Prevalence and Predictors of Incidental Thyroid Carcinoma in Patients With Graves' Disease Undergoing Thyroidectomy.

Graves' disease (GD) is the most common cause of hyperthyroidism, affecting approximately 0.5% of the US population.

While definitive treatment often involves radioactive iodine (RAI) or antithyroid drugs (ATDs), thyroidectomy is increasingly utilized, especially for patients with large goiters, compressive symptoms, coexisting suspicious nodules, or contraindications/failure of other therapies.

However, numerous studies over the past few decades have challenged this notion, reporting varying rates of incidental thyroid carcinoma (ITC) discovered in thyroidectomy specimens from GD patients. Understanding the true prevalence and identifying predictors of incidental thyroid cancer (ITC) in this population is crucial for appropriate patient counseling, surgical decision-making, and determining the optimal extent of thyroidectomy.

Identifying factors associated with an increased risk of incidental thyroid cancer in GD patients could help stratify risk and guide management. Several potential predictors in literatures reviews have been investigated, with some conflicting results:

• Presence of Nodules: The presence of thyroid nodules within the diffuse goiter of GD is a consistently reported risk factor for ITC.
• Age: Some studies suggest older age is a risk factor. However others, identified younger age as a predictor. This discrepancy requires further investigation.
• Sex: Male sex has been identified as a risk factor in some studies, although GD is much more prevalent in females.
• Body Mass Index (BMI): patients with cancer had a higher BMI.
• Thyroid Autoantibodies and Thyroglobulin: thyroid peroxidase antibodies (TPOAbs), thyroglobulin antibody(TgAbs), and thyroglobulin(Tg) levels but found no statistically significant differences between benign and malignant groups in their cohort undergoing total thyroidectomy for benign diseases. The role of specific GD-related antibodies (e.g., thyroid-stimulating hormone (TSH) receptor antibodies) as predictors requires further study.

The study will enroll approximately 280 patients , utilizing standardized data collection (demographics, clinical history, laboratory, imaging and operative data) and pathological examination protocols. The primary outcome is the prevalence of incidental thyroid cancer (ITC), secondary outcomes including predictors and histopathological characteristics.

Inclusion criteria

• Age 18 years or older.
• Confirmed diagnosis of Graves' disease based on clinical features (e.g., diffuse goiter, ophthalmopathy if present) and biochemical evidence (suppressed TSH, elevated free T4 and/or T3) and/or positive TSH receptor antibody (TRAb) test.
• Indication for total thyroidectomy for Graves' disease, based on established guidelines:

Relapse or persistence of hyperthyroidism after a course of antithyroid drugs (ATDs).

Intolerance or adverse reaction to ATDs. Patient preference for surgery over radioactive iodine (RAI) or long-term ATDs. Presence of a large goiter causing compressive symptoms. Coexisting suspicious thyroid nodule(s) on preoperative evaluation. Moderate to severe active Graves' ophthalmopathy where RAI is relatively contraindicated.

• Patient is scheduled for total thyroidectomy (near-total or subtotal thyroidectomy patients will be excluded).
• Ability and willingness to provide written informed consent.
• Ability to understand study procedures and requirements.

Exclusion criteria

• Age less than 18 years.
• Previous thyroid surgery.
• Previous neck irradiation.
• Preoperative diagnosis of thyroid malignancy confirmed by fine-needle aspiration (FNA) cytology (Bethesda V or VI) , the focus is on incidental carcinoma.
• Inability to provide informed consent (e.g., due to cognitive impairment).
• Patients undergoing thyroidectomy primarily for reasons other than Graves' disease (e.g., primary indication is large non-toxic MNG).
• Patients undergoing less than total thyroidectomy (e.g., lobectomy, subtotal thyroidectomy).