Editorials represent the opinions of the authors and JAMA and not those of the American Medical Association.


Improving the Long-term Management of Benign Thyroid Nodules Anne R. Cappola, MD, ScM; Susan J. Mandel, MD, MPH

Nodules have been reported to be present in 50% of thyroids in autopsy series.1 A minority of these thyroid nodules are palpable, leaving a broad opportunity for discovery of incidental thyroid nodules through imaging tests performed for other indications, including Related article page 926 carotid ultrasound and chest computed tomography. Indeed, detection of asymptomatic thyroid nodules as incidental findings on radiological evaluations that include the neck has increased over the past 3 decades.2 Once detected, these thyroid nodules require additional evaluation. The major concern with thyroid nodules is identification of the 7% to 9% that are cancerous3 and require treatment. Appropriate initial evaluation of a thyroid nodule includes thyrotropin measurement and a thyroid ultrasound. Recommendations for deciding which thyroid nodules require ultrasound-guided fine-needle aspiration to rule out thyroid cancer have evolved from reliance exclusively on size criteria. Refinements in ultrasound technology have allowed finer resolution of thyroid nodules and detection of thyroid nodule characteristics, several of which are associated with higher risk of a malignant nodule. The presence of these higher-risk sonographic characteristics, which include hypoechogenicity, irregular margins, taller-than-wide shape, intranodular vascularity, and microcalcifications,4,5 are also indications for initial fine-needle aspiration. There are few data to guide the long-term management of the majority of patients with thyroid nodules, which includes those with benign initial fine-needle aspiration results or in whom aspiration was not indicated based on size and ultrasound characteristics. The clinical concern is detecting the cancerous nodules that were not identified during initial evaluation, both aspiration false-negatives and ultrasound false-negatives, small thyroid nodules lacking highrisk ultrasound features. Current information about thyroid nodule biology suggests that benign thyroid nodules do not transform into malignant nodules; the nodule either arose as a benign nodule or as a malignant nodule. Therefore, ultrasound surveillance has been advocated to detect falsenegatives from the initial evaluation.4 Differentiated thyroid cancer is a low-mortality cancer, with overall 5-year survival rates surpassing 97%.6 Even though differentiated thyroid cancer is generally a slow-growing tumor, an untested assumption in following up patients with thyroid nodules is that nodules with significant growth, detected through serial ultrasounds, are more likely to harbor cancer. A reduction in

the frequency of thyroid ultrasound assessment would lead to cost savings and provide a schedule that is concordant with the low risk of detecting a clinically relevant thyroid cancer. The study by Durante et al7 in this issue of JAMA documents the frequency and factors associated with thyroid nodule growth and demonstrates just how low the risk of detecting a thyroid cancer is during follow-up surveillance. The authors performed a prospective, observational study in 8 Italian centers. For study inclusion, participants had at least 1 thyroid nodule and no thyroid dysfunction, and they either had a benign fine-needle aspiration test result or did not meet criteria for aspiration due to size and sonographic characteristics. The 992 enrolled patients returned annually for 5 years for thyroid ultrasound evaluation, unless significant nodule growth occurred (defined as greater than 20% and at least 2 mm in 2 dimensions) or concerning sonographic characteristics appeared, defined as hypoechogenicity, irregular margins, taller-than-wide shape, intranodular vascularity, and microcalcifications, triggering fine-needle aspiration evaluation. In addition, patients who had enrolled after a benign test result at baseline were offered a second aspiration at year 5. A total of 63% of patients with a benign nodule at baseline had repeat aspiration performed during follow-up. Among the 1567 nodules in the 992 enrolled patients, significant nodule growth and detectable nodule shrinkage occurred at similar frequency, with nodule growth in 15.4% of patients and shrinkage in 18.5%. Thyroid nodule growth was independently associated with multinodular glands and younger age of diagnosis. Thyroid cancer was detected during follow-up in only 0.3% (95% CI, 0.0%-0.6%) of the originally detected nodules. Not surprisingly, with additional followup, there was additional nodule discovery, in 9.3% (95% CI, 7.5%-11.1%) of patients, 1 of which was subsequently found to be a thyroid cancer. This study has 4 important implications for the follow-up of thyroid nodules. First, these prospective data provide reassurance about the validity of a benign cytology result obtained by ultrasound-guided fine-needle aspiration and confirm a very low false-negative rate, at 1.1%.8 Second, the practice of routine sonographic surveillance with repeat fine-needle aspiration for growth, as recommended by published guidelines,4 is not the most efficient strategy to detect the very small number of missed cancers among previously sampled cytologically benign nodules. The one-size-fits-all approach simply does not work. Instead, surveillance strategies should be individualized based on a nodule’s sonographic appearance. All 4 missed cancers in the pre-


(Reprinted) JAMA March 3, 2015 Volume 313, Number 9

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Opinion Editorial

viously biopsied nodules were associated with 1 suspicious ultrasound feature: 3 nodules were solid and hypoechoic and 1 nodule had microcalcifications. None appeared spongiform or had a noncalcified mixed cystic solid composition, patterns associated with benignity.5,9,10 Hence, these data suggest that sonographic surveillance for detection of a missed malignancy is not indicated for cytologically benign nodules that lack any of the accepted suspicious sonographic features as described by the authors: hypoechogenicity, irregular margins, taller-than-wide shape, intranodular vascularity, and microcalcifications. Instead, only a subset of nodules with a prior benign cytology result, those with 1 of these suspicious features, may require sonographic surveillance with repeat fineneedle aspiration for either development of additional suspicious sonographic imaging characteristics or growth, corroborating recent studies.11,12 For this subset, repeat sonographic imaging may be considered at a minimum of 2 years, based on findings from Durante et al. Third, many nodules detected on ultrasound are small (ie, < 1 cm) and not sonographically suspicious. In fact, fifty-four percent of nodules followed up in this study were initially classified as benign not through fine-needle aspiration but because they were smaller than 1 cm and lacked suspicious sonographic features. How reliable is the absence of these features at predicting benign disease? The answer is excellent. In the study by Durante et al, only 1 cancer was diagnosed during follow-up among the 852 sonographically benign nodules that ARTICLE INFORMATION Author Affiliations: Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia (Cappola, Mandel); Associate Editor, JAMA (Cappola). Corresponding Author: Anne R. Cappola, MD, ScM, Division of Endocrinology, Diabetes, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Translational Research Center, 3400 Civic Center Blvd, Bldg 421, 12th Floor, Philadelphia, PA 19104-5160 ([email protected] .med.upenn.edu). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. REFERENCES 1. Mortensen JD, Woolner LB, Bennett WA. Gross and microscopic findings in clinically normal thyroid glands. J Clin Endocrinol Metab. 1955;15(10):1270-1280. 2. Hoang JK, Langer JE, Middleton WD, et al. Managing incidental thyroid nodules detected on


were smaller than 1 cm. Of note, the trigger for fine-needle aspiration for this nodule was development of hypoechogenicity and irregular margins, not growth. Current guidelines provide no guidance for follow-up of sonographically detected subcentimeter nodules that are not aspirated and only recommend aspiration of those associated with a suspicious imaging feature, sonographically suspicious lymph nodes, or a history of risk factors associated with thyroid cancer. Although the study by Durante and colleagues did not evaluate cervical lymph nodes, a study limitation, it suggests that regular sonographic surveillance for sonographically benign small (

Improving the long-term management of benign thyroid nodules.

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