Hyperfunctioning distant metastases in high-grade differentiated thyroid carcinoma arising from HRAS-mutated follicular thyroid carcinoma: a case report and literature review

Background: Hyperfunctioning distant metastases from differentiated thyroid carcinoma (DTC) are rare but increasingly reported. We report hormone-producing lung and bone metastases from an HRAS-mutated high-grade differentiated thyroid carcinoma (HGDTC) originating from follicular thyroid carcinoma (FTC), with a brief literature review. The metastases showed a marked response to radioactive iodine (RAI). Patient findings: A 68-year-old woman presented with an enlarging thyroid nodule and multiple pulmonary nodules after starting antithyroid therapy for Graves' disease. Histopathology confirmed HGDTC arising from FTC, and next-generation sequencing identified an HRAS Gln61Arg mutation. Thyrotoxicosis persisted after total thyroidectomy. A post-therapeutic whole-body radioiodine scan demonstrated iodine-avid pulmonary nodules and a left iliac bone lesion, consistent with hyperfunctioning distant metastases. Summary: After two RAI treatments, thyroid function shifted from hyperthyroidism to hypothyroidism, and follow-up chest computed tomography showed a significant reduction in pulmonary metastatic lesions. Conclusions: Hyperfunctioning distant metastases from DTC present diagnostic and therapeutic challenges. This case highlights the consideration of functioning metastases in persistent post-thyroidectomy thyrotoxicosis and demonstrates the potential effectiveness of RAI therapy when metastatic lesions retain iodine avidity. Oncogenic mutations such as HRAS may contribute to the pathophysiology of hormone-producing metastases and provide insights into tumor differentiation and therapeutic responsiveness.