MON-413 - When Do Markedly Elevated Preoperative Thyroglobulin Levels Suggest Malignancy? an Exclusion-Based Analysis

Background: Serum thyroglobulin levels increase with expanding follicular cell mass and are frequently interpreted as a surrogate marker of tumor burden in thyroid cancer. However, markedly elevated preoperative thyroglobulin levels can arise from heterogeneous disease contexts, including both malignant and benign thyroid conditions, complicating their clinical interpretation.

Objectives: To characterize the clinicopathological contexts associated with markedly elevated preoperative serum thyroglobulin levels in patients with papillary thyroid cancer and benign thyroid disease, and to assess their potential clinical utility after exclusion of major benign contributors.

Methods: From 2019 to 2023, patients who underwent thyroid surgery for papillary thyroid cancer or benign thyroid disease were analyzed, focusing on cases with preoperative serum thyroglobulin levels ≥500 ng/mL. Tumor size, presence of distant metastasis, additional nodules, and diffuse thyroid disease (DTD) were evaluated. Subgroup analyses were performed according to lesion size categories and higher thyroglobulin thresholds (≥1000 ng/mL).

Results: Among 13,093 patients with papillary thyroid cancer and 1,197 patients with benign thyroid disease, a subset of patients (147 and 130, respectively) exhibited preoperative serum thyroglobulin levels ≥500 ng/mL. Among the 52 patients with tumors >4 cm, distant metastasis was observed in 4 (8%), 3 (6%) had an additional nodule >2 cm, and 2 (4%) exhibited diffuse thyroid disease (DTD). Among the 57 patients with tumors >2 cm but ≤4 cm, distant metastasis occurred in 4 (7%), 6 (11%) had an additional nodule >2 cm, and 5 (9%) exhibited DTD; two patients had both conditions. Among the 38 patients with tumors ≤2 cm, distant metastasis was observed in 1 (3%), whereas 20 (52%) had an additional nodule >2 cm and 10 (26%) exhibited DTD; two patients had both conditions. In benign thyroid disease, among 75 cases with multinodular lesions >4 cm, 2 (3%) exhibited DTD; among 16 cases with lesions >2 cm but ≤4 cm, 4 (25%) exhibited DTD; and among 39 cases with lesions ≤2 cm or no focal nodule, all patients (100%) exhibited DTD. Similar distribution patterns were observed in patients with preoperative thyroglobulin levels ≥1000 ng/mL.

Conclusion: Markedly elevated preoperative thyroglobulin levels are not cancer-specific and frequently reflect large benign nodules or diffuse thyroid disease. However, when these major benign contributors are excluded, markedly elevated thyroglobulin levels may raise clinical suspicion for substantial malignant disease burden and warrant thorough structural evaluation. These findings support an exclusion-based approach to the clinical interpretation of preoperative thyroglobulin levels rather than their use as a standalone diagnostic marker.

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