What is the appropriate diagnosis and treatment for a patient with cervical lymphadenopathy, considering their past medical history of cancer, infection, or autoimmune disorders?

Diagnostic and Treatment Approach to Cervical Lymphadenopathy

The diagnostic approach to cervical lymphadenopathy must prioritize immediate exclusion of life-threatening conditions (Kawasaki disease in children with fever ≥5 days), followed by systematic evaluation based on node characteristics, patient age, and risk factors, with biopsy reserved for nodes persisting beyond 2-4 weeks or those with high-risk features.

Immediate Life-Threatening Assessment

If fever has been present for ≥5 days with cervical lymphadenopathy ≥1.5 cm, urgently evaluate for Kawasaki disease by specifically assessing for bilateral nonexudative conjunctivitis, oral changes, polymorphous rash, and extremity changes. 1 This is critical because infants <6 months have the highest risk of coronary complications. 1 Diagnosis requires fever plus ≥4 of 5 principal clinical features, though experienced clinicians may diagnose with only 3 days of fever in classic presentations. 1

Initial Clinical Characterization

Node Location and Laterality

• Unilateral cervical lymphadenopathy is typical for nontuberculous mycobacterial (NTM) infections (95% of cases), bacterial adenitis, and metastatic squamous cell carcinoma. 2, 3
• Bilateral massive cervical lymphadenopathy suggests Rosai-Dorfman-Destombes disease or systemic conditions. 4, 3
• Supraclavicular nodes are abnormal and highly suspicious for malignancy, requiring urgent evaluation. 5, 6
• Epitrochlear nodes >5 mm are abnormal and warrant investigation. 5

Age-Specific Considerations

• Children aged 1-5 years: NTM lymphadenitis is most common, with 80% due to Mycobacterium avium complex (MAC), presenting as unilateral, non-tender cervical adenopathy. 2, 1
• Adults: Over 90% of mycobacterial cervical adenitis is caused by M. tuberculosis rather than NTM. 3
• Patients >40 years have increased malignancy risk. 5

High-Risk Features for Malignancy

• Node size >2 cm 1, 6
• Hard, fixed, or matted nodes 2, 6
• Supraclavicular location 5
• Systemic symptoms: unexplained weight loss, night sweats, fever 5, 6
• Male sex, white race 5
• Prolonged tobacco and alcohol use 1

Past Medical History Considerations

Cancer History

• Patients with prior malignancy require immediate evaluation for recurrence or metastatic disease. 5
• Prolonged tobacco/alcohol use increases risk of synchronous malignancies. 1
• Lymphoproliferative disorders occur with increased frequency in primary immunodeficiency diseases (PIDDs), particularly Common Variable Immunodeficiency (CVID), with 20% developing autoimmune diseases and increased lymphoma risk. 4

Infection History

• HIV-infected patients: Consider opportunistic infections, immune reconstitution syndrome (especially if recently started antiretroviral therapy), and lymphoma. 1, 3 Obtain hepatitis B, C serology and lactate dehydrogenase (LDH) as prognostic marker. 1
• Tuberculosis exposure: Obtain tuberculin skin test (PPD), recognizing that strongly positive PPD in children with granulomatous disease warrants anti-TB therapy while awaiting culture results. 2, 3
• Recent upper respiratory infection or dental problems: Suggests reactive or bacterial lymphadenitis. 1
• Tick exposure or endemic area: Consider tularemia with skin ulcer/eschar at entry site. 1

Autoimmune Disorders

• CVID patients have 20% prevalence of autoimmune diseases, with autoimmune cytopenias (thrombocytopenic purpura, hemolytic anemia) most common at 11-12%. 4
• Autoimmune lymphoproliferative syndrome (ALPS) features persistent lymphadenopathy affecting multiple nodal chains including cervical nodes. 3
• Inflammatory bowel disease patients on immunomodulators have increased risk of EBV-associated lymphoproliferative disorders. 4
• Consider Sjögren's syndrome in adults with persistent unilateral node and parotid swelling (lymphoma risk 5-18%). 1

Diagnostic Workup Algorithm

Initial Laboratory Testing

• Complete blood count with differential 1
• Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) to differentiate bacterial from viral infections 1
• Tuberculin skin test (PPD) for suspected mycobacterial adenitis 2, 1
• HIV serology if risk factors present 1

