BACKGROUND
Thyroid nodules are very common, occurring in up to 50% of the population. The concern about any thyroid nodule is whether it is a cancer. Overall, only 5-6% of thyroid nodules are cancer. The best way to determine of a nodule is cancer is to perform a thyroid biopsy. When a patient has a thyroid biopsy, there are 6 potential categories for the result based on their increasing risk of being cancer. These categories are the Bethesda scoring system. Bethesda I is non-diagnostic, meaning there are not enough cells to make a diagnosis, and Bethesda II is a benign result. Bethesda III and IV are atypical results in that the cells are not normal or abnormal. Bethesda V is suspicious for thyroid cancer and Bethesda VI is most likely to be thyroid cancer.

Overall, 20% thyroid nodule biopsies will fall into the Bethesda III or IV category, giving a risk of cancer ranging from 15-35%. The risk of cancer for Bethesda V biopsies is 65-74% and the risk of cancer in Bethesda VI biopsies is 94-97%. There are no long-term studies on how cancers in each of these Bethesda categories behave. The aim of the study is to separate cancers into categories based on their initial Bethesda category and monitor how each of the cancer in each category behaves.

THE FULL ARTICLE TITLE
Endo M et al. Indolent behavior of malignant Bethesda III nodules compared to Bethesda V/VI nodules. J ClinEndocrinol Metab 2024;109(9):2317-2324; doi: 10.1210/clinem/dgae108. PMID: 38415340.

SUMMARY OF THE STUDY
At a single hospital, all thyroid nodules biopsied and categorized as Bethesda III, IV, V, and VI in adults that were later found to be cancer were analyzed from 2007 to 2018. Small (<0.5 cm) thyroid cancers initially biopsied as Bethesda III or IV and medullary thyroid cancers were not considered in the study. Out of 556 cases, 69% of the patients were women, the average age was 48.4 years, and the Bethesda categories were spread out as follows: 87 Bethesda III, 109 Bethesda IV, 120 Bethesda V, and 240 Bethesda VI.

Bethesda categories III, IV, and VI were more likely to contain papillary thyroid cancer than Bethesda category V. Having more than one area of cancer in the sample and having a BRAF V600e genetic mutation was also more likely in Bethesda categories III, V, and VI as compared to Bethesda category IV. A mutation called NRAS seemed more likely to be found in Bethesda IV than Bethesda III biopsied nodules, but it was not an obvious enough difference to be significant.

Compared to the Bethesda III category, the Bethesda V and VI biopsied nodules were more likely to undergo a total thyroidectomy, have a more advanced cancer, including spread to the lymph nodes, invasion beyond the thyroid capsule, and an increased rate of recurrence after the initial treatment. The Bethesda V and VI nodules were less likely to ever be in a state where there was no evidence of disease compared to Bethesda III. Although Bethesda IV nodules were more likely to have spread into the lymphatic and blood vessels than Bethesda III nodules, otherwise there was no difference in cancer staging, extension beyond the thyroid capsule, likelihood of receiving radioactive iodine treatment, recurrence rate after initial treatment, spread to lungs or bones, or likelihood of dieing.

When comparing Bethesda categories III and IV to Bethesda categories V and VI, the latter group was more likely to have lymph node spread, multiple areas of cancer within the surgical sample, extension beyond the thyroid capsule, likelihood of having the BRAF V600e gene mutation, and spread to the lungs and bones. The Bethesda V and VI categories were less likely to ever be in a state where there was no evidence of disease compared to Bethesda III and IV categories. Only 7 out of the 87 Bethesda III category nodules eventually contained cancer that spread into the neck, lung, or bones after initial treatment, and all seven patients had thyroid nodules measuring larger than 2.5 cm. Overall, 2 of these 7 patients already had spread to the lungs and bones when the nodule was biopsied as Bethesda III category.

WHAT ARE THE IMPLICATIONS OF THIS STUDY?
This study suggests that thyroid cancers with initial Bethesda III biopsies are less likely to be aggressive cancers having extension beyond the thyroid capsule, spread to the lymph nodes, and more likely to achieve a state with no evidence of disease compared to Bethesda V and VI nodules. As such, if a patient has a nodule that has a Bethesda III biopsy, particularly it measures less than 2.5 cm, active surveillance (watching the nodule with ultrasound without surgery) or less aggressive initial treatment could be considered. This is an important finding and helps physicians and patients to determine the best treatment option for an individual patient.

— Pinar Smith, MD

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