What is the differential diagnosis for enlarged lymph nodes?

Differential Diagnosis for Enlarged Lymph Nodes

Enlarged lymph nodes have a broad differential diagnosis that can be systematically categorized into infectious, malignant, inflammatory/autoimmune, and miscellaneous etiologies, with the specific differential varying significantly based on patient age, lymph node location, size, and associated clinical features.

Malignant Causes

Lymphoproliferative Disorders

• Lymphoma (Hodgkin and non-Hodgkin) represents a primary concern, particularly in adults with persistent lymphadenopathy and in young males with mediastinal involvement 1
• Post-transplant lymphoproliferative disorders include reactive plasmacytic hyperplasia, infectious mononucleosis-like lesions, polymorphic PTLD, and monomorphic PTLD (B-cell and T-cell lymphomas) 1
• Adult T-cell leukemia/lymphoma (HTLV-I associated) should be considered in endemic areas 1

Metastatic Disease

• Metastatic carcinoma from various primary sites, with invasive ductal carcinoma being the most common cause of axillary lymphadenopathy 2
• Germ cell tumors (seminoma and nonseminomatous) are of primary concern in young males with mediastinal lymphadenopathy 1
• Other solid tumor metastases depending on lymph node location and patient history 2

Infectious Causes

Bacterial Infections

• Bacterial cervical lymphadenitis can mimic other causes of cervical lymphadenopathy 1
• Pneumonia and other thoracic infections commonly cause mediastinal lymphadenopathy >1 cm 1
• Localized infections with regional lymph node drainage patterns 3

Viral Infections

• Epstein-Barr virus (infectious mononucleosis) 1
• Measles, adenovirus, enterovirus 1
• HIV-related lymphadenopathy 1

Other Infectious Etiologies

• Leptospirosis 1
• Various other infectious diseases requiring microbiological characterization 4

Inflammatory and Autoimmune Causes

Granulomatous Diseases

• Sarcoidosis frequently causes mediastinal lymphadenopathy >1 cm 1
• Other granulomatous conditions 1

Autoimmune/Inflammatory Disorders

• Kawasaki disease presents with cervical lymphadenopathy ≥1.5 cm diameter, usually unilateral and confined to the anterior cervical triangle 1
• Juvenile rheumatoid arthritis 1
• Collagen vascular diseases 2

Drug-Related

• Drug hypersensitivity reactions 1
• Methotrexate and other immunosuppressive therapy can cause Hodgkin's lymphoma-like lesions 1

Miscellaneous Causes

Cardiac and Pulmonary

• Congestive heart failure can cause enlarged mediastinal nodes >2 cm 1
• Diffuse interstitial lung diseases including usual interstitial pneumonia, nonspecific interstitial pneumonia, extrinsic allergic alveolitis, respiratory bronchiolitis, cryptogenic organizing pneumonia, and desquamative interstitial pneumonia, with prevalence and extent correlating with disease severity 1

Other Systemic Conditions

• Toxic shock syndrome 1
• Staphylococcal scalded skin syndrome 1
• Stevens-Johnson syndrome 1
• Rocky Mountain spotted fever 1
• Mercury hypersensitivity reaction (acrodynia) 1
• Metabolic disorders 3

Key Clinical Discriminators

Size Thresholds

• Lymph nodes >1.5 cm in short axis diameter require workup for potential malignancy 5
• Nodes ≤15 mm were always reactive in one study, while nodes >25 mm were always pathologic 1, 5
• 15 mm short-axis threshold serves as a key decision point in management algorithms 1, 5

Morphologic Features Suggesting Malignancy

• Loss of fatty hilum is concerning 1, 5
• Round shape (rather than oval) independently predicts malignancy 5
• Heterogeneous echogenicity on ultrasound 5
• Central necrosis strongly suggests malignancy 5
• Convex pleural interface (versus straight or concave) suggests malignant hilar nodes 1

Clinical Context

• Age matters: In primary care, only 1% of patients with unexplained lymphadenopathy have malignancy, but this increases significantly in older adults 6
• Duration >1 month warrants invasive diagnostic procedures to rule out malignancy 3
• Localized lymphadenopathy often has infectious etiology, while generalized lymphadenopathy frequently indicates hematological systemic disease in adults 3
• B symptoms (fever, night sweats, weight loss) suggest lymphoma and require PET/CT imaging 1, 5

Common Pitfalls

• Do not rely on size alone: Normal-sized nodes can harbor microscopic metastases, and enlarged nodes may be hyperplastic rather than neoplastic 1
• Benign reactive nodes with follicular hyperplasia can appear enlarged and mimic malignancy 1
• In patients with known malignancy, benign nodes are typically smaller than malignant nodes, but this distinction is less reliable for incidental findings 1
• Needle biopsy sensitivity limitations: In patients with suspected lymphoma, needle biopsy has only 67-68% sensitivity, and excisional biopsy remains the gold standard 7