What is lymphadenopathy, its types, causes, and grading?

Lymphadenopathy: Definition, Types, Causes, and Grading

Definition

Lymphadenopathy is defined as abnormal enlargement of lymph nodes, generally considered present when nodes exceed 1 cm in diameter, though this threshold varies by anatomic location. 1 Supraclavicular, popliteal, iliac, and epitrochlear nodes (>5 mm) are considered abnormal regardless of size. 2

Types of Lymphadenopathy

Localized vs. Generalized Classification

The fundamental classification distinguishes localized lymphadenopathy (75% of cases) from generalized lymphadenopathy (25% of cases), which has critical diagnostic and prognostic implications. 3

Localized Lymphadenopathy

• Involves a single anatomic region or nodal chain 2
• Most commonly caused by regional pathology in the drainage area 3
• Cervical nodes are most frequently affected, followed by axillary and inguinal chains 4
• Unilateral presentation is more common (95% in certain infections) 4

Generalized Lymphadenopathy

• Defined as involvement of two or more non-contiguous nodal regions 2, 5
• Always indicates underlying systemic disease requiring comprehensive evaluation 3, 2
• Associated with HIV, lymphoma, tuberculosis, sarcoidosis, and autoimmune conditions 6, 7

Anatomic Location-Based Types

Specific nodal locations carry distinct diagnostic significance:

• Cervical lymphadenopathy: Most common site; involves anterior, posterior, submandibular, and supraclavicular chains 4, 8
• Supraclavicular nodes: Always suspicious for malignancy (thoracic or abdominal primary tumors) 3, 1
• Posterior cervical nodes: Particularly concerning for lymphoma, nasopharyngeal carcinoma, metastatic head/neck tumors, or tuberculosis 8
• Hilar/mediastinal nodes: Bilateral hilar adenopathy is characteristic of sarcoidosis (85% of stage 1 cases) 9
• Epitrochlear nodes: Abnormal when >5 mm; associated with lymphoma or infections 2

Causes of Lymphadenopathy

Infectious Causes

Infections account for the majority of lymphadenopathy in primary care settings, particularly in localized presentations. 1, 5

Bacterial Infections

• Streptococcus pneumoniae and Haemophilus influenzae cause recurring adenopathy, especially with immune dysfunction 6
• Staphylococcus aureus and gram-negative organisms occur in advanced disease and neutropenia 6
• Mycobacterial infections (tuberculosis and NTM) present with persistent adenopathy, fever, night sweats, and weight loss 6, 4
• In children aged 1-5 years, non-tuberculous mycobacteria are common causes of cervical adenopathy 4
• In adults, >90% of mycobacterial cervical adenitis is M. tuberculosis 4

Viral Infections

• HIV causes generalized lymphadenopathy through direct marrow suppression, immune destruction, and opportunistic infections 6, 7
• Epstein-Barr virus (EBV) and cytomegalovirus (CMV) produce adenopathy, particularly in immunocompromised hosts 6

Malignant Causes

Malignancy must be excluded in persistent or suspicious lymphadenopathy, particularly in high-risk anatomic locations. 8, 3

Hematologic Malignancies

• Chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma are primary causes of recurring adenopathy 6
• Lymphoma produces adenopathy through marrow infiltration, hypersplenism, or autoimmune mechanisms 6
• Multiple myeloma causes functional hypogammaglobulinemia despite elevated immunoglobulins, predisposing to infections and adenopathy 6

Solid Tumors

• Metastatic disease should be considered with supraclavicular or epitrochlear involvement 6, 1
• Nasopharyngeal carcinoma and head/neck primaries metastasize to posterior cervical nodes 8

Autoimmune and Inflammatory Conditions

Autoimmune disorders frequently present with generalized lymphadenopathy. 6, 2

• Systemic lupus erythematosus and rheumatoid arthritis cause adenopathy through immune complex deposition and chronic inflammation 6
• Autoimmune lymphoproliferative syndrome (ALPS) characteristically presents with chronic lymphadenopathy (≥6 months), hepatosplenomegaly, and autoimmune cytopenias 9, 6
• Kawasaki disease presents with unilateral cervical adenopathy ≥1.5 cm 4
• Rosai-Dorfman-Destombes disease presents with massive, painless, bilateral cervical lymphadenopathy 4

