What is the appropriate management for a patient presenting with thyroid nodules?

Management of Thyroid Nodules

All patients with thyroid nodules should undergo initial evaluation with TSH measurement and high-resolution ultrasound, followed by ultrasound-guided fine-needle aspiration biopsy (FNA) for nodules ≥1 cm with suspicious sonographic features or any nodule >1 cm in the presence of high-risk clinical factors. 1

Initial Diagnostic Workup

Laboratory Assessment

• Measure serum TSH as the first-line test to identify functional nodules that require radionuclide scanning rather than FNA 2, 3
• If TSH is suppressed, proceed to thyroid scintigraphy to identify "hot" nodules, which are managed with radioactive iodine or surgery rather than FNA 1
• Consider measuring serum calcitonin to screen for medullary thyroid carcinoma, which has higher sensitivity than FNA alone and detects 5-7% of thyroid cancers that FNA may miss 1
• Assess thyroid peroxidase antibodies if TSH is elevated to evaluate for underlying autoimmune thyroiditis 4

Ultrasound Risk Stratification

High-resolution ultrasound is the only appropriate initial imaging modality for thyroid nodule characterization, providing superior visualization compared to CT or MRI 1, 2

Suspicious ultrasound features warranting FNA include: 1

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

Reassuring features suggesting benign pathology include: 1

• Cystic or spongiform appearance 2
• Smooth, regular margins with thin halo 1
• Peripheral vascularity only (blood flow limited to capsule) 1

Indications for Fine-Needle Aspiration Biopsy

Size and Ultrasound-Based Criteria

Perform ultrasound-guided FNA when: 1

• Any nodule >1 cm with ≥2 suspicious ultrasound features (solid, hypoechoic, irregular margins, microcalcifications, central hypervascularity)
• Any nodule >4 cm regardless of ultrasound appearance due to increased false-negative rate
• Any nodule <1 cm with suspicious features PLUS high-risk clinical factors

High-Risk Clinical Factors That Lower FNA Threshold

The following clinical features warrant FNA even for smaller nodules (<1 cm): 1

• History of head and neck irradiation (increases malignancy risk approximately 7-fold)
• Family history of thyroid cancer, particularly medullary carcinoma or familial syndromes
• Age <15 years or male gender (higher baseline malignancy probability)
• Rapidly growing nodule (suggests aggressive biology)
• Firm, fixed nodule on palpation (indicates extrathyroidal extension)
• Vocal cord paralysis or compressive symptoms (suggest invasive disease)
• Suspicious cervical lymphadenopathy
• Focal FDG uptake on PET scan

Technical Approach to FNA

• Ultrasound guidance is mandatory for all FNA procedures, as it allows real-time needle visualization, confirms accurate sampling, and is superior to palpation-guided biopsy 1
• If initial FNA is nondiagnostic/inadequate (occurs in 5-20% of cases), repeat FNA under ultrasound guidance is mandatory 1
• Core needle biopsy (CNB) should be reserved for cases where repeat FNA remains nondiagnostic, though CNB carries higher hemorrhage risk 5

Management Based on Cytology Results (Bethesda Classification)

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

Surveillance is the standard of care for Bethesda II nodules without concerning features 1

• Repeat ultrasound at 12-24 months to assess for interval growth or development of suspicious features 1
• Monitor for compressive symptoms including dysphagia, dyspnea, or voice changes 1
• Surgery is indicated only when: 1
  • Compressive symptoms are present and clearly attributable to the nodule
  • Cosmetic concerns are significant and patient-driven
  • Large nodules (>4 cm) due to increased false-negative rate
• Molecular testing is generally not indicated for Bethesda II nodules, as the pretest probability of malignancy is so low (1-3%) that molecular markers add minimal clinical value 1

Bethesda III (AUS/FLUS) and IV (Follicular Neoplasm): Risk of Malignancy 12-34%

Molecular testing for BRAF, RAS, RET/PTC, and PAX8/PPARγ mutations should be considered to assist in management decisions 1

• The presence of any mutation is a strong indicator of cancer (97% of mutation-positive nodules are malignant) 1
• For Bethesda IV with normal TSH and "cold" appearance on thyroid scan, surgery should be considered for definitive diagnosis, as follicular carcinoma cannot be distinguished from follicular adenoma on cytology alone 1

Bethesda V (Suspicious) and VI (Malignant)

Immediate referral to an endocrine surgeon for total or near-total thyroidectomy 1

• Perform pre-operative neck ultrasound to assess cervical lymph node status 1
• Compartment-oriented lymph node dissection is indicated when lymph node metastases are suspected or proven 1

