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

<b>Background/Objectives:</b> 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 (<i>TERTp</i>) mutations are known to be associated with aggressive disease, their exact prognostic significance when occurring alone or with other molecular alterations remains underreported. <b>Methods:</b> This study examined patients with thyroid cancer treated at two tertiary care hospitals from 2017 to 2024. We compared tumor behavior in patients with <i>TERTp</i> 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. <b>Results:</b> 30 patients with <i>TERTp</i>-positive thyroid malignancies were included. <i>TERTp/BRAF V600E</i> was the most prevalent mutation combination (<i>n</i> = 13, 43.3%), followed by <i>TERTp</i> alone (<i>n</i> = 8, 26.7%) and <i>TERTp/RAS</i> (<i>n</i> = 7, 23.4%). <i>TERTp/EIF1AX/GNAS</i> and <i>TERTp/EIF1AX/PIK3CA</i> were the least common combinations (<i>n</i> = 1, 3.3% each). Nodules with <i>TERTp</i> and concurrent mutations were significantly more likely to be classified as high-risk (<i>p</i> = 0.006) and were more frequently associated with aggressive histologic subtypes (<i>p</i> = 0.003) compared to those with <i>TERTp</i> mutations alone, which tended to exhibit more benign behavior. <b>Conclusions:</b> Thyroid carcinomas harboring both <i>TERTp</i> and concurrent molecular alterations are associated with more aggressive features and a higher likelihood of being classified as high-risk. In contrast, <i>TERTp</i> mutations occurring alone do not confer an elevated risk.