What are the differential diagnoses for a patient with neck enlargement and normal thyroid function?

Differential Diagnoses for Neck Enlargement with Normal Thyroid Function

Critical Initial Principle

A neck mass in an adult patient should be considered malignant until proven otherwise, even when thyroid function tests are normal. 1

The presence of normal thyroid function (normal TSH, T3, T4) does not exclude thyroid malignancy or other serious pathology, as most thyroid cancers present with euthyroid status. 2

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Primary Malignant Differential Diagnoses

Head and Neck Squamous Cell Carcinoma (HNSCC)

• Most common cause of persistent neck masses in adults, particularly metastatic lymphadenopathy from occult primary tumors. 1
• HPV-positive oropharyngeal carcinoma frequently presents as isolated neck metastasis without obvious primary malignancy. 1
• High-risk features include: firm consistency, fixation to adjacent tissues, size >1.5 cm, ulceration of overlying skin. 1

Thyroid Malignancies (Despite Normal Function)

• Papillary thyroid carcinoma (60-80% of thyroid cancers): Most common, excellent prognosis, often presents as asymptomatic nodule. 3
• Follicular thyroid carcinoma: Cannot be distinguished from adenoma by cytology alone, requires surgical diagnosis. 3
• Medullary thyroid carcinoma (5-7%): Arises from calcitonin-producing C cells; serum calcitonin measurement has higher sensitivity than FNA. 1, 2
• Anaplastic thyroid carcinoma: Rapidly enlarging neck mass with dyspnea, dysphagia, neck pain, Horner's syndrome, hoarseness; >80% have history of goiter. 1, 4

Lymphoma

• Thyroid lymphoma: Difficult to distinguish clinically from anaplastic carcinoma; presents as rapidly enlarging anterior neck mass in elderly. 1, 4
• Nodal lymphoma: Can present as isolated cervical lymphadenopathy. 1

Salivary Gland Malignancies

• Can present as lateral neck masses; require specific imaging and tissue diagnosis. 1

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Benign Differential Diagnoses

Inflammatory/Infectious Etiologies

• Chronic lymphocytic thyroiditis (Hashimoto's): Presents with goiter, hypothyroidism, or both; confirmed by elevated thyroid autoantibodies and thyroglobulin. 5
• Subacute granulomatous thyroiditis (de Quervain's): Painful thyroid disorder; elevated ESR, elevated thyroglobulin, depressed radioactive iodine uptake. 5
• Subacute lymphocytic thyroiditis (silent thyroiditis): Autoimmune origin, common postpartum; hyperthyroid symptoms with depressed RAIU. 5
• Acute suppurative thyroiditis: Rare bacterial infection of thyroid. 5
• Reactive lymphadenopathy: History of recent infection, fluctuating size over <2 weeks. 1

Congenital/Developmental Lesions

• Thyroglossal duct cyst: Midline cystic lesion that moves with swallowing and tongue protrusion; characteristic location relative to hyoid bone. 6
• Branchial cleft cyst: Lateral neck mass, typically anterior to sternocleidomastoid. 6
• Ectopic thyroid tissue: Extremely rare in lateral neck; literature suggests lateral thyroid tissue is essentially metastatic papillary carcinoma, though rare benign cases exist. 7

Benign Thyroid Nodules

• Nodular goiter/colloid goiter: 95% of thyroid nodules are benign. 3
• Follicular adenoma: Cannot be distinguished from follicular carcinoma without surgical pathology. 3

Other Rare Benign Entities

• Riedel's thyroiditis (invasive fibrous thyroiditis): Slowly enlarging anterior neck mass, sometimes confused with malignancy. 5
• Solitary fibrous tumor: Extremely rare; can mimic cold thyroid nodule on scintigraphy. 8
• Vascular anomalies: Variant carotid artery anatomy can present as pulsatile anterior neck mass mimicking thyroid nodule. 9

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High-Risk Clinical Features Mandating Urgent Evaluation

