What are the guidelines for the workup of thyroid nodules?

Workup of Thyroid Nodules

Begin with serum TSH measurement before any imaging, as this determines the entire diagnostic pathway—if TSH is low, proceed to thyroid ultrasound followed by radioiodine uptake scan to evaluate for hyperfunctioning nodules; if TSH is normal or elevated, proceed directly to high-resolution thyroid ultrasound as the primary imaging modality. 1

Initial Laboratory Assessment

• Measure serum TSH first in all patients with thyroid nodules to determine thyroid functional status and guide subsequent imaging 1, 2
• If TSH is suppressed (low), perform thyroid ultrasound followed by radioiodine uptake scan with 99Tc to distinguish between solitary toxic adenoma, toxic multinodular goiter, or thyroiditis 1, 3
• If TSH is normal or elevated, proceed directly to ultrasound evaluation without radionuclide scanning 1, 4
• Do not rely on thyroid function tests alone for malignancy assessment, as most thyroid cancers present with normal thyroid function 5

Ultrasound Evaluation

Ordering the Study

• Specify "bilateral thyroid evaluation with central neck (level VI) assessment" to evaluate both thyroid lobes, isthmus, and central compartment lymph nodes 1
• Add "with lateral neck ultrasound (levels II-V)" if the nodule is >1 cm with suspicious features or if there is clinical suspicion for lymph node involvement 1
• Request evaluation for suspicious cervical lymphadenopathy including assessment of size, shape, echogenicity, cystic changes, microcalcifications, and abnormal vascularity 1

Suspicious Ultrasound Features Requiring FNA

High-risk sonographic features that warrant fine-needle aspiration include: 5, 2

• Microcalcifications (highly specific for papillary thyroid carcinoma with OR 6.4) 1
• Marked hypoechogenicity (solid nodules darker than surrounding thyroid parenchyma) 5
• Irregular or microlobulated margins (infiltrative borders rather than smooth contours) 5
• Absence of peripheral halo (loss of thin hypoechoic rim) 5
• Solid composition (higher malignancy risk than cystic nodules) 5
• Central hypervascularity (chaotic internal vascular pattern) 5

Reassuring Features

• Spongiform or cystic appearance suggests benign process not requiring additional testing 2
• Smooth, regular margins with thin halo 5
• Peripheral vascularity only (blood flow limited to capsule) 5

Fine-Needle Aspiration Biopsy (FNA) Indications

Size-Based Criteria

• Any nodule >1 cm with ≥2 suspicious ultrasound features requires ultrasound-guided FNA 5, 2
• Any nodule >2 cm should be evaluated even without suspicious features due to increased malignancy risk 5
• Any nodule >4 cm regardless of ultrasound appearance 5
• Nodules <1 cm require FNA only if suspicious ultrasound features are present PLUS high-risk clinical factors 5

High-Risk Clinical Factors That Lower FNA Threshold

These factors warrant FNA even for smaller nodules or those with fewer suspicious features: 5

• History of head and neck irradiation 5
• Family history of thyroid cancer (particularly medullary thyroid carcinoma or familial syndromes) 5
• Age <15 years or male gender 5
• Rapidly growing nodule 5
• Firm, fixed nodule on palpation (suggests extrathyroidal extension) 5
• Vocal cord paralysis or compressive symptoms 5
• Suspicious cervical lymphadenopathy 5
• Subcapsular location 5

FNA Technique

• Ultrasound-guided FNA is the preferred method due to accuracy, economy, safety, and effectiveness 5, 3
• All patients with suspicious nodules should undergo puncture biopsy to confirm pathological diagnosis before any definitive treatment 5
• If multiple nodules are present, prioritize the largest nodule for initial FNA, as size ≥3 cm carries 3-times greater malignancy risk 5

Interpretation of FNA Results: Bethesda Classification

The Bethesda System stratifies nodules into six categories with specific malignancy risks: 5

• Bethesda I (Nondiagnostic/Unsatisfactory): Repeat FNA under ultrasound guidance; if repeat remains nondiagnostic, assess number of suspicious ultrasound features 5
• Bethesda II (Benign): Very low malignancy risk (1-3%); surveillance appropriate for nodules without concerning ultrasound features 5
• Bethesda III (Atypia of Undetermined Significance/Follicular Lesion of Undetermined Significance): Consider molecular testing (BRAF V600E, RET/PTC, RAS, PAX8/PPARγ) or gene expression classifiers to guide management 5
• Bethesda IV (Follicular Neoplasm): If TSH is normal and thyroid scan shows "cold" nodule, proceed to surgery; malignancy rate 12-34% depending on subcategory 5
• Bethesda V-VI (Suspicious for Malignancy/Malignant): Immediate surgical referral for total or near-total thyroidectomy 5

Adjunctive Testing

Molecular Testing

• Consider for Bethesda III and IV categories to improve diagnostic accuracy 5
• BRAF, RAS, RET/PTC, and PAX8/PPARγ mutations: 97% of mutation-positive nodules are malignant 5

Serum Calcitonin

• Measure as part of diagnostic evaluation to screen for medullary thyroid cancer, which has higher sensitivity than FNA alone 5

Common Pitfalls to Avoid

• Do not perform routine thyroid cancer screening in the general population, as detection of early thyroid cancer has not improved survival 3
• Avoid FNA on nodules <1 cm without high-risk features, as this leads to overdiagnosis and overtreatment of clinically insignificant cancers 5
• Do not use CT or MRI as initial imaging; ultrasound provides superior visualization for thyroid nodule characterization 5
• Do not perform radionuclide scanning in euthyroid patients for malignancy determination, as it is not helpful 5
• Be aware that follicular neoplasms may be difficult to diagnose by FNA alone and may require surgical excision for definitive histological diagnosis 5

Follow-Up for Benign Nodules

• Nodules with Bethesda II (benign) cytology and no concerning ultrasound features can be managed with surveillance 5
• Overdiagnosis and overtreatment of benign thyroid nodules is common; avoid unnecessary procedures 5
• If clinical suspicion remains high despite benign FNA, consider evaluating additional nodules or repeat FNA 5