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

Introduction
Thyroid nodules with low thyroid-stimulating hormone (TSH) levels are rarely malignant (1), as TSH suppression is thought to limit the initiation and growth of thyroid cancer cells (2). Emerging evidence, however, shows that hyperfunctioning thyroid carcinoma can present as autonomous functioning thyroid nodules or as hyperfunctioning metastatic lesions (2). Fewer than 10% of individuals with differentiated thyroid carcinoma (DTC) develop distant metastases (3), and hyperfunctioning metastases occur in less than 1% (4). Although reports of hyperfunctioning metastases are increasing, cases involving high-grade differentiated thyroid carcinoma (HGDTC) remain exceedingly rare. Here, we report a case of HGDTC with an HRAS mutation in which hyperfunctioning metastases were identified through persistent thyrotoxicosis after total thyroidectomy and showed a marked response to radioiodine therapy.

Patient presentation
A 68-year-old woman presented with a recently enlarging thyroid nodule and multiple pulmonary nodules found on routine screening. She had been diagnosed with Graves’ disease three months earlier and was taking methimazole. She reported no respiratory or compressive symptoms—such as dyspnea, cough, sputum production, or dysphagia—and no thyrotoxic symptoms, including palpitations, heat intolerance, or weight loss. Chest radiography showed increased leftward tracheal deviation and new multiple lung nodules (Supplementary Figure 1B), compared with an image obtained 2 years earlier (Supplementary Figure 1A). While taking 7.5 mg of methimazole 7.5 mg daily, her thyroid function tests showed TSH 0.005 μIU/mL (reference range: 0.4–4.8), free T4 (fT4) 3.02 ng/dL (reference range: 0.8–1.71), T3 4.05 ng/mL (reference range: 0.6–1.6), and thyrotropin binding inhibitory immunoglobulin (TBII) 12.9 IU/L (reference range: 0–1.5). Thyroglobulin (Tg) was markedly elevated at 2, 253 ng/mL, with negative anti-thyroglobulin antibody (TgAb) and anti-microsome antibody (TPO Ab). Ultrasonographic (US) examination revealed diffusely hypoechoic thyroid parenchyma with decreased vascularity and a predominantly solid, isoechoic 4.0-cm nodule in the right thyroid lobe (Supplementary Figure 2). Fine-needle aspiration (FNA) performed elsewhere showed atypia of undetermined significance (AUS), prompting a core-needle biopsy (CNB), which demonstrated an indeterminate follicular lesion with architectural atypia. Chest computed tomography (CT) confirmed multiple pulmonary nodules, and positron emission tomography-computed tomography (PET-CT) showed fluorodeoxyglucose (FDG)-avid lesions in the right thyroid gland, both lungs, and the left iliac bone (Supplementary Figures 3A, 4). Although the CNB results were inconclusive, total thyroidectomy was performed because of the high suspicion for thyroid malignancy with distant metastases and to manage Graves’ disease. Pathology revealed HGDTC arising from widely invasive follicular thyroid carcinoma (FTC) (Supplementary Figure 5), with 5% tumor necrosis and a mitotic count of 5 per 10 high-power fields (HPF). Immunohistochemical staining was positive for thyroid transcription factor-1 (TTF-1), paired box gene 8 (PAX8), cytokeratin, Ki-67 (5%), cyclin D1, Tg, and BCL2. Next-generation sequencing (NGS) identified an HRAS gene mutation (p.Gln61Arg, c.182A>G) with a variant Allele Frequency (VAF) 42.25%.
After total thyroidectomy, she began levothyroxine (LT4) 100 µg daily but soon developed thyrotoxic symptoms. TBII remained elevated at 5.5 IU/L. Symptoms and laboratory evidence of thyrotoxicosis persisted despite dose reduction and eventual discontinuation of LT4. To treat suspected functional metastases, she received radioactive iodine (RAI) therapy at a dose of 150 mCi of I-131. The post-treatment whole-body iodine scan showed significant uptake in pulmonary nodules and the left iliac bone, consistent with metastatic disease (Supplementary Figure 6A). Following RAI therapy, Tg was 2, 790 ng/mL with negative TgAb, and TSH was 68.03 μIU/mL. Two weeks later, thyroid function tests indicated hypothyroidism (TSH 1.180 μIU/mL, fT4 0.39 ng/dL, and T3 0.61 ng/mL), and LT4 replacement was restarted at 50 µg and titrated to 125 µg to maintain TSH suppression below 0.1 μIU/mL. Six months later, she received an additional 200 mCi of RAI (I-131). The post-treatment iodine scan again showed significant uptake in iodine-avid lesions in both lungs and the left ilium (Supplementary Figure 6B), though less than before. At that time, Tg had decreased to 165 ng/mL; TgAb remained negative; TSH was 55.85 μIU/mL; and TBII had normalized. Over the following 6 months, after the second RAI therapy, serum Tg levels continued to decline, accompanied by a measurable reduction in pulmonary metastases on chest CT (Supplementary Figures 3 B, C).

