Serum thyroglobulin (Tg) levels increase with follicular cell mass and are considered a surrogate marker of tumor burden in thyroid cancer. However, markedly elevated preoperative Tg levels may occur in benign thyroid conditions, limiting their clinical interpretation. This study evaluated the clinical significance of markedly elevated preoperative Tg after excluding major benign contributors.

Patients who underwent thyroid surgery for papillary thyroid cancer (PTC) or benign thyroid disease from 2019 to 2025 were reviewed. Cases with preoperative Tg ≥500 ng/mL were analyzed, with additional analysis at ≥1000 ng/mL. Tumor size, distant metastasis, additional nodules >2 cm, and diffuse thyroid disease (DTD) were assessed.

Among 17,187 patients with PTC and 1,552 with benign thyroid disease, Tg ≥500 ng/mL was observed in 197 and 153 patients, respectively. In PTC, distant metastasis was present in 5.7% of tumors >4 cm, 5.3% of tumors >2–4 cm, and 2.0% of tumors ≤2 cm. In tumors ≤2 cm, elevated Tg was frequently accompanied by potential benign contributors: 45.1% had an additional nodule >2 cm and 29.4% had DTD. In benign disease, elevated Tg was mainly associated with large multinodular lesions or DTD; all patients with lesions ≤2 cm or no focal nodule had DTD. After adjustment for age and sex, absence of both additional nodules >2 cm and DTD was independently associated with advanced PTC, defined as tumor size >4 cm or distant metastasis (adjusted odds ratio 4.88, 95% CI 2.05–11.64; p<0.001). Similar patterns were observed at Tg ≥1000 ng/mL.

Markedly elevated preoperative Tg levels are not cancer-specific and frequently reflect large benign nodules or DTD. After excluding these contributors, markedly elevated Tg may raise suspicion for substantial malignant disease burden and should prompt thorough structural evaluation. These findings support an exclusion-based interpretation of preoperative Tg rather than its use as a standalone diagnostic marker.