Lymphadenopathy — Detailed Overview

1. Definition & Normal Node Parameters

• Soft, flat submandibular nodes <1 cm — often palpable in healthy children and young adults
• Inguinal nodes up to 2 cm — may be normal in adults
• Any supraclavicular or scalene node enlargement is always abnormal

2. Pathophysiology of Node Enlargement

3. Classification

By Distribution

By Duration

• Acute (<2 weeks)
• Subacute (2–6 weeks)
• Chronic (>6 weeks)

4. Etiology — Comprehensive Classification (Harrison's Table 70-1)

1. Infectious Diseases

2. Immunologic / Autoimmune Diseases

• Rheumatoid arthritis, juvenile RA
• Mixed connective tissue disease
• Systemic lupus erythematosus (SLE)
• Dermatomyositis, Sjögren's syndrome
• Serum sickness
• Drug hypersensitivity: diphenylhydantoin, hydralazine, allopurinol, primidone, gold, carbamazepine
• Angioimmunoblastic lymphadenopathy
• Primary biliary cirrhosis, graft-vs-host disease
• Silicone-associated lymphadenopathy
• IgG4-related disease
• Immune reconstitution inflammatory syndrome (IRIS)

3. Malignant Diseases

• Hematologic: Hodgkin's disease, non-Hodgkin's lymphomas, acute/chronic lymphocytic leukemia, hairy cell leukemia, malignant histiocytosis, amyloidosis
• Metastatic: Carcinomas from breast, lung, GI tract, thyroid, melanoma, genitourinary cancers

4. Lipid Storage Diseases

5. Endocrine

6. Other

• Castleman's disease (giant lymph node hyperplasia)
• Sarcoidosis
• Dermatopathic lymphadenitis
• Kikuchi's disease (histiocytic necrotizing lymphadenitis)
• Rosai-Dorfman disease (sinus histiocytosis with massive lymphadenopathy)
• Kawasaki's disease (mucocutaneous lymph node syndrome)
• Histiocytosis X, Familial Mediterranean fever
• Congestive heart failure (passive congestion)

Key epidemiologic point: In primary care, >2/3 of patients with lymphadenopathy have nonspecific or viral causes. <1% have a malignancy. In referred patients, 84% had benign diagnoses; 16% had malignancy (lymphoma or metastatic adenocarcinoma). — Harrison's 22E

5. Clinical Assessment

History

• Symptoms: Sore throat, cough, fever, night sweats, fatigue, weight loss, node pain
• Age: Children/young adults → mostly benign (viral URTIs, mono, toxoplasmosis); after age 50, malignancy incidence rises
• Exposures: Animal contact (cat-scratch disease), sexual history (STIs), travel (endemic mycoses, TB, leishmaniasis)
• Medications: Diphenylhydantoin and others can cause drug-induced lymphadenopathy
• Occupation, tobacco use (ENT exam essential in adults with cervical adenopathy + smoking)

Physical Examination

Lymphoma nodes tend to be large, discrete, symmetric, rubbery, firm, mobile, nontender. Metastatic nodes are often hard, nontender, fixed. — Harrison's 22E

6. Regional Adenopathy — Anatomical Clues

7. Imaging Findings

CT Chest — Mediastinal Lymphadenopathy

Axial contrast CT chest: enlarged mediastinal, left hilar, and aortocaval nodes (blue arrows). Differential includes lymphoma, metastasis, sarcoidosis, and granulomatous disease.

CT Abdomen — Retroperitoneal Lymphadenopathy

Coronal CT abdomen/pelvis: multiple enlarged para-aortic and paracaval nodes (red arrows) with involvement of iliac chains — appearance characteristic of lymphoma or metastatic disease.

Clinical Photo — Supraclavicular Lymphadenopathy

Subtle left supraclavicular adenopathy (arrows). Any supraclavicular enlargement warrants investigation for malignancy.

Sarcoidosis — Radiographic Pattern (Grainger & Allison)

• Bilateral symmetrical hilar and paratracheal lymphadenopathy in ~70–80% of sarcoidosis patients
• Occasionally asymmetrical; unilateral in only 1–5%
• Nodes can calcify, sometimes in eggshell pattern (shared by silicosis and histoplasmosis)
• Nodal enlargement maximal on first radiograph; usually resolves within 6–12 months
• "Icing sugar" calcification pattern characteristic

8. Diagnostic Workup

Laboratory Tests

• CBC with differential — atypical lymphocytes (EBV/CMV), leukocytosis (bacterial), blasts (leukemia), cytopenias (lymphoma/leukemia)
• ESR, CRP, LDH
• Monospot / EBV serology, CMV IgM
• Throat culture (if pharyngitis present)
• HIV testing (generalized adenopathy)
• PPD/IGRA (TB exposure risk)
• ANA, RF (if autoimmune suspected)
• Serum protein electrophoresis
• Chest X-ray — mediastinal adenopathy, pulmonary infiltrates

