Small Thyroid Tumors Pose Little Risk, Confirmed by Large Population Study

Duke University research team reported no need to biopsy thyroid nodules measuring less than 2.5 cm since there is no apparent effect on survival.

Interviews with Jenny Hoang, MBBS and Gary Clayman, MD, DMD

Thyroid cancer is a commonly diagnosed cancer with low mortality,1 raising the question of whether this condition results in overdiagnosis and unnecessary intervention. To examine this dilemma, Jenny Hoang, MBBS, of Duke University Medical Center and colleagues looked at tumor size and histology at the time of diagnosis to quantify the risk of metastasis and mortality.2

For this study, the Duke team used the Surveillance, Epidemiology, and End Results (SEER) 18 database to examine the probability of tumor extent at diagnosis.2 Specifically, they looked at tumor size and histology at the time of diagnosis to quantify the risk of metastasis and mortality.  The authors determined that increasing tumor size did not affect survival until a threshold of 2.5 cm2 was reached,2 as published in Thyroid.

No need to biopsy thyroid nodules of less than 2.5 cm as there is little risk of cancer.Thyroid nodules measuring less than 2.5 cm pose little risk to patients, and do not require intervention.

Determining the risk of various cancers has become a hotly debated topic of late. Issues such as how frequently to perform mammography or how early to start performing colonoscopies, and then when to perform biopsies for small thyroid tumors that may be discovered is still being determined.3,4

Assessing Nodule Size to Determine Course of Thyroid Cancer Care

In thyroid cancer, risk stratification systems using sonographic features and nodule size have become the newest strategies in considering the appropriateness of proceeding to biopsy.2 The lower limit for recommending a biopsy has been generally 1 cm because papillary microcarcinomas have an indolent clinical course.5 The size thresholds for low suspicion nodules may be even larger, with a range from 1.5 cm – 2.5 cm.2

Although the American Joint Committee on Cancer established size thresholds of 2 cm and 4 cm for T-staging for thyroid cancer, little research has been done in large populations to determine the accuracy of using tumor size for prognosis.2 Dr. Hoang et al used the SEER Program of the National Cancer Institute to examine the relationships between the tumor size of papillary thyroid carcinoma (PTC), follicular thyroid carcinoma (FTC) and other thyroid cancers on survival, T4 stage, nodal disease, and distant metastases.2

The SEER 18 database was queried to find cases of thyroid carcinoma with a year of diagnosis from 2004-2014, known age, tumor size between 1 mm and 150 mm, and malignant behavior.2 112,128 patients met the inclusion criteria.2 Using the International Classification of Diseases for Oncology, 3rd Edition, cases were subdivided by histology for papillary carcinoma (89% of tumors included), follicular carcinoma (8%), with the remainder being mostly medullary and anaplastic thyroid carcinomas.2

In most cases, tumor sizes were taken from surgical pathology reports, with a small number from imaging or noninvasive clinical evidence.2 Regional nodal disease (N1 status), distant metastases (M1 status), and status of advanced tumor stage (T4) were also recorded.

Influence of Nodule Size for Thyroid Carcinoma

In papillary thyroid carcinoma (PTC), the risk of T4—advanced locally invasive cancer—increases linearly as the primary tumor size increases without a threshold effect.2 In follicular thyroid carcinoma (FTC), the probability of T4 increases almost linearly once the tumor is 4 cm in size.

“That data suggest that when the tumor is less than 2.5 cm, the probability of local invasion is less than 5% for PTC and 1% for FTC, meaning the risks for T4 stage are low for both types of cancer,” said Dr. Hoang.

The risk of N1 status, regional nodal disease, showed a linear increase for primary tumors 0 – 2 cm in PTC and non-DTC cancers.2 Above this size, there was a plateau effect. The maximum probability for N1 status was slightly below 40% for PTC. Below a tumor size of 5 cm, FTC had an extremely low risk of N1 status, and even above 5 cm is less than 20%,2 according to the findings.

Finally, the risk of M1 status showed no threshold effect, with low, gradual increases in probability as tumor size increased.2 For non-DTC histologies, the probability of distant metastases increased quickly with tumor size increases.

Assessing Effect of Tumor Size on Patient Survival

The authors used a multivariate Cox regression model to show the effect of tumor and patient characteristics on survival. The significant findings from this analysis showed several things:

  •  Non-DTC histologies show an elevated hazard ratio compared to the baseline scenario of PTC (1.04; p = 0.34)
  • Regional nodal disease shows statistically significant elevated hazard ratios (1.1-1.4)
  • Patients with distant metastases also have elevated hazard ratios, ranging from 1.63 (p = 0.01) to 6.17 (p < 0.000001) in patients with distant lymph node metastases or both distant nodal and non-nodal metastases, respectively.

The authors found that all-cause mortality risk does not exceed the baseline in terms of the size of the tumor until it reaches 2.5 cm. Above this threshold, partial hazard ratios increase linearly with log size, with partial hazards being 10% and 20% above baseline when tumors were 3.1 cm and 3.7 cm, respectively.

“Our study correlated primary tumor size with all-cause mortality and found very little change in mortality until tumor size exceeded 2.5 cm. This suggests that increasing the size cut-off for biopsy to 2.5 cm is unlikely to result in an abrupt increase in cancer-related deaths,” Dr. Hoang told EndocrineWeb.

She added, “it seems excessive that several thyroid societies recommended biopsy of low suspicion solid thyroid nodules at a 1.5 cm threshold. The risk of the low suspicion nodule being malignant is less than 5%, and even if the nodule is malignant, it would unlikely be aggressive.”

Gary Clayman, DMD, MD, who was not associated with the study, told EndocrineWeb, “the study findings do not warrant a guideline change, at least not yet. The paper does not address the potential morbidity risks such as the ability to spare normal thyroid tissue and maintain wellness, that the risk of surgery may increase with increasing tumor size, and the potential for lymph node metastases increases with tumor size and is known to be correlated with increased operative morbidity.”

Dr. Hoang fended of the criticism saying, “in fact, the American College of Radiology has already moved to a 2.5 cm threshold.6 Their risk stratification system known as ACR TI-RADS was published in 2017 and has a 2.5 cm threshold for biopsy of TI-RADS 3 nodules (solid nodules with no other suspicious features). With more research, there may even be the opportunity to move to a 3 cm size threshold.”

Continue Reading:
How Might Molecular Testing Advance the Care of Patients with Thyroid Nodules Looking to Avoid Unnecessary Surgery?
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