What is the differential diagnosis for a unilateral cervical lymph node that is swollen and firm?

Differential Diagnosis for Unilateral Cervical Lymph Node Swelling (Firm)

A firm, unilateral cervical lymph node >1.5 cm in an adult should be considered malignant until proven otherwise, with metastatic head and neck squamous cell carcinoma and lymphoma being the most common causes. 1

Immediate Risk Stratification

High-Risk Features Suggesting Malignancy

• Firm texture with size >1.5 cm strongly suggests malignancy (malignant nodes are typically firm to palpation and >1.5 cm diameter) 1
• Reduced mobility in longitudinal or transverse planes indicates possible invasion of adjacent structures 1
• Age >40 years significantly increases malignancy risk 1, 2
• Duration ≥2 weeks without resolution warrants urgent evaluation 2
• Supraclavicular location or multiple matted nodes are particularly concerning 1, 3

Critical Pitfall

Do NOT assume firmness alone excludes cystic metastases—HPV-positive oropharyngeal cancers can present with soft, cystic nodes, but firm texture remains highly suspicious for solid malignancy. 4

Primary Differential Diagnoses

Malignant Causes (38% of persistently enlarged nodes) 5

Metastatic Head and Neck Squamous Cell Carcinoma

• Most common malignant cause in adults with firm unilateral cervical adenopathy 1
• Risk factors: tobacco use, alcohol abuse, age >40 years 1, 2
• Associated symptoms: hoarseness, otalgia, dysphagia, unexplained weight loss 2
• HPV-positive oropharyngeal cancer increasingly common even without traditional risk factors 1, 4

Lymphoma

• Presents with firm, rubbery nodes that may be unilateral or bilateral 4, 5
• Systemic symptoms: night sweats, unexplained weight loss, fever 2
• Sixty-two cases of malignant lymphoma identified in one series of 326 patients with persistent cervical adenopathy 5

Metastatic Thyroid Carcinoma

• Papillary thyroid cancer commonly metastasizes to cervical nodes 4
• May present with firm lateral neck mass before primary thyroid lesion is identified 4

Infectious Causes

Bacterial Lymphadenitis (Acute)

• Caused by Staphylococcus aureus or Streptococcus pyogenes in 40-80% of cases 6
• Presents with warmth, erythema of overlying skin, localized tenderness, fever 2
• Only prescribe antibiotics if clear bacterial infection signs are present—multiple antibiotic courses without improvement delay malignancy diagnosis 2

Mycobacterial Infections

• Tuberculous adenitis: >90% of mycobacterial cervical adenitis in adults is M. tuberculosis 7
• Typically unilateral, painless, posterior cervical or supraclavicular location 8
• High index of suspicion needed; tuberculin skin test (PPD) indicated 2, 7

Nontuberculous Mycobacteria (NTM)

• Most common in children aged 1-5 years (95% unilateral, 80% due to MAC) 2, 7
• Excisional biopsy without chemotherapy is treatment of choice with 95% success rate 2

Cat-Scratch Disease

• Common cause of subacute/chronic unilateral lymphadenitis 6
• History of cat exposure or scratch is key diagnostic clue 6

Tularemia (Ulceroglandular Form)

• Consider with tick exposure or endemic area residence 2
• Look for skin ulcer/eschar at entry site with tender regional adenopathy 2

Autoimmune/Inflammatory Causes

Kawasaki Disease

• If fever ≥5 days with unilateral cervical lymphadenopathy ≥1.5 cm, urgently evaluate for Kawasaki disease 1, 2
• Look for: bilateral nonexudative conjunctivitis, oral changes (strawberry tongue, lip cracking), polymorphous rash, extremity changes 1
• Cervical lymphadenopathy is least common principal feature but may be most prominent initial finding 1
• Diagnosis requires fever plus ≥4 of 5 principal clinical features 1

Other Autoimmune Conditions

• Rosai-Dorfman-Destombes disease: massive, painless, typically bilateral (but can be unilateral initially) 7
• Autoimmune lymphoproliferative syndrome (ALPS): persistent lymphadenopathy affecting multiple chains 7

Mandatory Workup Algorithm

Step 1: Detailed History and Physical Examination

• Document fever duration, pattern, night sweats, weight loss 2
• Tobacco and alcohol use history (increases synchronous malignancy risk) 2
• Sexual history (oral sex, multiple partners increase HPV-related cancer risk) 1
• Assess for trismus, reduced tongue protraction, earache (suggests deeper involvement) 2
• Examine all nodal chains to exclude generalized lymphadenopathy 3

Step 2: Initial Laboratory Testing

• Complete blood count with differential, ESR, CRP 2
• Tuberculin skin test (PPD) if mycobacterial infection suspected 2, 7
• HIV serology if risk factors present 2

Step 3: Imaging

• CT neck with IV contrast or MRI with contrast for all high-risk patients (age >40, firm texture, size >1.5 cm, duration ≥2 weeks) 2, 4
• Ultrasound can differentiate Kawasaki disease lymphadenopathy from bacterial lymphadenitis 1, 2
• Ultrasound features helpful for etiology: echogenicity, calcification, intranodal cystic necrosis, matting 9

Step 4: Tissue Diagnosis

• Fine-needle aspiration (FNA) is first-line tissue diagnosis (positive predictive value 91.3% for benign, 75% for malignant) 2
• Image-guided FNA directed at solid components for optimal yield 4
• Excisional biopsy if FNA non-diagnostic (diagnostic yield >95%) 2, 7
• Never perform open excisional biopsy before imaging and FNA if malignancy suspected—risks tumor spillage and worsens outcomes 4

Urgent Referral Criteria

Refer to otolaryngology urgently if: 2

• Lymphadenopathy persists ≥2 weeks without significant fluctuation
• Lymphadenopathy fails to resolve after appropriate antibiotic course
• Size >2 cm, multiple levels of adenopathy, or supraclavicular location
• Fixed/non-mobile mass
• Associated symptoms: hoarseness, otalgia, dysphagia, unexplained weight loss

Key Clinical Pearls

• Lymph nodes >1 cm diameter are generally considered abnormal; >1.5 cm significantly increases malignancy concern 1, 3
• Rock hard, rubbery, or fixed consistency mandates malignancy workup 3
• Supraclavicular nodes are malignant until proven otherwise 3
• Persistently swollen cervical lymph nodes (38% malignancy rate in one series) require prompt biopsy 5
• Observation period of 2-4 weeks only appropriate for benign-appearing nodes in low-risk patients 3
• In HIV-infected patients starting antiretroviral therapy, consider immune reconstitution syndrome 7