to me, the only thing that really precludes further testing is two benign FNAs from the same nodule,” Ettleson said.

The authors and Ettleson had no disclosures to report.