What is the differential diagnosis and management approach for a patient presenting with cervical lymphadenopathy?

Cervical Lymphadenopathy: Differential Diagnosis and Management

Differential Diagnosis by Category

Infectious Causes (Most Common)

Bacterial Infections:

• Acute bacterial lymphadenitis presents with rapid onset, warmth, erythema of overlying skin, localized tenderness, and fever, typically following upper respiratory infection or dental problems 1, 2
• Mycobacterial infections differ dramatically by age: in children aged 1-5 years, nontuberculous mycobacteria (NTM), particularly Mycobacterium avium complex, cause 80% of mycobacterial cervical lymphadenitis and present as unilateral, non-tender nodes developing insidiously without systemic symptoms 3
• In adults, tuberculous lymphadenitis accounts for over 90% of mycobacterial cervical lymphadenopathy 3
• Tularemia (ulceroglandular form) presents with tender regional adenopathy and skin ulcer/eschar at tick bite entry site in endemic areas 2

Viral Infections:

• Reactive lymphadenitis from viral upper respiratory infections is the most common cause in children, affecting up to 90% of children aged 4-8 years 4
• Infectious mononucleosis presents with the clinical triad of fever, pharyngitis, and cervical lymphadenopathy with relative lymphocytosis and positive monospot test 5
• Cytomegalovirus causes lymphocytosis with negative monospot test 5

Other Infections:

• Toxoplasmosis presents with monocytosis, negative tuberculin test, and positive indirect fluorescent antibody test 5
• In HIV-infected patients, opportunistic infections including cryptococcosis (1.5%), Talaromyces marneffei (1.5%), and other fungi occur exclusively 6

Malignant Causes

In HIV-Negative Adults:

• Metastatic carcinomas (14%) are most common, including small cell carcinomas, adenocarcinomas, squamous cell carcinomas, and hepatocellular carcinoma 6
• HPV-positive oropharyngeal cancer presents with bilateral, massive, painless cervical lymphadenopathy and has better prognosis than HPV-negative disease 1
• Non-Hodgkin lymphoma should be considered in adults with persistent unilateral nodes and systemic symptoms, especially with unexplained weight loss, night sweats, or parotid swelling (Sjögren's-associated lymphoma risk 5-18%) 2

In HIV-Positive Patients:

• Non-Hodgkin's lymphoma (2.4%) is most common, followed by Kaposi's sarcoma (0.9%) and metastatic squamous cell carcinomas (0.7%) 6
• Malignant lesions overall account for only 4.2% of cervical lymphadenopathy in HIV patients versus 20.6% in HIV-negative patients 6

Classic Nodal Rosai-Dorfman-Destombes Disease:

• Presents with bilateral, massive, painless cervical lymphadenopathy with or without intermittent fevers, night sweats, and weight loss 7

Marginal Zone Lymphomas:

• Nodal MZL typically presents with disseminated lymphadenopathy (mostly cervical and abdominal), with 10-20% having B symptoms 7

Autoimmune/Inflammatory Causes

• Sarcoidosis presents with negative tuberculin test and hilar lymphadenopathy on chest x-ray 5
• Kawasaki disease requires urgent evaluation if fever ≥5 days with cervical lymphadenopathy ≥1.5 cm, looking specifically for bilateral nonexudative conjunctivitis, oral changes, polymorphous rash, and extremity changes 2

Risk Stratification for Malignancy

High-risk features mandating immediate workup include:

• Age >40 years 1, 8
• Male sex 8
• Supraclavicular location 1, 8
• Size >2 cm 2, 8
• Fixed or firm consistency 1, 2
• Duration ≥2 weeks without significant fluctuation 1, 2
• Constitutional symptoms: unexplained weight loss >10%, night sweats, fever 1
• Generalized lymphadenopathy (≥2 regions) 8

Diagnostic Algorithm

Initial Assessment

History must document:

• Duration of lymphadenopathy (≥2 weeks is high-risk) 1
• Fever pattern and duration (≥5 days requires Kawasaki evaluation in children) 2
• Constitutional symptoms: night sweats, weight loss >10% body weight, performance status 1, 2
• Cancer risk factors: tobacco use, alcohol consumption, HPV-related sexual history, prior malignancy 1
• Infectious exposures: recent URI, dental problems, tuberculosis exposure, HIV risk factors, tick exposure 2
• Age: children 1-5 years peak for NTM; adults >40 years higher malignancy risk 1, 3

