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Study of Natural History of Benign Thyroid Nodules Shows Only Rare Progression to Cancer

Kim, Meeri PHD

doi: 10.1097/01.COT.0000466408.71686.15


A new prospective, observational study of the frequency, magnitude, and factors associated with benign thyroid nodule growth during the first five years after diagnosis shows that any transition to thyroid cancer in such patients is rare.

The study, in the March 3rd issue of the Journal of the American Medical Association (2015;313:926-935), looked at 992 patients with one or more asymptomatic, sonographically or cytologically benign thyroid nodules from eight hospital-based thyroid-disease referral centers in Italy. Nodules were assessed for changes with yearly thyroid ultrasound examinations that reported overall size, baseline factors associated with growth, new nodule appearances, and thyroid cancer diagnosis.

The majority of nodules, 69 percent, remained stable in size throughout follow-up and exhibited no significant growth or shrinkage throughout follow-up. Even for those nodules that did grow bigger, the rate of size increase was extremely slow and had no bearing on whether they became malignant or not. Thyroid cancer was detected in only 0.3 percent of the original nodules.

Despite the fact that thyroid nodules are common in adults, the amount of evidence to guide long-term management—particularly those that appear benign upon initial evaluation—has been largely insufficient. For instance, current guidelines recommend reassessment of cytology if significant growth is observed, despite there being a previously untested connection between growing nodules and risk of malignancy.

These new results suggest that guidelines like these for benign thyroid nodule surveillance should be updated and reconsidered.

An unexpected side effect of improvements in medical imaging has been the detection of asymptomatic thyroid nodules during radiological evaluations that include the neck. In adult populations, the prevalence of thyroid nodules has been estimated to be 40 to 50 percent.

“What we now observe is an epidemic of thyroid nodules, especially in females,” said the study's senior author, Sebastiano Filetti, MD, Professor of Internal Medicine at Sapienza University of Rome.

“This is due mainly to the technique of detection—i.e., incidental findings—by using diagnostic imaging like CT scan and Doppler.”

Once nodules are discovered, a fine-needle aspiration biopsy for larger or sonographically suspicious nodules can separate out the benign from the malignant lesions. While the protocol for a malignant lesion is clear, the next steps are less obvious for those patients with a cytologically benign or sonographically nonsuspicious thyroid nodule. Current guidelines lack both precision and a strong basis of clinical evidence for how physicians should proceed in terms of follow-up, Filetti said.

Even though more than 90 percent of the detected nodules turn out to be clinically insignificant benign lesions, they can still incite anxiety in patients, particularly in light of repeated visits and testing.

Asked for her perspective, Louise Davies, MD, MS, Associate Professor of Surgery at the Geisel Medical School at Dartmouth, said: “One of the big issues is how do you follow these people, how much do you follow up, and when is it okay to stop looking? Previous guidelines have always seemed to me unsatisfying, that even a benign thyroid nodule should continue to be followed—it brings people into the medical system in a way that is not necessarily justified.”

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ATA Guidelines

The American Thyroid Association guidelines (Thyroid 2009;19:1167-1214) advise repeating thyroid ultrasonography after six to 18 months and if nodule size is stable, every three to five years. However, if significant growth has been observed, then the physician should reassess the nodule's cytology using fine-needle aspiration.

But some experts are not convinced that such follow-up is necessary.

“What do I do with this nodule? It's benign, but how many times in the next 10 years do I have to check—every six months? Every three?” Filetti said. “This was the motivation, to find out both for the patient and the physician in order to make strong points in the guidelines if nodules are benign.”



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Study Details

Filetti and his colleagues studied a total of 1,567 nodules from patients recruited between 2006 and 2008, who had an average age of 52.4, and 82 percent of whom were female. A significant growth/shrinkage consisted of at least a 20 percent increase or decrease (with a minimum of two millimeters in magnitude) in two or more nodule diameters.

For 184 of 992 patients (18.5%), a nodule shrank in size. In 153 out of 992 patients (15%), growth was seen in 174 nodules (11%) and was associated with the presence of multiple nodules, main nodule volumes larger than 0.2 mL, and being male.

“For the 15 percent for whom we found growth, does that mean it's dangerous? he asked. “No: the growth was really small, and the growing does not mean it's malignant,” he said. Growth of benign nodules was slow enough not to be detectable clinically, only by imaging. For example, the average largest diameter increase reported in the study was 4.9 mm over the five years.

Of the five original nodules later found to be cancerous (0.3%), only two had expanded in size during follow-up. All were first discovered by ultrasound, which suggests that surveillance could focus on this method of detection rather than performing a repeat fine-needle biopsy. In addition, new nodules were detected during follow-up in 93 patients (9.3%), including one cancerous lesion.

Summing up, Filetti said that that when a nodule is classified as benign, nothing more than a “soft follow-up” is called for. In other words, physicians can administer a second ultrasound examination one year later, and in the absence of changes, perform a reassessment after five years.

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Accompanying Editorial

In an accompanying editorial, Anne Cappola, MD, ScM, Associate Professor of Medicine in the Division of Endocrinology, Diabetes, and Metabolism at the Perelman School of Medicine at the University of Pennsylvania, outlined the importance of the study for shaping future guidelines on the follow-up of thyroid nodules.

She said that in particular, she hopes the findings will reduce unnecessary expense and resources dedicated to frequent follow-up for the vast majority of benign lesions that do not require that.



“It's really a matter of being more efficient in finding the ones you need to monitor closely and letting the ones go that you don't need to worry about,” she said in an interview.

The baseline ultrasound should be used to guide future surveillance of benign nodules on a case-by-case basis. If a worrisome sonographic feature is present—for example, hypoechogenicity, irregular margins, taller-than-wide shape, intranodular vascularity, or microcalcifications—then the patient may be followed more closely. If the baseline ultrasound is nonsuspicious, however, repeated and strict follow-up is likely inappropriate.

“It's an issue in terms of cost and inconvenience, but the big issue is patient worry,” Cappola said. “Patients don't understand how they could have this thing in their neck and not have it be a cancer.”

The data support the validity of a benign cytology result obtained by ultrasound-guided fine-needle aspiration, she continued. The test in this study had an extremely low false-negative rate of just 1.1 percent.

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‘Hard Evidence to Present to Patients’

Davies said she applauds the researchers for giving her hard evidence that she can present to her patients with benign thyroid nodules, particularly the ones worried about thyroid cancer.

“It was the low rate of cancer identification that really struck me most as a relief. Also, the fact that size increase was not a harbinger of malignancy, especially if the nodule wasn't sonographically suspicious—that's very reassuring. These are real things that you can take to your patients and say, ‘The likelihood that we're missing a cancer here is really low.’”

She also notes that the American Thyroid Association is in the midst of an overhaul of its guidelines, although it isn't clear whether these new results will be taken into account.

Overtesting by physicians, although often originating from a place of good intentions, can drive both heightened costs and patient anxiety. For instance, through her own research, Davies has discovered that physicians order multiple tests at once—such as inappropriate thyroid ultrasounds when all that was needed for the particular patient was a thyroid-stimulating hormone blood test (Laryngoscope 2010;120:2446-2451).

“Among my patients who are in other forms of cancer surveillance, even cancer survivors, they describe to me not being able to sleep well for days and weeks before their appointments, due to the anxiety that comes up with the waiting and the wondering. I think that's something we physicians underestimate.”

Also, she stressed that because thyroid nodules are so common, it may not be practical from a workforce standpoint to closely watch over that many individuals when the vast majority of nodules will remain benign.

Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
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