What is the management plan for a patient with bilateral thyroid multiple nodules ranging in size from 1.36 to 2.25 cm and a normal Thyroid-Stimulating Hormone (TSH) level?

Management of Bilateral Multiple Thyroid Nodules (1.36-2.25 cm) with Normal TSH

All nodules ≥1 cm with normal TSH require ultrasound-guided fine-needle aspiration (FNA) biopsy to exclude malignancy, prioritizing the largest nodule first, followed by any additional nodules with suspicious ultrasound features. 1

Initial Diagnostic Workup

Mandatory First Steps

• Perform high-resolution thyroid ultrasound to characterize all nodules using standardized risk stratification (TI-RADS classification) and assess for suspicious features 1, 2
• Measure serum TSH to confirm euthyroid status (already done - normal) 2
• Complete neck ultrasound to evaluate cervical lymph nodes for suspicious features such as loss of fatty hilum, microcalcifications, cystic change, or hypervascularity 1

Ultrasound Risk Stratification

Assess each nodule for high-risk features that substantially increase malignancy probability:

Major suspicious features (1 point each): 1, 3

• Microcalcifications (highly specific for papillary thyroid carcinoma)
• Marked hypoechogenicity (darker than surrounding thyroid tissue)
• "Taller-than-wide" orientation on transverse view
• Increased central/intranodular vascularity (chaotic blood flow pattern)

Minor suspicious features (0.5 points each): 1, 3

• Irregular or microlobulated margins
• Absence of peripheral halo
• Solid composition (vs. cystic/mixed)
• Size >3 cm

Critical high-risk features (3 points each): 3

• Rapid growth/enlargement
• Pathologically altered cervical lymph nodes

FNA Biopsy Strategy

Which Nodules to Biopsy

Perform FNA on: 1, 4

1. The largest nodule first (2.25 cm) - cancer occurs in 72% of cases in the largest nodule when multiple nodules are present
2. Any additional nodule ≥1 cm with ≥2 suspicious ultrasound features (solid, hypoechoic, irregular margins, microcalcifications, central hypervascularity)
3. Up to 4 nodules total should be considered for FNA to adequately exclude cancer in multinodular thyroid disease 4

Important Context

• The prevalence of thyroid cancer is identical (14.8-14.9%) in patients with solitary vs. multiple nodules 4
• However, individual nodule malignancy risk decreases as the number of nodules increases 4
• In patients with multiple nodules, cancer is multifocal in 46% of cases 4
• The overall malignancy rate for thyroid nodules is 7-15% 2

Management Based on FNA Results (Bethesda Classification)

Bethesda II (Benign) - Malignancy Risk 1-3%

• Surveillance with repeat ultrasound at 12-24 months to assess for interval growth or development of suspicious features 1, 5
• No surgery required unless compressive symptoms (dysphagia, dyspnea, voice changes) or cosmetic concerns 1
• Consider surgery for nodules >4 cm due to increased false-negative rate 1

Bethesda III (AUS/FLUS) or IV (Follicular Neoplasm)

• Consider molecular testing (BRAF, RAS, RET/PTC, PAX8/PPARγ mutations) to refine malignancy risk 1
• Repeat FNA under ultrasound guidance if initial sample inadequate 1, 5
• Surgery for definitive diagnosis if molecular testing positive or high clinical suspicion 1, 2

Bethesda V (Suspicious) or VI (Malignant)

• Immediate referral to endocrine surgeon for total or near-total thyroidectomy 1, 5
• Pre-operative neck ultrasound to assess lymph node compartments 5
• Compartment-oriented lymph node dissection if metastases suspected 5

High-Risk Clinical Factors That Lower FNA Threshold

Even for nodules <1 cm, perform FNA if ANY of these factors present: 1

• History of head and neck irradiation (increases risk 7-fold)
• Family history of thyroid cancer (especially medullary carcinoma or familial syndromes)
• Age <15 years or male gender
• Rapidly growing nodule
• Firm, fixed nodule on palpation
• Vocal cord paralysis or compressive symptoms
• Suspicious cervical lymphadenopathy
• Focal FDG uptake on PET scan

Additional Diagnostic Considerations

Serum Calcitonin Measurement

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

Thyroid Scintigraphy

• NOT indicated with normal TSH - radionuclide scanning is not helpful in determining malignancy in euthyroid patients 1, 2
• Only perform if TSH is suppressed to distinguish toxic adenoma from toxic multinodular goiter 1

Common Pitfalls to Avoid

• Do not delay FNA for nodules ≥1 cm - size alone is an indication regardless of ultrasound appearance 1
• Do not rely on TSH levels for malignancy assessment - most thyroid cancers present with normal thyroid function 1
• Do not perform only one FNA in multinodular disease - up to 4 nodules should be sampled to adequately exclude cancer 4
• Do not override reassuring FNA when worrisome clinical findings persist - false-negative results occur in 11-33% of cases 1
• Do not biopsy nodules <1 cm without high-risk features - leads to overdiagnosis of clinically insignificant papillary microcarcinomas 1

Natural History and Surveillance

If FNA results are benign: 6

• Only 11-15% of benign nodules show significant growth over 5 years
• Nodule growth is associated with: multiple nodules, larger baseline volume (>0.2 mL), male sex, and age <60 years
• Thyroid cancer develops in only 0.3% of cytologically benign nodules during follow-up
• 18.5% of nodules shrink spontaneously