A recent article published in the Journal of Clinical Endocrinology & Metabolism examines how to determine the optimal or appropriate time for review or intervention for benign thyroid nodules detected by initial fine needle aspiration (FNA) of the thyroid.
The investigators screened 1,369 eligible patients for follow-up study from the 2,010 patients at their institution with FNA-confirmed benign thyroid nodules, using a thyroid nodule larger than 25 px on ultrasound and normal or elevated thyroid stimulating hormone levels as the criteria.
The underlying data (e.g., clinical examination, laboratory tests, surgical pathology reports, and thyroid ultrasonography) of the initially screened patients were reviewed to determine the nature of the thyroid nodules and the patients ultimately enrolled in the study. This cohort study included 89.9% female patients, with a mean age of 50 years and a mean nodule size of 60 px.
All patients were followed for a mean of 8.5 years (ranging from 0.25 to 18.1 years), with 44% of patients monitored for more than 10 years. Twenty-four percent of patients (325/1369) underwent thyroidectomy and the remaining 76% (n=1014) were re-evaluated for analysis at the last follow-up visit.
Interestingly, of the patients with pathologically confirmed thyroid cancer, 1.3% (n=18) had a false negative FNA result (i.e., the patient had a thyroid cancer that was not confirmed by puncture), and the majority of these were papillary thyroid cancers (89%, n=16). No thyroid cancer-related deaths occurred during the study period.
Does early or repeated thyroid ultrasound follow-up after FNA has identified a benign thyroid nodule help to reduce the false-negative rate on FNA? This was the focus of this study. The results showed that the false-negative rate was 7.5%, 7.8%, and 8.2% if the follow-up ultrasound was performed within 2, 3, or 4 years after FNA, respectively, and 7.5%, 6.6%, and 4.5% if the follow-up ultrasound was performed after 2, 3, or 4 years, respectively (p values were not statistically significant).
The frequency of the event of a benign nodule on thyroid ultrasound but subsequent thyroid cancer confirmed by thyroidectomy was the focus of this study. The results showed that 7.5%, 6.6%, and 8.2% of patients had false negatives on FNA if ultrasound follow-up was performed within 2, 3, or 4 years of follow-up, respectively; in addition, using FNA as a criterion for determining benignity or malignancy, there were false negative rates of 7.4%, 6.6%, and 4.5% at 2, 3, and 4 years of follow-up, respectively. However, these differences were not statistically significant.
Based on the above findings (i.e., low thyroid cancer-related mortality and no increase in corresponding mortality despite a false-negative rate), the investigators concluded the following, “These results support the recommendation that patients with benign nodules confirmed by initial FNA be reassessed for benign or malignant thyroid nodules after 2 to 4 years.”
Unresolved
This article by Nou et al. is an important guide to endocrine clinical practice and gives reasonable guidance on the frequency of follow-up thyroid ultrasound in patients with benign thyroid nodules.
However, there are several issues that need to be noted.1. Problems with this study itself as a retrospective design. The study did not have a systematic assessment of thyroid nodules before they were diagnosed to determine the extent of the nodules, and could only compare itself at a two-dimensional level with each patient as a reference.2. The experience of cytologic pathologists varies, thus limiting the generalization of these results to other study sites.
In addition, most patients did not undergo surgical treatment, so thyroid cancer in these patients may not have been detected. The authors also mention in the article that some patients with thyroid nodules may have been treated with thyroidectomy after the study was terminated for observation.
It is now accepted that it is important to monitor thyroid nodules based on history, physical examination, and thyroid ultrasound findings to confirm the growth of the nodule and whether its growth is predisposed to malignant transformation to thyroid cancer. Although benign thyroid nodules can also grow, in most cases thyroid FNA combined with ultrasound, history and physical examination will identify the nodule as benign or malignant.
Current recommendations
The American Thyroid Association (ATA) has published guidelines for the treatment of thyroid nodules that include recommendations for monitoring thyroid nodules confirmed as benign by FNA.
The guidelines state, “All benign thyroid nodules should be followed up with continuous ultrasound for 6 to 18 months after the initial FNA examination. If there is no change in nodule size (i.e., less than 50% change in volume or less than 20% increase in size in at least two orientations for solid nodules or the solid portion of cystic nodules), the interval between the next clinical or ultrasound follow-up may be extended, for example, once every 3 to 5 years. If an enlarged nodule is detected by palpation or ultrasound (more than 50% change in volume or 20% increase in size in at least two directions and at least 2 mm in the solid portion of a solid or cystic nodule), a repeat FNA should be performed preferably under ultrasound guidance.”
The results of this study by Nou et al. appear to be consistent with these previous recommendations of the ATA guidelines. The difference is that the ATA guidelines recommend ultrasound follow-up 6 to 18 months after the initial FNA examination, whereas Nou et al. recommend re-evaluation at 2 years after the initial FNA examination. Further prospective systematic studies are needed to answer this question.
Undoubtedly, this study by Nou et al. has deepened our understanding of this issue. However, considering some of the issues mentioned above, the variation in the experience of cytopathologists around the world, and the fact that in clinical decision making we do not want to compromise the diagnosis of invasive thyroid cancer by false negative results of FNA (which is unlikely but still possible), my personal recommendation at this time remains to perform thyroid ultrasound 6 to 18 months after the initial FNA examination, with subsequent follow-up based on Nou et al. and ATA guidelines recommend less frequent surveillance.
The optimal follow-up interval for monitoring patients with benign thyroid nodules on FNA remains unknown, but a reasonable approach may be to perform clinical, laboratory, and imaging examinations every 1-2 years, with an initial reassessment 6-18 months after the initial evaluation, followed by reassessment at 4-5 years or longer intervals.
These patients may require lifelong monitoring, and it is just not clear from current studies in this area what the appropriate monitoring interval is.