No Link Between Size of Thyroid Nodule and Cancer Risk

Nancy A. Melville

July 25, 2018

Large solitary thyroid nodules of indeterminate nature show no increased risk of being malignant or aggressive compared with smaller nodules and can be safely diagnosed with an initial thyroid lobectomy, according to new research.

"The take-home message is that most malignancies among indeterminate thyroid nodules are low-risk regardless of tumor size, thus, size should not be driving more aggressive diagnostic surgeries for cytologically indeterminate thyroid nodules," first author Pablo Valderrabano, MD, PhD, told Medscape Medical News.

"A lobectomy should be the default surgical management for cytologically indeterminate thyroid nodules larger than 4 cm in the absence of other indications for total thyroidectomy," said Valderrabano, a postdoctoral fellow in the Department of Head and Neck–Endocrine Oncology at H. Lee Moffitt Cancer Center and Research Institute in Tampa, Florida.

Valderrabano and colleagues note that more than 60,000 unnecessary thyroid surgeries are performed each year to diagnose cytologically indeterminate thyroid nodules, often based on concerns about a large size, generally larger than 4 cm. The practice is supported by American Thyroid Association guidelines (Thyroid. 2016;26:1-133), which currently indicate that total thyroidectomy may be a preferred approach for indeterminate nodules larger than 4 cm.

For the study, published online July 19 in JAMA Otolaryngology-Head & Neck Surgery, Valderrabano and colleagues analyzed results from 652 indeterminate thyroid nodules from 589 patients who were evaluated at their facility between October 2008 and April 2016.

Of the nodules, 546 were smaller than 4 cm and 106 were 4 cm or larger. There were no significant differences in baseline characteristics between patients or nodules in the two groups.

Moreover, there were no significant differences in the rate of malignancies between the nodules smaller than 4 cm group (140 of 546; 26.5%) and 4 cm or larger (33 of 106; 31.1%).

Of tumors that were malignant, most were low risk in both groups, including 70% of nodules in the less than 4 cm group and 72% of those 4 cm or larger.

In addition, when size was analyzed as a continuous variable, the researchers saw no increased risk of the nodule being cancerous with increasing size (odds ratio, 1.03; 95% CI, .92 – 1.15) or with aggressiveness of the cancers that were found.

Nodule size was furthermore not significantly associated with extrathyroidal extension, positive margins, lymph node metastasis, or distant metastasis. A weak association was observed between the presence of distant metastasis and larger malignant tumors (effect size, 0.16; 95% CI, 0.01 – 0.30).

Tumor size was furthermore not associated with a response to therapy (effect size, 0.13; 95% CI, 0.07 – 0.33), and as of the most recent follow-up visit, 83.8% (88 of 105) patients with malignant tumors in the smaller than 4 cm group had no evidence of disease, as did 84.0% (21 of 25) of those in the 4 cm or larger group.

Should Nodule Guidelines Be Updated?

The findings come in the wake of a recent major shift in the approach to indeterminate thyroid nodules, with some nodules reclassified in an effort to reduce unnecessary diagnostic thyroidectomies.

With strong evidence of the indolent nature of most thyroid cancers, nodules that once met criteria as encapsulated follicular variant of papillary thyroid carcinomas (EFVPTC) are now classified as noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). The shift means that nearly 40% of the indeterminate thyroid nodules that would previously have been classified as cancer are now considered premalignant and are sufficiently treated with a diagnostic lobectomy.

Under the previous criteria, of the 652 nodules examined in the current study, 173 (26.5%) would have been histologically malignant, but under the new criteria, only 114 (17.5%) are considered malignant.

Either way, the new findings suggest that tumor size does not increase the risk in indeterminate nodules.

"Unlike what has been traditionally thought, we found no differences in the risk of cancer, or even the aggressiveness of the cancers, finding that more than 90% of the cytologically indeterminate thyroid nodules were either benign or low risk cancers (including NIFTPs) for which a lobectomy would be sufficient initial treatment, regardless of tumor size," Valderrabano said.

"Moreover, size was not associated with response to therapy, with nearly 85% of the malignant tumors in both groups having excellent response (no evidence of disease) at last follow up visit."

Evidence shows that most nodules initially classified as being indeterminate do commonly turn out to be low risk, and Valderrabano said that distinction should be underscored.

"It is important to stress that the type of malignancies that are found among thyroid nodules with cytologic diagnosis of malignancy (Bethesda VI) are different from the malignancies that are found among thyroid nodules with indeterminate cytology," he explained.

"Whereas in the former we typically find classical variant papillary thyroid cancer, the most common type of thyroid cancer, in the latter (indeterminate nodules) we find follicular pattern malignancies or 'borderline' lesions, most frequently encapsulated follicular variant papillary thyroid carcinomas, many of which are noninvasive thus qualifying for NIFTP diagnosis, and minimally invasive follicular thyroid carcinomas."

He continued, "Clinicians are becoming increasingly aware of this difference and our results suggest that it holds true for larger tumors too."

With research showing the complication rate of thyroid lobectomies to be nearly half that of total thyroidectomies (11% vs 20%), the findings are important, Valderrabano said. "The data that we present in this manuscript are quite compelling," he said.

"Probably other studies will need to confirm that these results are reproducible in other institutions before the ATA guidelines are modified. However, we think that a treatment de-escalation in the management of indeterminate thyroid nodules is necessary and in the line of what has been proposed for differentiated thyroid cancer in the last iteration of the guidelines," he continued.

"We would support a change in that same direction for indeterminate thyroid nodules in the next iteration of the guidelines."

In a commentary published with the findings, Kepal N. Patel, MD, and Hunter J. Underwood, MD, of the Division of Endocrine Surgery, Department of Surgery, at NYU Langone Medical Center, agree that the study contributes important evidence following the reclassification of thyroid nodules.

"Valderrabano and colleagues conducted a well-timed study investigating the association of nodule size with clinical and pathologic outcomes in patients with cytologically indeterminate lesions in the NIFTP era," they said.

"With these data, the authors suggest that thyroid lobectomy is sufficient initial surgical management for indeterminate thyroid nodules regardless of size, directly challenging the most recent American Thyroid Association guidelines."

In light of the shifting classification for indeterminate cytology and emerging evidence on larger nodule size, some research conclusions may even need to be reconsidered, the commenters suggested.

"Of most importance, studies drawing conclusions regarding cancer and aggressive potential of indeterminate thyroid nodules before the NIFTP paradigm shift must be viewed in context and possibly revisited."

The study was funded, in part, by a grant from the Biostatistics Core Facility at the H. Lee Moffitt Cancer Center and Research Institute. The study and commentary authors have reported no relevant financial relationships.

JAMA Otolaryngol Head Neck Surg. Published online July 19, 2018. Abstract, Commentary

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