Discussion
We present a case of HGDTC arising from HRAS-mutant FTC, complicated by hyperfunctioning lung and left iliac bone metastases that caused persistent thyrotoxicosis after total thyroidectomy and responded well to RAI therapy.
Several risk factors have been proposed to contribute to hyperfunctioning primary thyroid carcinoma and functioning metastases. Most reported hyperfunctioning primary thyroid carcinomas are FTCs, and about two-thirds of metastatic hyperfunctioning thyroid carcinomas are also FTCs (2, 4, 5). These patterns suggest that FTC is more likely than papillary thyroid carcinoma (PTC) to give rise to hyperfunctioning tumors, either as primary lesions or as metastases. Tumor size may also play a role, as mean tumor sizes in reported cases often exceed 4 cm (2, 5). In the setting of impaired autoregulation, a large primary or metastatic tumor may produce enough thyroid hormone to cause hyperthyroidism, which is consistent with our case (6). Although most autonomously functioning thyroid nodules are benign, malignancy should still be considered. Because many hyperfunctioning primary or metastatic thyroid carcinomas are follicular in origin, distinguishing follicular adenoma from FTC using FNA or CNB remains difficult, though these procedures can still support evaluation. In individuals who develop thyrotoxicosis after thyroid surgery, metastatic hyperfunctioning thyroid carcinoma should be considered, and whole-body scintigraphy with complementary imaging modalities is recommended to identify metastatic lesions (2).
Associations between gene mutations and the mechanisms driving hyperfunctioning thyroid carcinoma and its metastases have been explored and are summarized in Table 1. Activating mutations in the TSH receptor (TSHR) or guanine nucleotide-binding protein alpha s (Gsα) can stimulate cAMP signaling, increasing hormone production and leading to hyperthyroidism (7). Over the past three decades, numerous reports have described hyperfunctioning thyroid carcinoma harboring TSHR mutations, suggesting a pathogenic mechanism of this rare entity (7–17). Niepomniszcze et al. and Shinkai et al. demonstrated that concurrent activating mutations in TSHR and major oncogenic drivers (KRAS G12C or BRAF V600E) may jointly promote tumorigenesis and autonomous hormone production (14, 18). Another proposed mechanism is overexpression of 5-iodothyronine deiodinase (D2), which increases intratumoral conversion of T4 to T3 and may contribute to autonomous thyroid hormone production (4).
Activation of other oncogenes, including RAS, may also contribute to malignant transformation (19–23). RAS mutations activate the PI3K/AKT/mTOR and MAPK signaling pathways, both of which are central to thyroid carcinogenesis (24). In PTC, RAS mutations are typically associated with more indolent, follicular-patterned phenotype, including follicular variant PTC and NIFTP, with lower rates of extrathyroidal extension and lymph node metastasis, and better preservation of thyroid differentiation and radioiodine responsiveness compared with BRAF V600E–mutated tumors (19, 25). In FTC, RAS mutations are the most common genetic alterations, often involving codon 61 of NRAS or HRAS and codons 12 or 13 of KRAS (19). Although RAS mutations have been linked to increased risk of distant metastasis and disease-specific mortality, as reported by Riccio et al. (21), growing evidence suggests that many RAS-mutated DTCs may retain sodium-iodide symporter expression and radioiodine avidity (26). Supporting this, Mu et al. demonstrated that distinct mutational profiles underlie radioiodine uptake patterns, with BRAF and TERT promoter mutations predominating in RAI-refractory tumors. In contrast, most RAS-mutated tumors remain radioiodine-avid despite occasional late-stage loss of radioiodine uptake (9). These findings underscore the molecular heterogeneity of RAI-refractory DTC and suggest that RAS-mutated tumors may maintain relatively preserved responsiveness to radioiodine therapy, reinforcing the importance of mutation-informed treatment strategies.
Consistent with this, HRAS—unlike other RAS isoforms—can be selectively inhibited by farnesyltransferase inhibitors (FTIs). Tipifarnib has demonstrated preclinical antitumor activity in HRAS-driven thyroid malignancies, particularly when combined with MEK inhibitors, and clinical trials evaluating this approach are currently ongoing (27).
In conclusion, this case of HRAS-mutated HGDTC arising from FTC with hyperfunctioning metastases illustrates a rare but clinically important presentation that responded well to RAI therapy. Consistent with prior reports implicating other oncogenic mutations in hormone-producing metastatic disease, this case suggests that HRAS may also contribute to hormone overproduction through shared molecular pathways. Advances in molecular diagnostics may support more individualized treatment strategies that improve disease control while reducing treatment-related morbidity.