Imaging Strategy

• Ultrasound: First-line imaging, particularly useful in obese patients with no palpable lymphadenopathy and to differentiate Kawasaki disease from bacterial lymphadenitis. 1
• CT chest/abdomen/pelvis with oral and IV contrast: Indicated if malignancy suspected. 1
• MRI: Provides detailed evaluation of lymph nodes and surrounding soft tissues for soft tissue assessment. 1

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. 1 Do not prescribe multiple courses of antibiotics without clear bacterial infection signs, as this delays malignancy diagnosis. 1

Observation vs. Immediate Biopsy

• Observe for 2-4 weeks if node characteristics suggest benign reactive process without high-risk features. 2, 1
• Immediate referral to otolaryngology if:
  • Lymphadenopathy persists ≥2 weeks without significant fluctuation 1
  • Node fails to resolve after appropriate antibiotic course 1
  • High-risk features present (size >2 cm, supraclavicular location, hard/fixed/matted, systemic symptoms) 1, 5

Critical pitfall: Partial resolution may represent infection in an underlying malignancy; if node has not completely resolved, proceed to definitive workup. 2

Biopsy Strategy

Fine-needle aspiration (FNA) is preferred over open biopsy for initial tissue sampling, with positive predictive value of 91.3% for benign and 75% for malignant causes. 1, 7 FNA is safe, accurate, and requires close communication between experienced cytologist and surgeon. 7

Excisional biopsy has diagnostic yield >95% and should be performed if FNA is non-diagnostic. 2, 1, 3 This is particularly important for:

• Suspected lymphoma (requires adequate tissue for immunophenotypic, cytogenetic, and molecular genetic analysis) 1
• NTM lymphadenitis in children: Excisional biopsy without chemotherapy is the treatment of choice with 95% success rate. 2, 1

Treatment Based on Etiology

Nontuberculous Mycobacterial Lymphadenitis (Children)

Complete surgical excision is the primary treatment with approximately 95% success rate. 2, 1 For larger lymph nodes (≥5 cm) or those in difficult anatomical sites, or for children with recurrent disease or high surgical risk, consider clarithromycin multidrug regimen in combination with corticosteroids to reduce risk of disseminated disease. 2, 1

Bacterial Lymphadenitis

Antibiotics appropriate for acute unilateral cervical lymphadenitis, especially in children with systemic symptoms (fever, rapid onset, tenderness, overlying erythema). 5

Malignancy

• Metastatic squamous cell carcinoma: External beam radiation therapy (EBRT) to cover gross disease, parametria, and nodal volumes at risk, along with concurrent platinum-based chemotherapy. 1
• Lymphoma: Treat per standard guidelines; in HIV-infected patients, treat without modifications based solely on HIV status. 1
• Brachytherapy may be indicated depending on extent of disease and patient factors. 1

Immunodeficiency-Associated Lymphoproliferation

• CVID patients with autoimmune, lymphoproliferative, or malignant diseases are treated as they would be in other clinical settings. 4
• Stem cell transplantation can be considered for patients with CVID with malignancy or severe organ damage, though experience is limited. 4
• For IBD patients on immunomodulators with suspected EBV-associated lymphoproliferative disease, discontinuation of immunosuppressive therapy may result in spontaneous regression. 4

Tularemia

Streptomycin 30 mg/kg/day in 2 divided doses or gentamicin 3-5 mg/kg/day for 7-10 days. 1

Critical Pitfalls to Avoid

• Never use corticosteroids without appropriate diagnosis, as they can mask histologic diagnosis of lymphoma or other malignancy. 5, 6
• Do not mistake NTM lymphadenitis for bacterial infection in children aged 1-5 years with unilateral, non-tender cervical node; inappropriate antibiotic treatment delays proper surgical management. 2
• Do not perform extensive workup in absence of histologic diagnosis indicative of malignant process. 7
• Recognize that reactive cervical lymphadenopathy from respiratory infections typically resolves within days of completing treatment; persistence beyond 2 weeks warrants further investigation. 2
• A lymph node ≥1.5 cm that has persisted for ≥2 weeks without significant fluctuation places patient at increased risk for malignancy or chronic infection. 2