Physical examination must assess:

• Node characteristics: size, consistency (firm/fixed/rubbery), mobility, tenderness 1, 2
• Overlying skin: warmth, erythema suggesting bacterial infection 2
• Signs of extensive disease: trismus, reduced tongue protraction, earache 2
• Other nodal regions to determine localized versus generalized lymphadenopathy 8

Laboratory Workup

Initial blood tests:

• Complete blood count with differential, ESR, CRP 1, 2
• Lactate dehydrogenase (LDH) 1
• Liver function tests 1

Additional testing based on clinical suspicion:

• Tuberculin skin test (PPD) for suspected mycobacterial adenitis 2, 3
• Monospot test for infectious mononucleosis 5
• HIV serology if risk factors present 2, 6
• PSA for males with adenocarcinoma, AFP and hCG for midline lymphadenopathy, chromogranin A for suspected neuroendocrine tumor 1

Imaging Strategy

CT scan of neck with contrast is the primary imaging modality for evaluating cervical lymphadenopathy 1

• Ultrasound is useful for differentiating cystic from solid masses, guiding fine-needle aspiration, and evaluating nodes in obese patients with non-palpable adenopathy 1, 2
• CT chest, abdomen, and pelvis with contrast is required when malignancy is suspected 1, 2
• MRI provides detailed evaluation of lymph nodes and surrounding soft tissues 2

Antibiotic Trial Decision

Only prescribe antibiotics if clear signs of bacterial infection are present: warmth, erythema of overlying skin, localized tenderness, fever, tachycardia, or recent upper respiratory infection/dental problem 2

• Do not prescribe multiple courses of antibiotics without clear bacterial infection signs, as this significantly delays cancer diagnosis 1, 2
• Reactive cervical lymphadenopathy from respiratory infections typically resolves within days of completing treatment 3

Tissue Diagnosis

Fine-needle aspiration (FNA) is the first-line tissue sampling method, with positive predictive value of 91.3% for benign and 75% for malignant causes 1, 2

• Excisional biopsy is the gold standard with diagnostic yield >95% and is indicated when FNA is non-diagnostic 1, 2
• For suspected lymphoma, flow cytometry, immunophenotyping, and cytogenetic and molecular genetic analysis must be performed 1, 2
• In children aged 1-5 years with unilateral, non-tender cervical node, excisional biopsy without chemotherapy is the treatment of choice for NTM lymphadenitis with 95% success rate 2, 3

Management by Etiology

Bacterial Lymphadenitis

• Treat with appropriate antibiotics only when clear bacterial signs present 2
• Follow-up within 2 weeks to evaluate resolution 3

NTM Lymphadenitis in Children

• Complete surgical excision is primary treatment with 95% success rate 3
• For larger lymph nodes (≥5 cm) or difficult anatomical sites, clarithromycin multidrug regimen may be considered 3

Tuberculous Lymphadenitis

• Anti-TB therapy is required, with public health notification mandatory 3

Malignancy

• For metastatic squamous cell carcinoma, external beam radiation therapy to cover gross disease, parametria, and nodal volumes at risk, along with concurrent platinum-based chemotherapy 2
• Treat per standard cancer guidelines without modifications based solely on HIV status 2

Critical Pitfalls to Avoid

• Never prescribe multiple courses of antibiotics without clear infectious etiology, as this significantly delays cancer diagnosis 1
• Do not use corticosteroids without appropriate diagnosis 8
• Do not assume partial resolution after antibiotics excludes malignancy; infection may occur in underlying malignancy 3
• Infants <6 months with Kawasaki disease have highest risk of coronary complications and require especially high suspicion 2
• Distinguish tuberculosis from NTM in children, as only 10% of culture-proven mycobacterial cervical lymphadenitis is tuberculosis, but this distinction fundamentally changes treatment and requires public health notification 3

Urgent Referral Criteria

Refer to otolaryngology urgently if:

• Lymphadenopathy persists ≥2 weeks without significant fluctuation 2
• Lymphadenopathy fails to resolve after appropriate antibiotic course 2
• Lymph node size >2 cm, multiple levels of adenopathy, or supraclavicular location 2
• Fixed, firm, or ulcerated nodes 3