Large thyroid nodules in asymptomatic patients show malignancy and false-negative rates on fine needle aspiration (FNA) that are similar to those of small nodules, suggesting that nodule size alone should not be a reason for surgical resection, according to findings from a new meta-analysis.

"Based on these data, surgical resection of large cytologically benign nodules is not recommended in the absence of other clinical indications," for thyroidectomy, say, Nicole A. Cipriani, MD, assistant professor of pathology, University of Chicago, Illinois, and coauthors of the study, recently published in Thyroid.

With conflicting data on whether larger nodule size is associated with a greater risk of malignancy and false-negative FNA rates, some surgeons choose to err on the side of caution and respect larger thyroid nodules, regardless of FNA results.

But the issue is controversial. The surgery itself is associated with potential risks, including increased physical and psychological morbidity, as well as a heavier financial burden, compared with the alternative approach of close clinical follow-up of cytologically benign nodules.

To assess the existing evidence, Cipriani and a team of multiple reviewers analyzed findings from 35 studies that stratified thyroid nodules by size and included data on benign and other cytology. The analysis included more than 20,000 nodules, of which more than 7000 had benign cytology.

Of 21 datasets that allowed for comparison of malignancy rates by thyroid nodule size, 81% showed malignancy rates of larger nodules to be similar to or lower than rates of smaller nodules. The overall malignancy rate of large nodules (3 cm or greater) was 13.1% compared with 19.6% among nodules 3 cm or smaller (odds ratio [OR], 0.72).

And in studies stratifying nodules as 4 cm or greater, the malignancy rate was similar, at 20.9%, to that of nodules 4 cm or smaller, at 19.9% (OR, 0.85). False-negative FNA rates according to nodule size were available in 17 datasets, with only one study linking higher false-negative rates with larger nodules.

In those studies, the overall false-negative rate of nodules 3 cm or greater was 7.2% compared with 5.7% of those smaller than 3 cm (OR, 1.47; CI, 0.80 – 2.69). And the overall false-negative rate of nodules 4 cm or greater was only slightly higher than that of nodules smaller than 4 cm, at 6.7% vs 4.5% (OR, 1.38; CI, 1.06 – 1.80), which was again not statistically significant.

Of note, papillary thyroid carcinoma and non-invasive encapsulated follicular variant of papillary thyroid carcinoma were the most commonly reported false-negative diagnoses (39.4% and 23.7%, respectively).

Guidelines Reflect Unclear Evidence

Although some studies have attempted to correlate larger thyroid nodule size with the risk of malignancy or false-negative FNA, the overall inconsistency of evidence is reflected in the American Thyroid Association (ATA) guidelines, which state that "based on the evidence, it is still unclear if patients with thyroid nodules 4 cm or larger and benign cytology carry a higher risk of malignancy and should be managed differently than those with smaller nodules."