Imaging

• Ultrasound: First line for superficial nodes — identifies necrosis, guides biopsy; nodes with central necrosis warrant immediate surgical attention
• CT chest/abdomen/pelvis: Staging, detecting non-palpable adenopathy; CT identifies nodes in mediastinum, retroperitoneum, and iliac chains
• PET-CT: Preferred for lymphoma staging and treatment response
• MRI: Useful for delineating lymphatic channels (e.g., cystic hygroma, pelvic nodes)

9. Indications for Lymph Node Biopsy

• Nodes ≤1.0 cm² (1×1 cm) → almost always benign; observe with exclusion of mono/toxoplasmosis
• >2 cm diameter in younger patients (9–25 y) → predictor of malignant or granulomatous disease
• >2.25 cm² (1.5×1.5 cm) → best cutoff to distinguish malignant/granulomatous from benign

• Supraclavicular location (always abnormal)
• Fixed, nontender, progressively enlarging node
• Constitutional symptoms: night sweats, unexplained weight loss, fever (B symptoms)
• Mediastinal adenopathy on imaging
• Failure to resolve after 4–6 weeks of observation (or antibiotic therapy when appropriate)
• Splenomegaly without obvious cause

• Excisional biopsy preferred for lymphoma (fresh specimen, not formalin — enables flow cytometry, immunophenotyping, cytogenetics)
• Core needle biopsy — acceptable for some solid malignancies
• Fine-needle aspiration (FNA) — useful for rapid cytology but insufficient for lymphoma diagnosis

10. Specific Conditions — Key Features

Infectious Mononucleosis (EBV)

• Generalized lymphadenopathy + pharyngitis + fever + splenomegaly
• Atypical lymphocytes on smear; positive monospot; EBV IgM
• Posterior cervical > anterior cervical involvement

Tuberculosis / Atypical Mycobacteria

• Cervical nodes most common (scrofula)
• Nontuberculous mycobacteria: fluctuant nodes, violaceous overlying skin, positive AFB cultures, tuberculin skin test positive; surgical excision often required (most NTM resistant to standard chemotherapy)

Cat-Scratch Disease (Bartonella henselae)

• Painful regional adenopathy, self-limited
• Cat exposure history (not always present)
• Diagnosis: indirect immunofluorescence antibody (moderate specificity) or PCR of biopsy
• Usually resolves without treatment

Lymphoma

• Hodgkin's: rubbery, discrete, symmetric nodes; mediastinal involvement common; Reed-Sternberg cells on biopsy
• Non-Hodgkin's: more variable distribution; systemic symptoms less predictable; excisional biopsy + flow cytometry required

Metastatic Cancer

• Hard, nontender, fixed nodes
• Location guides primary: neck (head/neck, thyroid); axilla (breast, melanoma); supraclavicular (lung, GI, testis, ovary); inguinal (genitourinary, melanoma, rectal)
• Virchow's node (left supraclavicular): Troisier's sign → GI primary (gastric cancer most classic)

Sarcoidosis

• Bilateral hilar lymphadenopathy ± paratracheal nodes ± parenchymal disease
• Granulomas on biopsy (non-caseating)
• ACE level elevated in ~60%; hypercalcemia possible

Kawasaki Disease

• Cervical lymphadenopathy + fever >5 days, conjunctival injection, rash, oral changes, extremity changes
• Children <5 years most commonly affected
• Risk of coronary artery aneurysms

Kikuchi's Disease (Histiocytic Necrotizing Lymphadenitis)

• Young women, self-limited
• Tender cervical adenopathy + fever
• Histology: necrotic foci with histiocytes, no neutrophils

11. Approach Algorithm

Lymphadenopathy detected
        ↓
Localized or Generalized?
        ↓
History + Physical Exam + CBC, ESR, monospot, CXR
        ↓
Obvious cause found (viral URTI, dental) → Treat and observe 4–6 weeks
        ↓ (no resolution or high-risk features)
Size ≥2 cm? Fixed? Supraclavicular? B symptoms? Constitutional symptoms?
        ↓ YES → Biopsy (excisional preferred)
        ↓ NO  → Targeted workup (serology, TB testing, CT imaging)

Summary Table

• Harrison's Principles of Internal Medicine 22E (2025) — Chapters 70 (Lymphadenopathy and Splenomegaly)
• Goldman-Cecil Medicine — Hematologic section
• Sabiston Textbook of Surgery — Neck masses, lymphadenopathy
• Grainger & Allison's Diagnostic Radiology — Sarcoidosis imaging