What is the recommended diagnostic workup for a thyroid nodule?

Diagnostic Workup for Thyroid Nodules

The recommended diagnostic workup for a thyroid nodule begins with high-resolution ultrasound of the thyroid and central neck, measurement of serum TSH, and ultrasound-guided fine-needle aspiration (FNA) for nodules ≥1 cm or smaller nodules with suspicious features. 1

Initial Assessment

Step 1: Ultrasound Evaluation

• Perform high-resolution ultrasound using a high-frequency transducer to characterize nodule size, composition, echogenicity, margins, calcifications, and vascularity. 2, 1
• Ultrasound is the only appropriate initial imaging modality—do not order CT, MRI, or radionuclide scanning in euthyroid patients, as these do not add value for malignancy risk assessment. 2
• Systematically evaluate both central and lateral cervical lymph node basins for suspicious characteristics including loss of fatty hilum, microcalcifications, cystic change, or abnormal vascularity. 2, 1

Step 2: Measure Serum TSH

• Obtain serum TSH before FNA, as higher TSH levels are associated with increased risk of differentiated thyroid cancer. 1, 3
• If TSH is suppressed, proceed to radionuclide thyroid scan with 99mTc to identify hyperfunctioning ("hot") nodules, which are rarely malignant and do not require FNA. 3, 4
• If TSH is normal or elevated, proceed with risk stratification based on ultrasound features. 3

Ultrasound Risk Stratification

High-Risk Features Warranting FNA

Perform ultrasound-guided FNA when any of the following suspicious features are present: 2, 1

• Microcalcifications (hyperechoic spots ≤1 mm representing psammoma bodies—highly specific for papillary thyroid carcinoma) 2, 1
• Marked hypoechogenicity (solid nodules darker than surrounding thyroid parenchyma) 2, 1
• Irregular or microlobulated margins (infiltrative borders rather than smooth contours) 2, 1
• Absence of peripheral halo (loss of thin hypoechoic rim normally surrounding benign nodules) 2, 1
• Central hypervascularity (chaotic internal vascular pattern) 2, 1
• Taller-than-wide shape on transverse view 1
• Solid composition (higher malignancy risk than cystic nodules) 2, 5

Size-Based FNA Thresholds

Apply the following algorithm based on nodule size and ultrasound features: 2, 1

• Nodules ≥1 cm: Perform FNA regardless of ultrasound appearance 6, 1
• Nodules <1 cm: Perform FNA only if ≥2 suspicious ultrasound features PLUS high-risk clinical factors are present 2, 1
• Nodules ≥4 cm: Perform FNA regardless of ultrasound appearance due to increased false-negative rate 2

High-Risk Clinical Factors

Perform FNA even for smaller nodules (<1 cm) when any of these clinical factors are present: 2, 1

• History of head and neck irradiation (increases malignancy risk approximately 7-fold) 2, 1
• Family history of thyroid cancer, particularly medullary carcinoma or familial syndromes (MEN 2A/2B, familial adenomatous polyposis, Carney complex, Cowden syndrome) 2, 1
• Age <15 years or male gender 2, 1
• Rapidly growing nodule 2, 1
• Firm nodule fixed to adjacent structures 1
• Vocal cord paralysis or compressive symptoms (dysphagia, dyspnea, voice changes) 2, 1
• Suspicious cervical lymphadenopathy 2, 1
• Focal FDG uptake on PET scan 2

Fine-Needle Aspiration Technique

• Use ultrasound guidance rather than palpation-guided biopsy—it provides real-time needle visualization, improves sampling accuracy, and yields higher diagnostic certainty. 2, 7
• For mixed solid-cystic nodules, target the solid component as it carries the highest malignancy risk. 2
• If initial FNA is inadequate or nondiagnostic (occurs in 5-20% of cases), repeat FNA under ultrasound guidance. 2, 1

Cytology Interpretation Using Bethesda System

FNA results should be categorized according to the Bethesda System for Reporting Thyroid Cytopathology: 2, 1

• Bethesda I (Nondiagnostic): Repeat FNA under ultrasound guidance 1
• Bethesda II (Benign): Malignancy risk 1-3%—manage with surveillance ultrasound at 12-24 months 2
• Bethesda III (AUS/FLUS): Consider molecular testing (BRAF, RAS, RET/PTC, PAX8/PPARγ) or repeat FNA 2, 1
• Bethesda IV (Follicular Neoplasm): If TSH normal and thyroid scan shows "cold" appearance, consider surgery for definitive diagnosis 6, 1
• Bethesda V (Suspicious for Malignancy): Refer immediately for total or near-total thyroidectomy 2, 7
• Bethesda VI (Malignant): Refer immediately for total or near-total thyroidectomy with pre-operative lymph node assessment 2, 7

Adjunctive Testing

Serum Calcitonin

• Measure serum calcitonin as part of the diagnostic evaluation to screen for medullary thyroid cancer, which has higher sensitivity than FNA alone (detects 5-7% of thyroid cancers that FNA may miss). 6, 1, 7

Molecular Testing

• Consider molecular testing for BRAF, RAS, RET/PTC, and PAX8/PPARγ mutations in cases with indeterminate cytology (Bethesda III/IV) to refine malignancy risk and guide surgical decision-making. 6, 2, 1
• The presence of any mutation is a strong indicator of cancer—97% of mutation-positive nodules are malignant. 6, 2

Critical Pitfalls to Avoid

• Do not override a reassuring FNA when worrisome clinical findings persist—false-negative results occur in up to 11-33% of cases, particularly in nodules 3-6 cm due to encapsulated follicular variant of papillary carcinoma. 2, 8
• Do not rely on thyroid function tests (TSH, T3, T4) for malignancy assessment—most thyroid cancers present with normal thyroid function. 2
• Do not perform FNA on pure cystic nodules without solid components or suspicious features—these can be safely observed. 2
• Avoid overdiagnosis of papillary microcarcinomas (<1 cm)—FNA is not routinely recommended for nodules <1 cm without high-risk features, as this leads to unnecessary thyroidectomies without improving mortality or quality of life. 2

Surgical Referral Indications

Refer immediately to an endocrine surgeon when: 2, 7

• Bethesda V (suspicious) or VI (malignant) cytology is confirmed 2, 7
• Follicular neoplasia (Bethesda IV) with normal TSH and "cold" thyroid scan 6, 1
• Molecular testing is positive for high-risk mutations 2
• Compressive symptoms are present and clearly attributable to the nodule 2
• Metastatic, multifocal, or familial differentiated thyroid carcinoma is diagnosed 2