II. Epidemiology

  1. Incidence of Unexplained Lymphadenopathy in primary care: 0.6%
  2. Cancer risk in unexplained adenopathy (primary care)
    1. Age over 40 years: 4% cancer risk
    2. Age under 40 years: 0.4% cancer risk

III. Definitions

  1. Lymphadenopathy
    1. Lymph Nodes with abnormal size
    2. Lymph Nodes with abnormal consistency
    3. Lymph Nodes of abnormal number
  2. Classifications
    1. Localized Lymphadenopathy
      1. Limited to one area of involvement
    2. Generalized Lymphadenopathy
      1. Two or more non-contiguous areas

VI. History: Exposures

  1. See Medication Causes of Lymphadenopathy
  2. Animal Exposures
    1. Cat Exposure (Cat Scratch Disease or Toxoplasmosis)
    2. Ingestion of undercooked meat (Toxoplasmosis, Brucellosis, Anthrax)
    3. Rabbit, sheep or cattle wool, hair or hide (Anthrax, Brucellosis, Tularemia)
    4. Rodents and associated fleas (Bubonic Plague)
  3. Tick Bite (Lyme Disease or Tularemia)
  4. Tuberculosis exposure
  5. Intravenous Drug Abuse
  6. Blood Transfusion history
  7. Sexually Transmitted Disease exposure
    1. See Lymphadenopathy Causes
    2. HIV Infection
    3. Lymphogranuloma venereum
    4. Syphilis
    5. Chancroid
  8. Occupational or hobby exposure
    1. Hunters or Trappers (Tularemia)
    2. Fish handlers (Erysipeloid)
    3. Mining, masonry or metal work (Beryllium or Silicon exposure)

VII. History: Travel

  1. See Lymphadenopathy in the Febrile Returning Traveler
  2. Travel to Southwestern United States
    1. Coccidioidomycosis
    2. Bubonic Plague
  3. Travel to Southeastern or central United States
    1. Histoplasmosis
  4. Travel to Southeast Asia and Australia
    1. Scrub Typhus
  5. Travel to central or west Africa
    1. African Trypanosomiasis (African Sleeping Sickness)
  6. Travel to central or south America
    1. American Trypanosomiasis (Chagas' Disease)
  7. Travel East Africa, China, Latin America, Mediterranean
    1. Kala-azar (Leishmaniasis)
  8. Travel to Mexico, Peru, Chile, Pakistan, Egypt, Indonesia
    1. Typhoid Fever

VIII. Risk Factors: Malignant cause of Lymphadenopathy

  1. Age >40 years old
  2. Lymphadenopathy >4-6 weeks (esp if not returned to baseline by 8-12 weeks)
  3. Generalized Lymphadenopathy (at least 2 regions involved)
  4. Male gender
  5. White race
  6. Supraclavicular Lymphadenopathy
  7. Lymphadenopathy associated with fever, Night Sweats, weight loss, Hepatomegaly or Splenomegaly

IX. Symptoms

  1. Isolated Lymphadenopathy <2 weeks or >12 months without change
    1. Malignancy unlikely
    2. Exception: Low grade or indolent Lymphoma (which have associated systemic symptoms)
  2. Symptoms associated with malignancy (e.g. Leukemia, Lymphoma, solid malignancy metastases)
    1. Fever, Night Sweats and weight loss
    2. Splenomegaly, Hepatomegaly or Bruising
    3. Lymphadenopathy >5mm supraclavicular, popliteal or iliac
  3. Symptoms associated with Connective Tissue Disease (e.g. RA, SLE, Sjogren Syndrome, Dermatomyositis)
    1. Fever, chills
    2. Arthralgias and myalgias
    3. Rash
    4. Joint Stiffness

X. Signs

  1. Abnormal Lymph Node size criteria
    1. Epitrochlear, popliteal or iliac Lymphadenopathy >0.5 cm
    2. Inguinal Lymphadenopathy >1.5 cm
    3. Isolated Lymphadenopathy in children >1.5 to 2.0 cm
    4. Other Lymphadenopathy >1.0 cm
  2. Tenderness to palpation
    1. Does not differentiate benign from malignant nodes
  3. Lymph Node consistency
    1. Rock-hard nodes: Metastatic cancer
    2. Firm-Rubbery nodes: Lymphoma
    3. Soft nodes: Inflammation or infection
    4. Shotty nodes (multiple small buckshot size): Viral
  4. Matted Nodes (connected nodes)
    1. Benign causes
      1. Tuberculosis
      2. Sarcoidosis
      3. Lymphogranuloma venereum
    2. Malignant causes
      1. Metastatic cancer
      2. Lymphoma
  5. Splenomegaly
    1. Infectious Mononucleosis
    2. Hodgkin's Disease
    3. Non-Hodgkin's Lymphoma
    4. Chronic Lymphocytic Leukemia
    5. Acute Leukemia
    6. Rarely associated with metastatic cancer

XI. Evaluation: Initial Tests

  1. Evaluation should be directed at region of primary Lymphadenopathy
    1. Specific regional approaches are preferred over more broad, shotgun approaches
    2. See Neck Masses in Children
    3. See Neck Masses in Adults
  2. Indications
    1. Specific indications based on location and exposures
    2. Generalized Lymphadenopathy
  3. Tests
    1. Complete Blood Count with manual differential
    2. Monospot (MononucleosisSerology)
  4. Management
    1. Consider antibiotics for persistent acute anterior cervical Lymphadenitis with systemic symptoms in children
    2. Empiric options should target Staph aureus and Group A Streptococcus (Cephalosporins, