Recommendations for Assessing Malignancy of Indeterminate Thyroid Nodules

When diagnosing and managing indeterminate thyroid nodules, both American Thyroid Association (ATA)-based ultrasound risk classification features and cytological subcategorization should be considered before making treatment recommendations and management decisions. This is according to research results published in Thyroid.

Researchers sought to evaluate and combine the ATA’s thyroid nodule ultrasound risk categories with the cytological subcategorizations of indeterminate thyroid nodules in order to evaluate the association with outcomes and malignancy rates. Study investigators hypothesized that the creation of uniform guidelines would result in a reduction of unnecessary surgeries and associated complications.

Investigators conducted a retrospective cohort study including 238 patients with indeterminate thyroid nodules at 2 centers in Brazil between 2016 and 2018. For each patient, ultrasound classification based on ATA guidelines and cytological subcategorization were determined, with 5 cytological subgroups: nuclear atypia related to papillary thyroid carcinoma, but insufficient to categorize as suspicious; architectural atypia without nuclear atypia; both architectural and nuclear atypia; oncocytic pattern without nuclear atypia; and nuclear atypia not related to papillary thyroid carcinoma.

The most frequently observed cytological subcategorization was nuclear atypia (62% of patients), while 13% had architectural and nuclear atypia. In 15% and 10% of cases, cytological patterns included oncocytic patterns and architectural atypia, respectively.

The overall prevalence of malignancy in this cohort was 39.5% (39.7% prevalence in Bethesda category III [BIII] nodules and 39.1% in Bethesda category IV [BIV] nodules). Among malignant lesions, 89.4% included papillary thyroid carcinoma and its variants. Patients with malignant nodules were younger (44.5±13.7 years) but had similar serum thyroid-stimulating hormone levels as patients with benign nodules.

Risk of malignancy was highest in the architectural and nuclear atypia subgroup, followed by the nuclear atypia subgroup. Comparatively, the oncocytic pattern subgroup had the lowest malignancy risk. Nuclear atypia presence in indeterminate specimens was both “positively and significantly associated with cancer risk,” according to researchers (odds ratio, 7.8; 95% CI, 2.3-27.1).

Within papillary thyroid carcinoma and its variants only, indeterminate nodules with nuclear atypia had a 7.6-fold higher malignancy risk compared with the reference group; a similar 7.5-fold association was found in a separate analysis of those with BIII nodules.

Researchers also examined ultrasound patterns in order to evaluate risk of malignancy according to ATA-based categories. Cancer odds in the ATA ultrasound low-risk nodules were lower than those in indeterminate nodules with an intermediate or high ultrasound-defined risk. Similar results were found when researchers stratified for papillary thyroid carcinoma and its variants. Malignancy prevalence in nodules with a “highly suspicious” ultrasound category based on ATA Criteria was 68.5% — significantly higher than indeterminate nodules with low-risk ultrasound patterns per the ATA.

“When combining ATA-based [ultrasound] classification with cytological nuclear findings, we found that the [risk of malignancy] in nodules with low-risk [ultrasound] features and with [nuclear atypia] remained at ~25%,” the researchers wrote.

Study limitations include referral bias due to the enrolled centers treating more complex, high-risk cancer patients compared with other centers as well as its retrospective design and the inability to confirm the analysis of all cytological samples by two pathologists.

“The risk of cancer in [indeterminate thyroid nodules] can rise and reach almost 80% when combined findings of [nuclear atypia] and ATA-based high-risk sonographic features are present,” the researchers concluded. “Our findings show that considering these criteria in combination can achieve a malignancy rate that confirms a high-risk subcategory of indeterminate nodules and supports a surgical approach for their treatment.”


Larcher de Almeida AM, Delfim RLC, Vidal APA, et al. Combining the American Thyroid Association’s ultrasound classification with cytological subcategorization improves the assessment of malignancy risk in indeterminate thyroid nodules. Published online December 10, 2020. Thyroid. doi:10.1089/thy.2019.0575