Majority of Benign Thyroid Nodules Do Not Grow Over Time and Cancer is Rarely Found

Introduction: Detection of asymptomatic thyroid nodules has become increasingly common, largely owing to detection of small incidentally discovered nodules. Consensus is lacking regarding the optimal follow-up of cytologically benign and sonographically nonsuspicious nodules.

Current guidelines from the American Thyroid Association (ATA) recommend serial ultrasound examinations and repeat cytology examination if significant growth in the nodule is observed. However, no reliable predictors of nodule growth have been identified. In addition, it is unclear whether nodule growth increases the risk for malignancy.

Methods: Researchers studied the frequency, magnitude, and factors associated with changes in thyroid nodule size. The study involved 992 patients (82% women; mean age, 52.4 years) with 1 to 4 asymptomatic, cytologically or sonographically benign thyroid nodules. Patients were recruited from 8 hospital-based thyroid disease referral centers in Italy between 2006 and 2008. Data collected during the first 5 years of follow-up through January 2013 were analyzed.

Results: The majority of patients (69%) showed no significant change in nodule size. Nodules decreased in size spontaneously in 184 patients (18.5%), with a mean reduction in the largest diameter of 3.7 mm and mean reduction in volume of 0.5 mL.

Significant nodule growth (ie, 20% increase ≥2 nodule diameters, with a minimum increase of 2 mm) occurred in 153 of the 992 patients (15.4%), many of whom had multiple nodules. Overall, 174 of the 1,567 original nodules (11.1%) increased in size. In multivariate analysis, nodule growth was associated with the presence of multiple nodules, main nodule volumes >0.2 mL, and male gender. Age ≥60 years was associated with a lower risk for growth compared with age <45 years. In women, multiple nodes, larger nodule volumes, and nulliparity were linked to nodule growth.

Thyroid cancer was diagnosed in 5 original nodules (0.3%), only 2 of which had grown in size. New nodules developed in 93 patients (9.3%), and cancer was detected in 2 of these new nodules.

Conclusion: After 5 years of follow-up, a majority of asymptomatic, benign thyroid nodules remained the same size or decreased. Diagnoses of thyroid cancer were rare in this study and occurred in 0.3% of original nodules.



Durante C, Costante G, Lucisano G, et al. The natural history of benign thyroid nodules. JAMA. 2015;313(9):926-935.

Commentary by Priyathama Vellanki MD

Dr. Priyathama Vellanki is an Assistant Professor, Division of Endocrinology, Metabolism and Lipids at Emory University School of Medicine in Atlanta, GA.

Thyroid nodules are common with an estimated prevalence of 37% in some autopsy series.1 Up to 10% are incidentally found.2 Of these, a vast majority of thyroid nodules are benign and only 5% are malignant.3 Many retrospective studies have shown that most thyroid nodules, which are initially benign, stay benign.4,5 However, the natural course of benign nodules has not been prospectively studied, and the ideal long-term follow-up is not known.

For benign nodules, the 2009 American Thyroid Association (ATA) guidelines recommend follow-up with thyroid ultrasound (US) every 6-18 months and to repeat fine-needle aspiration (FNA) if there is a significant change in nodule size.6 Significant change is defined as an increase of at least 2 mm, a 20% increase in 2 dimensions or a 50% change in volume. Also, it is currently unclear which nodules may grow and require more frequent monitoring.

This study by Durante et al is a large multi-center prospective study conducted in 8 hospital-based thyroid referral centers in 4 academic institutions in Italy. The authors examined the clinical course of benign nodules over a 5 year period. The study included 1567 nodules in 992 patients that were benign by cytology from FNA and also those that were benign by ultrasonographic features. Enrolled subjects underwent yearly follow-up thyroid US. Repeat FNAs were performed if there was a significant change in size of the nodule or if there was interval development of suspicious features such as microcalcifications, irregular margins, or other changes. In addition, patients with an initial benign cytology result were offered a repeat FNA at the end of 5 years if they did not need a repeat FNA within the 5 year period.

Results showed that in the majority of patients (69%) there was no change in nodule size over the 5 years. Eleven percent (11%) of nodules grew significantly as defined by the ATA guidelines in 15.4% of patients. Repeat FNA was performed in 365 patients; in 109 patients due to significant growth. Only 5 or 0.3% of the 1567 nodules had thyroid cancer in a nodule that was thought to be initially benign. Only 9.3% of these patients developed new nodules and only 2 of them developed thyroid cancer. In the nodules that showed thyroid cancer, there was no association with size at presentation or growth. In addition, the study also addressed predictors of thyroid nodule growth.

This confirms the results of most of the retrospective studies; benign nodules usually stay benign and the size of a nodule at presentation does not predict malignancy. This study also suggests that perhaps the change in nodule size shouldn't necessarily be a criterion for a repeat FNA. This study also brings into question the frequency of repeated surveillance thyroid ultrasounds in benign nodules.

The strengths of this study are it was prospectively conducted in a large number of people at multiple centers. Evaluation of the nodules was performed by a single experienced endocrinologist at each site throughout the study, therefore ensuring consistency. However, a weakness of this study was that it was performed in Italy, in areas where there is more iodine deficiency, which can cause thyroid abnormalities. Therefore, it may not be applicable to the general population. Nevertheless, this study demonstrates that thyroid cancer is rarely missed if initial cytology was benign. The study suggests guidelines be adjusted to include less frequent surveillance, which could lead to a decrease in the use of resources.

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