Malignant Nodules Can Be Identified by Their Location in the Thyroid

Nodules located in the thyroid isthmus are at greater risk of being malignant than those found in the lateral lobes, whereas those in the lower portion of the lobes are at least risk. Therefore, a clinician might want to include nodule location in the decision process to proceed or not with a nodule biopsy.

The prevalence of nodules on the thyroid seems to be increasing. A study out of Korea suggests that one in three individuals have thyroidal nodular growths1. They are more often found in women, in older populations, and cultures with widespread iodine deficiency1,2.

Few nodules are found through manual palpation. In contrast, though, ultrasounds are an accurate and cost-effective method for locating these growths. Despite the ubiquity of nodule presence in the population, when they are discovered, a patient's initial fear is malignancy.

Malignant nodules are found in about 10% of the total nodules found3-5. A procedure called Fine Needle Aspiration (FNA) is used to biopsy the nodule. FNA is a safe and straightforward procedure, yet it is still invasive. Because of this, some researchers have sought to find characteristics that can help determine the risk of a cancerous nodule, thus making the decision to have an FNA, or not, more reasonable.

The Current System: Summarizing the ACR-TIRAD

Currently, most clinics rely on the American College of Radiology's Thyroid Imaging Reporting and Data System (ACR-TIRAD) to decide if an FNA is warranted. The ACR-TIRAD uses ultrasound data and a point system based on nodule composition, echogenicity (nodule fluid content), shape, nodule margins, and echogenic foci (particulates within the nodule of differing echogenicity)6-8.

The total point value is divided into five levels, with TR1 and TR2 being the lowest. No recommendation for an FNA is advised at these levels. The need for an FNA at levels TR3, TR4, and TR5 is supported not only by the TIRAD points but by nodule size. The following are recommendations for FNA:

          TR3: 3 points, nodule size >=2.5 cm

          TR4: 4-6 points, nodule size >= 1.5 cm

          TR5: >7 points, nodule size >=1 cm

If a thyroid nodule meets the point level but not the size requirements, then the recommendation is follow-up. Overall, the accuracy of the ACR-TIRAD is high6-8, but there is another nodule quality that has been overlooked and may provide an easier path to the FNA decision.

Location is of critical importance

A recent study published in Thyroid looked at the risk of malignant nodules based on location in the thyroid4. Their specific aim was to determine if the location of a nodule made it more or less likely to be malignant. The thyroid was divided into four locations: isthmus, upper, middle, or lower portions of the thyroid lobe.

Note that this and other studies have found no differences between left and right side nodules3-5, so location data were collapsed across the two sides. Other variables included: gender, age, family history, and ACR-TIRAD measures. The study used multivariate regression modeling on retrospective ultrasound data from 3,241 nodules.

"This is a provocative study that used the same data sets that helped establish the ACR‐TIRAD," endorses endocrine expert, Bryan McIver, M.D., Deputy Physician-in-Chief, Department of Head and Neck, and Endocrine Oncology at the Moffitt Cancer Center.

Nodules in the isthmus are at greater risk

The regression model revealed that location was an independent predictor of malignancy. Meaning that when all other variables were held constant, such as the ACR-TIRAD score, where the nodules were found was significant. Nodules in the lower lobe were least at risk, a result confirmed by two earlier studies using smaller sample sizes3,5. Only 8.1% of nodules in the lower portion of the lobe were cancerous.

Using the lower lobe, then, as the reference, the odds ratios (OR) for the other three areas were calculated. Nodules found in the isthmus were 2.4 times more likely to be malignant than those in the lower lobe (OR= 2.4, 95% confidence interval (CI)= 1.6-3.6). This was followed by the upper portion with an OR of 1.9 (CI= 1.4-2.8), and the middle portion with an OR of 1.3 times (CI= 0.9-1.7). Thus, location without any other additional information can provide insight into the need for an FNA.  

Lead author Sina Jasim, M.D., Assistant Professor of Internal Medicine, Division of Endocrinology, Washington University School of Medicine, says this about their work: "The findings support the concept that thyroid tissue should not be considered homogenous, and may determine not only the propensity to form nodules but also risk of malignant transformation. Further research to help elucidate the pathophysiology of this observation is indicated."

The multivariate regression also confirmed previous expectations regarding thyroid nodules, such as gender and age, as independent factors. Despite women having a disproportionate number of nodules, men were at higher risk of having a cancerous nodule (OR= 1.8, CI= 1.4-2.5).

Malignancy risk also decreased with age. While older individuals had more nodules, they were also more likely to be benign (OR= 0.9, CI=0.97-0.98). Younger individuals had a slightly greater risk of malignant nodules.

The ACR-TIRAD, as expected, was also an independent predictor of malignancy, although nodule size was not. The prevalence of malignant nodules at each TIRAD level (TR1-TR5)  reported in the current study were similar to those reported elsewhere6,8.

The likelihood of malignant tumors increased with each TR level. Compared to TR1, the risk of a cancerous nodule in TR2 was 4.4 times more likely, 13 times greater in TR3, and at least 25 times more likely in TR4 and TR5. The interesting finding here was that when the TIRAD data was separated into its ultrasound components, nodule size was not an independent indicator of malignancy. Size contributed to the overall soundness of the regression model, but it could predict malignancy on its own.

Should location be added to the ARC-TIRAD score?

Because nodule location appears to be associated with malignancy risk, including location as a measure in the ACR-TIRAD assessment may elevate the accuracy of this tool. Unfortunately, the authors did not report the findings of a multivariate model based solely on these two variables. However, Dr. Jasim told EndocrineWeb the following:

 "It is recommended that isthmus nodule location be factored in when estimating the risk of thyroid cancer using current guidelines. Probably even a consideration should be given to adding a point to the current ACR-TIRADS guidelines for nodule location in the isthmus or using a lower size threshold for FNA or follow-up."

Dr. McIver's enthusiasm for the study is also tempered with some caution.  He states that "in large population‐based, retrospective studies, statistically significant patterns can emerge that may not be meaningful in the care of patients. A second confirmatory study, also based on a large population, is needed before a serious discussion about including nodule location in the ACR‐TIRAD could be had; a study to determine if the predictive value is more accurate with its inclusion. Location, as an objective ultrasound measure, might do this, especially if it were used in lieu of a more subjective measure, such as the degree of hypoechogenicity of the nodule, for example."

This latest large population study is a sound jumping-off point for additional investigations by researchers. For clinicians, it may be pointed out that nodule location is automatically part of the ultrasound exam. Noting its location, particularly if it is in the isthmus, might help clinicians in their decision to proceed or not with an FNA, especially when the ARC-TIRAD score falls into the more ambiguous levels TR2, TR3, and TR4.

The authors report no competing conflicts concerning their involvement in conducting or discussing this study.


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