How should a large thyroid nodule be evaluated and managed, including work‑up, treatment for compressive symptoms, hyperthyroidism, and potential malignancy?

Management of Large Thyroid Nodules

For a large thyroid nodule, begin with serum TSH measurement to determine the diagnostic pathway, followed by thyroid ultrasound with central neck evaluation; if TSH is low, proceed to radioiodine uptake scan to identify hyperfunctioning nodules that rarely require biopsy, but if TSH is normal or elevated, use ultrasound features to guide fine-needle aspiration biopsy decisions, with surgery indicated for malignancy, compressive symptoms, or progressive growth. 1, 2

Initial Diagnostic Algorithm

Step 1: Thyroid Function Assessment

• Measure serum TSH first as it is the single best initial test and determines all subsequent management 1, 2
• If TSH is low or suppressed: proceed directly to radioiodine uptake scintigraphy to identify hyperfunctioning ("hot") nodules, which are rarely malignant and do not require fine-needle aspiration 1, 2
• If TSH is normal or elevated: proceed to ultrasonographic evaluation without radionuclide scanning 1, 2
• Do not routinely measure serum calcitonin in all patients, though it may be considered if medullary thyroid carcinoma is suspected 2

Step 2: Ultrasonographic Evaluation

• Perform thyroid ultrasound of the thyroid and central neck in all patients with palpable thyroid nodules 1, 2
• Lateral neck ultrasonography may also be performed to assess for lymphadenopathy 1, 2
• Ultrasound is superior to CT or MRI for characterizing nodules, as cross-sectional imaging cannot differentiate benign from malignant nodules unless there is gross invasion or metastatic disease 3

Risk Stratification Based on Ultrasound Features

High-Risk Sonographic Features Requiring FNA

The following ultrasound characteristics are suspicious and warrant fine-needle aspiration biopsy regardless of size 1, 2:

• Microcalcifications (highly suspicious for malignancy) 1, 2
• Central hypervascularity 1, 2
• Taller-than-wide shape 1, 2
• Irregular margins 4
• Hypoechoic appearance 4

Clinical Risk Factors That Lower FNA Threshold

High-risk clinical features that should prompt earlier intervention include 2:

• Age <15 years or male sex 1, 2
• History of radiation exposure to the head and neck 1, 2
• Family history of thyroid cancer or associated syndromes (MEN 2A/2B, familial adenomatous polyposis, Carney complex, Cowden's syndrome) 2
• Nodule that is firm, fixed, or rapidly growing 2
• Presence of cervical lymphadenopathy 1, 2
• Vocal cord paralysis or symptoms of invasion 2

Management Based on Findings

Indications for Surgical Intervention

Surgery is the definitive treatment and is indicated for 5, 6:

• Confirmed or suspected malignancy on FNA 6, 4
• Compressive symptoms including dyspnea, orthopnea, obstructive sleep apnea, dysphagia, or dysphonia 3, 6
• Progressive growth: nodules increasing by ≥2 mm within 1 year or volume increase of ≥50% 5
• Cosmetic concerns in select cases 6

Total or near-total thyroidectomy is the most radical procedure that achieves cure, avoids future reoperation, and facilitates postoperative management if malignancy is present 6. Partial thyroidectomy (hemithyroidectomy) is appropriate for unilateral nodules and preserves thyroid function 5.

Alternative Treatment Options

For Hyperfunctioning Nodules

• Radioiodine therapy may be used for management of hyperfunctioning ("hot") thyroid nodules identified on scintigraphy 6, 7

For Benign Nodules with Symptoms

• Thermal ablation (radiofrequency ablation or microwave ablation) is a minimally invasive alternative for benign nodules causing clinical symptoms, cosmetic concerns, or maximum diameter ≥2 cm, while preserving thyroid function 1
• Percutaneous ethanol injection (PEI) should be first-line treatment for relapsing benign cystic lesions 8

For Presumed Benign Nodules Without Symptoms

• Simple observation is acceptable for presumably benign thyroid nodules without suspicious features 6, 4
• Levothyroxine suppressive therapy is not recommended 8

Follow-Up Protocol

For Nodules Under Surveillance

• Initial follow-up at 1 month after initial evaluation, then at 3,6, and 12 months during the first year 1, 5
• Annual ultrasound for benign nodules after the first year 1, 2
• Repeat FNA if nodule increases by ≥3 mm in any dimension or develops new suspicious features 1, 2
• Low-risk patients with nodules <6 mm without suspicious features may not require routine follow-up 2

After Thermal Ablation

• Follow-up should assess volume reduction rate, improvement in compression symptoms and cosmetic problems, presence of residual nodules, recurrence, metastasis, complications, and thyroid function 1
• TSH suppression therapy is recommended after thermal ablation for malignant thyroid nodules, with target TSH 0.5-2.0 mU/L for absolute indications and <0.5 mU/L for relative indications 1

After Surgery

• Initial follow-up one month after procedure, with subsequent assessments at 3,6, and 12 months during the first year, including thyroid function testing and ultrasound surveillance of remaining thyroid tissue 5

Critical Pitfalls to Avoid

• Do not perform radionuclide scanning in euthyroid patients as it is not helpful in determining malignancy; although cold nodules are more likely malignant, most nodules are cold and most cold nodules are benign, resulting in low positive predictive value 3
• Do not use FDG-PET/CT for initial evaluation of palpable thyroid nodules as there is no evidence to support its use 3
• Avoid overtreatment by using FNAC in conjunction with high-resolution ultrasound to accurately identify patients requiring surgery 9
• Do not delay intervention for nodules with documented progressive growth or compressive symptoms, as these warrant definitive management 5
• Recognize that accurate preoperative diagnosis is not always possible, and while unnecessary surgery can be diminished, it cannot be completely eliminated without risking undertreatment of a highly curable cancer 9