Thyroid Cancer Rare in Patients With Asymptomatic Benign Nodules


Key Points

  • During 5 years of follow-up on 992 patients with one to four asymptomatic, sonographically or cytologically benign thyroid nodules, thyroid cancer was rare, occurring in just 0.3% of nodules.
  • Significant nodule growth was observed in 15% of the patients.
  • Nodule growth was associated with the presence of multiple nodules.

A prospective, multicenter, observational study involving 992 consecutive patients with one to four asymptomatic, sonographically or cytologically benign thyroid nodules found that “the majority of nodules exhibited no significant size change during 5 years of follow-up or they actually decreased in size,” and “thyroid cancer was rare,” occurring in just 0.3% of nodules. The authors of the study, published in JAMA, concluded, “These findings justify reconsideration of the current guideline recommendations for follow-up of asymptomatic thyroid nodules.”

Patients for the study were recruited at eight hospital-based thyroid disease referral centers in Italy between 2006 and 2008. The mean age of the patients was 42.4 years, 82% were women, and 42.6% had a family history of nodular thyroid disease. Yearly thyroid ultrasound examinations assessed baseline nodule growth, the primary endpoint.

“Size changes were considered significant for growth if an increase of 20% or more was recorded in at least 2 nodule diameters, with a minimum increase of 2 mm,” Durante et al explained. The secondary endpoints were sonographic detection of new nodules and the diagnosis of thyroid cancer during follow-up.

Nodule Size Changes Occurred Early

Data analyzed during the first 5 years of follow-up, through January 2013, showed that thyroid cancer was diagnosed in five original nodules, and only two of them had grown. An incidental cancer was found at thyroidectomy in a nonvisualized nodule. New nodules developed in 93 patients (9.3%), and one cancer was detected.

“Growth considered significant by American Thyroid Association standards was observed in only 15% of the patients,” the researchers reported. “Growth was slow, steady, and limited in magnitude, with a mean 5-year largest diameter increase of 4.9 mm, and which was generally restricted to the main nodule in patients with multinodular disease. Nodule size changes occurred early, starting from the 1-year follow-up visit.”

Growth Associated With Multiple Nodules

Nodule growth was associated with the presence of multiple nodules, with odds ratios (OR) of 2.2 for two nodules, 3.2 for three nodules, and 8.9 for four nodules. Other factors associated with nodule growth included nodule diameters of 7.5 mm or more and male gender. An age of 60 years or older was associated with a lower risk of growth than an age younger than 45 years. Nodules shrank spontaneously in 184 individuals (18.5%).

“Current guidelines suggest, based on expert opinion, repeating thyroid ultrasonography after 6 to 18 months and, if nodule size is stable, every 3 to 5 years,” the study authors noted. “The indolent behavior and limited growth observed in our study confirm that nodules that were benign based on initial fine-needle aspiration or subcentimeter and sonographically nonsuspicious can be safely managed with a second ultrasound examination 1 year after the first (early follow-up) and in the absence of changes, reassessment after 5 years (long-term follow-up). This approach should be suitable for 85% of patients, whose risk of disease progression is low. Closer surveillance may be appropriate for nodules occurring in younger patients or older overweight individuals with multiple nodules, large nodules (> 7.5 mm), or both.”

Four Important Implications

“Thyroid nodules are pervasive, whereas thyroid cancer is not. The findings from Durante et al represent an important step in improving the efficiency and mitigating the expense of follow-up for the vast majority of thyroid nodules that are either cytologically or sonographically benign,” according to an accompanying editorial by Anne R. Cappola, MD, ScM, and Susan J. Mandel, MD, MPH, of the Perelman School of Medicine at the University of Pennsylvania, Philadelphia. (Dr. Cappola is also an Associate Editor of JAMA.) They pointed out that the study has four 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%.”

“Second, the practice of routine sonographic surveillance with repeat fine-needle aspiration for growth, as recommended by published guidelines, 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.”

“Third, many nodules detected on ultrasound are small (ie, < 1 cm) and not sonographically suspicious. In fact, 54% 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.”

As the fourth and final implication, the editorialists noted that although 69% of the nodules remained stable in size, “size increase was not a harbinger of malignancy, especially if the nodule had no sonographically suspicious features.” They cited the “insights about predicting when growth is most likely to occur” provided by the investigators, such as multinodular glands, larger nodule size, and younger age. “An important consideration, however, was that the Italian population studied had mild-to-moderate iodine insufficiency, which could differ in thyroid nodule growth rates from iodine-sufficient populations, such as in the United States.”

Sebastiano Filetti, MD, of Università di Roma Sapienza, Rome, Italy, is the corresponding author of the JAMA article. Dr. Cappola is the corresponding author of the JAMA editorial.

The study was funded by grants from the Umberto Di Mario Foundation, Banca d’Italia, and the Italian Thyroid Cancer Observatory Foundation. The study authors reported no potential conflicts of interest.

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