Patient History Red Flags

• History of head and neck irradiation: Strongest risk factor for thyroid malignancy; increases risk ~7-fold. 2, 3
• Family history of thyroid cancer: Particularly medullary carcinoma or MEN syndromes. 2, 3
• Age <15 years or male gender: Higher baseline malignancy probability. 2
• Rapidly growing mass: Suggests aggressive biology (anaplastic carcinoma, lymphoma, sarcoma). 1, 4

Physical Examination Red Flags

• Firm, fixed mass: Indicates extrathyroidal extension. 1, 2
• Size >1.5 cm: Increased malignancy risk. 1
• Ulceration of overlying skin: Highly suspicious for malignancy. 1
• Suspicious cervical lymphadenopathy: Highly suspicious for papillary carcinoma or metastatic HNSCC. 2, 3
• Vocal cord paralysis/hoarseness: Suggests recurrent laryngeal nerve involvement. 1, 3
• Horner's syndrome: Rare but indicates sympathetic chain involvement; thyroid pathology is commonest cause when associated with neck mass. 4

Associated Symptoms

• Dysphagia, dyspnea, stridor: Indicate mass effect or invasion. 1, 3
• Neck pain: Uncommon in benign disease. 1

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Diagnostic Algorithm for Neck Enlargement with Normal Thyroid Function

Step 1: Risk Stratification

Identify patients at increased risk for malignancy if mass has been present ≥2 weeks without significant fluctuation OR is of uncertain duration AND lacks infectious etiology. 1

Step 2: Imaging

Order neck CT with contrast (or MRI with contrast) for all patients deemed at increased risk for malignancy. 1

• Ultrasound is preferred initial modality for thyroid-specific evaluation; can detect nodules as small as 5mm. 2
• CT/MRI provides detailed assessment of tumor extension, invasion, and lymph node involvement. 1, 6

Step 3: Tissue Diagnosis

Ultrasound-guided fine-needle aspiration (FNA) is the gold standard for thyroid nodules and suspicious neck masses. 1, 2

FNA indications:

• Any thyroid nodule >1 cm. 1, 2
• Nodules <1 cm with suspicious ultrasound features (hypoechogenicity, microcalcifications, irregular borders, absence of peripheral halo, central hypervascularity) PLUS high-risk clinical factors. 1, 2
• Any neck mass with physical exam features suggesting malignancy. 1

If FNA is nondiagnostic or indeterminate:

• Repeat FNA under ultrasound guidance. 2
• Consider core needle biopsy for improved diagnostic accuracy. 2
• For follicular neoplasia with normal TSH and "cold" scan: proceed to surgery for definitive diagnosis. 1

Step 4: Adjunctive Testing

• Serum calcitonin measurement: Should be integral part of thyroid nodule evaluation; higher sensitivity than FNA for medullary thyroid carcinoma. 1, 2
• Thyroid autoantibodies and thyroglobulin: Confirm chronic lymphocytic thyroiditis. 5
• ESR: Elevated in subacute granulomatous thyroiditis. 5

Step 5: Specialist Referral

Immediate referral to head and neck surgeon/endocrine surgeon for:

• Malignant or suspicious cytology (Bethesda V/VI). 2
• Rapidly enlarging mass with concerning features (anaplastic carcinoma, lymphoma). 1, 4
• Follicular neoplasia requiring surgical diagnosis. 1

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Critical Pitfalls to Avoid

• Do not assume normal thyroid function excludes thyroid malignancy: Most thyroid cancers are euthyroid. 2
• Do not override worrisome clinical findings with reassuring FNA: False-negative rates range 11-33%. 2
• Do not delay imaging in high-risk patients: Diagnostic delays directly worsen prognosis in HNSCC and anaplastic carcinoma. 1
• Do not confuse pulsatile masses with thyroid nodules: Consider vascular anomalies. 9
• Do not rely on radionuclide scanning in euthyroid patients: Ultrasound features are far more predictive of malignancy. 2