What is the differential diagnosis and evaluation approach for a patient with a thyroid nodule, considering factors such as age, sex, family history of thyroid disease or cancer, and thyroid function (thyroid-stimulating hormone (TSH) level)?

Differential Diagnosis for Thyroid Nodules

Benign Conditions (>90% of all nodules)

The vast majority of thyroid nodules are benign, with approximately 50% of thyroids examined by ultrasound containing nodules that are almost always benign. 1

• Colloid nodules/nodular goiter – The most common benign finding, representing hyperplastic thyroid tissue with colloid accumulation 1, 2
• Follicular adenoma – Benign encapsulated follicular neoplasm that cannot be distinguished from follicular carcinoma by FNA alone 2, 3
• Hashimoto's thyroiditis nodules – Solid, isoechoic nodules in the setting of chronic lymphocytic thyroiditis, typically benign hyperplastic/adenomatoid nodules 4
• Simple cysts – Pure cystic lesions without solid components, which can be safely observed 4
• Complex cysts – Mixed solid-cystic nodules with lower malignancy risk than purely solid nodules 4

Malignant Conditions (5-15% of nodules)

Thyroid carcinoma occurs in approximately 5-15% of thyroid nodules, with lifetime risk of diagnosis less than 1% in the general population. 1, 5, 3

• Papillary thyroid carcinoma (PTC) – Accounts for approximately 80-85% of thyroid malignancies; well-detected on FNA with characteristic features including psammoma bodies and nuclear grooves 1, 2
• Follicular thyroid carcinoma – Represents 10-15% of thyroid cancers; cannot be distinguished from follicular adenoma by FNA alone, requiring surgical histology to assess capsular/vascular invasion 1, 2
• Hürthle cell carcinoma – Variant of follicular carcinoma with oncocytic cells; also requires surgical diagnosis 1
• Medullary thyroid carcinoma (MTC) – Arises from parafollicular C-cells; 10-year survival approximately 75%; diagnosed or suspected on FNA in only 50% of cases; serum calcitonin measurement has higher sensitivity than FNA 1, 2
• Anaplastic thyroid carcinoma – Rare but almost uniformly lethal; presents with rapidly growing, fixed mass 1
• Thyroid lymphoma – Rare; often occurs in setting of Hashimoto's thyroiditis 2

Risk Stratification Based on Clinical Features

The pretest probability of malignancy increases approximately 7-fold when high-risk clinical features are present. 1

High-Risk Clinical Factors:

• Age <15 years or male gender – Higher baseline malignancy probability 1, 2
• History of head and neck irradiation – Increases malignancy risk approximately 7-fold; nodules develop at rate of ~2% per year after radiation exposure 1, 2
• Family history of thyroid cancer – Particularly medullary carcinoma or familial syndromes (MEN 2A/2B, familial adenomatous polyposis, Carney complex, Cowden's syndrome) 1, 2
• Rapidly growing nodule – Suggests aggressive biology 1, 2
• Firm nodule fixed to adjacent structures – Indicates extrathyroidal extension 1, 2
• Vocal cord paralysis – Suggests recurrent laryngeal nerve invasion 1, 2
• Enlarged regional lymph nodes – Associated with metastatic disease 1, 2

Suspicious Ultrasound Features:

• Microcalcifications – Highly specific for papillary thyroid carcinoma, representing psammoma bodies 1, 4, 2
• Marked hypoechogenicity – Solid nodules darker than surrounding thyroid parenchyma 1, 4
• Irregular or microlobulated margins – Infiltrative borders rather than smooth contours 1, 4
• Absence of peripheral halo – Loss of thin hypoechoic rim normally surrounding benign nodules 1, 4
• Central hypervascularity – Chaotic internal vascular pattern (peripheral vascularity only is reassuring) 1, 4
• Solid composition – Higher malignancy risk compared to cystic nodules 4
• Taller-than-wide shape – Shape orientation suggesting invasive growth 6, 2

Evaluation Algorithm

Fine-needle aspiration is the preferred procedure for evaluating suspicious thyroid nodules, with ultrasound guidance improving accuracy. 1, 6

Step 1: Measure TSH

• If TSH is low → Perform radionuclide thyroid uptake scan to identify hyperfunctioning ("hot") nodules, which rarely require biopsy due to low malignancy risk 6, 7, 3
• If TSH is normal or elevated → Proceed directly to ultrasound evaluation 6, 7

Step 2: High-Resolution Ultrasound

• Characterize nodule size, composition, echogenicity, margins, calcifications, and vascularity 4, 6, 2
• Evaluate cervical lymph nodes for suspicious features 2

Step 3: FNA Indications

• Any nodule >1 cm with suspicious ultrasound features (hypoechogenicity, microcalcifications, irregular borders, solid composition, central hypervascularity) 1, 4, 2
• Any nodule <1 cm with suspicious features PLUS high-risk clinical factors 1, 4
• Any nodule >4 cm regardless of ultrasound appearance due to increased false-negative rate 4
• Suspicious cervical lymphadenopathy present 4
• Focal FDG uptake on PET scan 2

Step 4: Bethesda Classification

FNA specimens should be categorized according to the Bethesda System (categories I-VI), with malignancy risk ranging from 1-3% (Bethesda II, benign) to >97% (Bethesda VI, malignant) 4, 2, 7, 5

Step 5: Additional Testing When Indicated

• Serum calcitonin measurement – To screen for medullary thyroid cancer, which has higher sensitivity than FNA alone 4, 2
• Molecular testing (BRAF, RAS, RET/PTC, PAX8/PPARγ) – For indeterminate cytology (Bethesda III/IV); 97% of mutation-positive nodules are malignant 4, 2, 7

Critical Pitfalls to Avoid

• Do not rely on thyroid function tests to assess malignancy risk – Most thyroid cancers present with normal thyroid function 4
• Do not use radionuclide scanning in euthyroid patients to determine malignancy – Ultrasound features are far more predictive 4, 6
• Do not override a reassuring FNA when worrisome clinical findings persist – False-negative results occur in up to 11-33% of cases 4, 2
• Do not perform FNA on nodules <1 cm without high-risk features – This leads to overdiagnosis and overtreatment of clinically insignificant cancers 4