Clinical and Histopathological Features of Thyroid Cancer with Promoter Molecular Alterations in Isolation Versus with Concurrent Molecular Alterations: A Multicenter Retrospective Study.

Molecular testing of thyroid nodules enables the detection of genetic alterations, which can help assess the risk of malignancy and tumor behavior. While telomerase reverse transcriptase () mutations are known to be associated with aggressive disease, their exact prognostic significance when occurring alone or with other molecular alterations remains underreported. This study examined patients with thyroid cancer treated at two tertiary care hospitals from 2017 to 2024. We compared tumor behavior in patients with molecular alterations occurring alone and with concurrent molecular alterations. Aggressive histologic subtypes were defined as tall-cell, hobnail, and columnar variants of papillary carcinoma, as well as poorly differentiated and anaplastic carcinoma. High-risk disease was defined according to the 2015 ATA guidelines as gross extrathyroidal extension, lymph node metastasis >3 cm, postoperative elevated serum thyroglobulin, distant metastases, and/or positive resection margins. Statistical analysis was performed to assess differences between groups. 30 patients with -positive thyroid malignancies were included. was the most prevalent mutation combination ( = 13, 43.3%), followed by alone ( = 8, 26.7%) and ( = 7, 23.4%). and were the least common combinations ( = 1, 3.3% each). Nodules with and concurrent mutations were significantly more likely to be classified as high-risk ( = 0.006) and were more frequently associated with aggressive histologic subtypes ( = 0.003) compared to those with mutations alone, which tended to exhibit more benign behavior. Thyroid carcinomas harboring both and concurrent molecular alterations are associated with more aggressive features and a higher likelihood of being classified as high-risk. In contrast, mutations occurring alone do not confer an elevated risk.