Granulomatous Diseases

Sarcoidosis commonly presents with bilateral hilar lymphadenopathy. 9, 6

• Asymptomatic bilateral hilar adenopathy is confirmed as sarcoidosis in 85% of cases 9, 6
• Alternative diagnoses include tuberculosis (38% of non-sarcoid cases) and lymphoma (25%) 9, 6
• Sarcoidosis with Löfgren's syndrome, lupus pernio, or Heerfordt's syndrome has sufficiently high clinical suspicion that lymph node sampling may not be required 9, 6

Primary Immunodeficiency Disorders

• Common variable immunodeficiency (CVID) presents with lymphadenopathy in 15-20% of patients 6
• ALPS requires persistent lymphadenopathy/splenomegaly >6 months affecting ≥2 nodal chains (if isolated adenopathy) plus elevated TCR αβ double-negative T cells ≥1.5% of total lymphocytes 9

Iatrogenic and Drug-Related Causes

• Methotrexate, corticosteroids, and chemotherapy increase infection risk and cause drug-induced lymphadenopathy 6
• CAR T-cell therapy produces prolonged cytopenias and lymphadenopathy weeks to months post-infusion 6
• Heavily pretreated patients receiving multiple chemotherapeutic regimens face 90% risk of serious infectious complications 6

Grading and Risk Stratification

Physical Examination Characteristics

Node characteristics determine risk stratification and urgency of evaluation. 8, 2, 5

Size Criteria

• Nodes >1 cm are generally considered abnormal 1
• Nodes >1.5 cm are concerning for malignancy 8
• Nodes >2 cm, particularly in children, raise suspicion for malignancy or granulomatous disease 5

Consistency and Mobility

• Firm or hard nodes suggest malignancy 8, 2
• Matted or fused nodes indicate malignancy or granulomatous disease 5
• Fixed nodes (immobile, adherent to surrounding structures) are highly suspicious for malignancy 8
• Tender nodes typically indicate infection or inflammation 2

High-Risk Features Requiring Urgent Evaluation

• Supraclavicular location (always worrisome for malignancy) 3, 1, 2
• Epitrochlear nodes >5 mm 2
• Persistence >2-4 weeks without resolution 8, 1, 2
• Presence of B symptoms (fever, night sweats, unintentional weight loss) 8, 2, 5
• Ulceration of overlying skin 8

Duration-Based Classification

Temporal progression guides diagnostic approach. 8, 1, 5

• Acute lymphadenopathy (<2 weeks): Usually infectious, observation with or without antibiotics is appropriate if benign features present 8, 1
• Subacute lymphadenopathy (2-4 weeks): Warrants close observation in low-risk patients; proceed to imaging/biopsy if high-risk features present 1, 2
• Chronic lymphadenopathy (>4 weeks): Requires imaging, laboratory studies, and consideration of biopsy 5
• ALPS-specific criterion: Persistent lymphadenopathy >6 months 9

Risk Factors for Malignancy

The following factors significantly increase malignancy risk and warrant aggressive evaluation: 2, 5

• Age >40 years 2
• Male sex 2
• White race 2
• Supraclavicular location 2
• Systemic symptoms (B symptoms) 2
• Hard, fixed, or matted nodes 8, 5
• Nodes >2 cm 5

Common Pitfalls to Avoid

Do not use corticosteroids empirically without tissue diagnosis, as they mask histologic features of lymphoma and other malignancies. 2, 5 This is a critical error that can delay diagnosis and worsen outcomes.

Do not assume bilateral hilar lymphadenopathy is always benign sarcoidosis—tuberculosis (38%) and lymphoma (25%) account for significant alternative diagnoses requiring exclusion. 9

Do not wait to evaluate supraclavicular or infraclavicular nodes—these locations are always suspicious and require immediate workup regardless of other features. 3, 1

Do not rely solely on fine-needle aspiration for posterior cervical adenopathy—excisional biopsy (>95% diagnostic yield) is preferred when lymphoma or metastatic disease is suspected. 4, 8