What is the recommended approach to evaluate a thyroid nodule?

Evaluation of a Thyroid Nodule

Perform high-resolution ultrasound immediately for any palpable thyroid nodule or goiter, followed by serum TSH measurement, then proceed to ultrasound-guided fine-needle aspiration for nodules ≥1 cm with suspicious features or any nodule ≥4 cm regardless of appearance. 1, 2

Initial Diagnostic Workup

Step 1: High-Resolution Ultrasound

• Order high-resolution ultrasound (using high-frequency transducer ≥7.5 MHz) as the first imaging study to characterize nodule size, composition, echogenicity, margins, calcifications, and vascularity 1, 2
• Ultrasound can detect nodules as small as 5 mm and is superior to CT or MRI for thyroid evaluation 1
• Never order radionuclide scanning in euthyroid patients, as ultrasound features are far more predictive of malignancy 1, 2

Step 2: Measure Serum TSH

• Obtain TSH level after ultrasound is performed to identify hyperfunctioning nodules 3, 4
• If TSH is suppressed, proceed to thyroid scintigraphy with 99mTc to distinguish hot (hyperfunctioning) from cold nodules 3, 5
• Hot nodules are rarely malignant and do not require FNA 4, 5
• Cold nodules or normal/elevated TSH require evaluation by ultrasound-guided FNA based on size and sonographic features 3, 4

Step 3: Assess High-Risk Clinical Features

Document the following factors that lower the threshold for FNA even in smaller nodules 1, 2:

• History of head and neck irradiation (increases malignancy risk 7-fold) 1
• Family history of thyroid cancer, particularly medullary carcinoma or familial syndromes 1, 2
• Age <15 years or male gender (higher baseline malignancy probability) 1, 2
• Rapidly growing nodule (strongest predictor of malignancy) 1
• Firm, fixed nodule on palpation (suggests extrathyroidal extension) 1
• Vocal cord paralysis or compressive symptoms (dysphagia, dyspnea, voice changes) 1
• Suspicious cervical lymphadenopathy on examination or ultrasound 1, 2

Ultrasound Risk Stratification

High-Risk Sonographic Features (Warrant FNA)

Identify ≥2 of the following suspicious features 1, 2:

• Microcalcifications (hyperechoic spots ≤1 mm; highly specific for papillary thyroid carcinoma with 93.6% specificity) 1, 2
• Marked hypoechogenicity (solid nodule darker than surrounding thyroid parenchyma) 1, 2
• Irregular or microlobulated margins (infiltrative borders rather than smooth contours) 1, 2
• Absence of peripheral halo (loss of thin hypoechoic rim) 1, 2
• Solid composition (higher malignancy risk than cystic nodules) 1
• Central hypervascularity (chaotic internal vascular pattern) 1
• Taller-than-wide shape on transverse view 2

Reassuring Features (Lower Risk)

• Peripheral vascularity only (blood flow limited to capsule) 1
• Smooth, regular margins with thin halo 1
• Spongiform appearance 1
• Pure cystic composition without solid components 1

Indications for Ultrasound-Guided Fine-Needle Aspiration

Absolute Indications for FNA 1, 2

• Any nodule ≥1 cm with ≥2 suspicious ultrasound features 1, 2
• Any nodule ≥4 cm regardless of ultrasound appearance (due to increased false-negative rate) 1, 2
• Any nodule with suspicious cervical lymphadenopathy 1, 2
• Nodules <1 cm with suspicious features PLUS high-risk clinical factors (head/neck irradiation, family history, age <15 years) 1, 2
• Focal FDG uptake on PET scan (regardless of nodule size) 1

Do NOT Perform FNA 1

• Pure cystic nodules without solid components or suspicious features 1
• Nodules <1 cm without suspicious features and no high-risk clinical factors (to avoid overdiagnosis of clinically insignificant papillary microcarcinomas) 1, 2
• Hot nodules on scintigraphy with suppressed TSH 4, 5

FNA Technique and Interpretation

Procedural Approach

• Always use ultrasound guidance rather than palpation-guided biopsy for superior accuracy, real-time needle visualization, and ability to place marker clips 1, 2
• Sample the solid portion of mixed cystic-solid nodules, as the solid component carries highest malignancy risk 1
• If initial FNA is inadequate (occurs in 5-20% of cases), repeat FNA under ultrasound guidance is mandatory 1, 2

Bethesda Classification System 1, 4

Cytology results are reported using six categories with corresponding malignancy risk:

• Bethesda I (Nondiagnostic/Inadequate): Repeat FNA under ultrasound guidance 1
• Bethesda II (Benign): 1-3% malignancy risk; surveillance with repeat ultrasound at 12-24 months 1
• Bethesda III (AUS/FLUS): Consider molecular testing or repeat FNA 1, 2
• Bethesda IV (Follicular Neoplasm): Consider molecular testing or surgical excision for definitive diagnosis 1, 2
• Bethesda V (Suspicious for Malignancy): Immediate referral for total or near-total thyroidectomy 1
• Bethesda VI (Malignant): Immediate referral for total or near-total thyroidectomy 1

Adjunctive Testing

Molecular Testing 1, 2

• Order molecular testing for BRAF, RAS, RET/PTC, and PAX8/PPARγ mutations for Bethesda III (AUS/FLUS) or IV (Follicular Neoplasm) results 1, 2
• 97% of mutation-positive nodules prove malignant at surgery 1, 2
• Molecular testing helps guide surgical decision-making for indeterminate cytology 1, 2

Serum Calcitonin 1, 2

• Measure serum calcitonin as part of initial diagnostic workup to screen for medullary thyroid cancer, which has higher sensitivity than FNA alone 1, 2
• Calcitonin detects 5-7% of thyroid cancers that FNA may miss 1

Surveillance Protocol for Benign Nodules

For Bethesda II (Benign) Results 1

• Repeat ultrasound at 12-24 months to assess for interval growth or development of suspicious features 1
• Monitor for compressive symptoms (dysphagia, dyspnea, voice changes) 1
• Significant growth is defined as ≥3 mm increase in any dimension, which warrants repeat FNA 1

Indications for Surgery Despite Benign Cytology 1

• Compressive symptoms clearly attributable to the nodule 1
• Significant cosmetic concerns that are patient-driven 1
• Large nodules >4 cm (higher false-negative rate) 1
• Development of suspicious features on follow-up ultrasound 1

Critical Pitfalls to Avoid

• Never rely on thyroid function tests (TSH, T3, T4) alone for malignancy assessment, as most thyroid cancers present with normal thyroid function 1, 2
• Do not override a benign FNA when highly suspicious clinical or ultrasound features persist, as false-negative results occur in 11-33% of cases 1, 2
• Avoid performing FNA on nodules <1 cm without high-risk features, as this leads to overdiagnosis and overtreatment of clinically insignificant cancers 1, 2
• Never proceed directly to surgery without tissue diagnosis (except for hot nodules causing thyrotoxicosis) 1
• Do not order routine thyroid cancer screening in the general population, as detection of early thyroid cancer has not been shown to improve survival 3