Cytologically non-malignant thyroid nodules with three or more high-risk genetic mutations have poor outcomes.

Background: While traditional risk stratification for thyroid cancer primarily focused on tumor pathology, molecular profiling is increasingly recognized for its clinical relevance. There are limited data on tumors with three or more mutations, especially when presenting with non-malignant cytology. This study aims to evaluate the clinical behavior of cytologically non-malignant thyroid nodules with three or more potent oncogenic mutations. Methods: Electronic medical records of patients at our institution with thyroid nodules who underwent molecular testing were reviewed to identify cases with cytologically benign or indeterminate thyroid nodules that harbored three or more oncogenic mutations. Clinical, cytological, and molecular data were analyzed to assess tumor behavior. Results: Four of six cases were histologically malignant at index surgery. One histologically benign case developed distant metastases 7 years later. Retrospective analysis of the two histologically benign cases and the one case with low-risk histology demonstrated significant intratumoral heterogeneity. The benign case that developed distant metastases was found to have an area of intratumoral heterogeneity whose genetic profile matched the metastases. Conclusions: Despite bland cytological and ultrasonographic features, these tumors exhibited aggressive behavior. The molecular profile of thyroid cancers should be considered when determining treatment, especially in cases with multiple high-risk mutations, as they may behave more aggressively than predicted by cytology or imaging alone.