Special Considerations

Autonomously Functioning Nodules

• If TSH is suppressed and nodule is "hot" on radionuclide scan, medical management with radioactive iodine is preferred over surgery, and FNA is not indicated 1
• If nodule is "cold" on scan despite suppressed TSH, proceed to ultrasound-guided FNA 1

Elderly Patients (≥70 Years)

Surgical management should be tempered in patients ≥70 years old presenting without high-risk findings, especially when comorbid illness is identified 6

• Only 1.5% of patients ≥70 years old have significant-risk thyroid cancer (anaplastic, medullary, poorly differentiated, or distant metastases) 6
• The presence of non-thyroidal malignancy or coronary artery disease at the time of nodule evaluation is associated with increased mortality (hazard ratio 2.32) compared to thyroid cancer risk 6
• All significant-risk thyroid cancers are preoperatively identifiable by imaging and/or cytology 6

Retrosternal Extension

CT neck with contrast is the preferred imaging modality for substernal thyroid nodules, as it is superior to ultrasound for visualizing retrosternal extension and defining tracheal compression severity 5

• Evaluate for obstructive symptoms including dyspnea, orthopnea, obstructive sleep apnea, dysphagia, and dysphonia 5
• Surgical management is recommended for nodules causing significant compression symptoms, suspected malignancy, or progressive growth 5
• Thermal ablation may be considered for benign nodules with retrosternal extension when the patient has contraindications to surgery or refuses surgical intervention 5

Alternative Treatment: Thermal Ablation

Indications for Thermal Ablation of Benign Nodules

Thermal ablation is an optional treatment for benign thyroid nodules that meet the following criteria: 4

• Nodules confirmed as benign by biopsy with solid composition ≥10%
• Nodules causing clinical symptoms such as compression, cosmetic concerns, or anxiety
• Nodules with maximal diameter ≥2 cm and increasing gradually
• Autonomously functioning thyroid nodules
• Recurrent nodules after chemical ablation

Indications for Thermal Ablation of Malignant Nodules (Papillary Thyroid Carcinoma)

Absolute indications (all criteria must be met): 4

• Cancer nodule with maximal diameter ≤1 cm
• Single cancer nodule
• No invasion of trachea, large blood vessels, or other perithyroid structures
• No signs of cervical lymph node metastasis (cN0)
• No signs of distant metastasis (cM0)

Relative indications (when surgical resources available): 4

• Cancer nodule located in isthmus
• Cancer nodule adjacent to capsule or with capsular invasion
• Cancer nodule with maximal diameter >1 cm and ≤2 cm
• Multiple cancer nodules (number ≤3 and maximal diameter ≤1 cm)
• Patients who cannot tolerate surgical resection due to concomitant diseases or refuse surgery

Contraindications to Thermal Ablation

4

• Severe bleeding tendency
• Severe cardiopulmonary insufficiency or inability to cooperate
• Contralateral vocal cord paralysis on treatment side
• Pregnant and lactating women (use with caution)
• Diffuse sclerosing papillary carcinoma
• Malignancies other than papillary thyroid carcinoma

Follow-Up After Thermal Ablation

Initial follow-up at 1 month post-procedure, then at 3,6, and 12 months during the first year 4

• After the initial 12 months, re-evaluate malignant nodules every 6 months and benign nodules annually 4
• Follow-up should include thyroid and neck ultrasound, assessment of clinical symptoms and complications, and laboratory tests 4
• Contrast-enhanced ultrasound (CEUS) is advisable to assess the extent and blood supply of the ablation zone 4
• Volume reduction rate (VRR) should be calculated: [(Preoperative volume – ablation zone volume at follow-up) × 100]/preoperative volume 4

TSH Suppression Therapy After Thermal Ablation of Malignant Nodules

TSH suppression therapy is advisable following thermal ablation of malignant thyroid nodules 4

• For nodules meeting absolute indications, target TSH level should be 0.5–2.0 mU/L 4
• For nodules meeting relative indications, target TSH level should be <0.5 mU/L 4
• Follow-up assessments at 3,6, and 12 months during the first year, then every 6 months once TSH control is achieved 4

Critical Pitfalls to Avoid

• Do not rely on thyroid function tests (TSH, T3, T4) for malignancy assessment, as most thyroid cancers present with normal thyroid function 1
• Avoid performing FNA on nodules <1 cm without high-risk features, as this leads to overdiagnosis and overtreatment of clinically insignificant cancers 1
• Do not override a reassuring FNA when worrisome clinical findings persist, as false-negative results occur in up to 11-33% of cases 1
• Avoid proceeding directly to thyroidectomy without tissue diagnosis, as this may result in inappropriate surgical extent 1
• Do not use CT or MRI as initial imaging for thyroid nodule characterization; ultrasound is superior 1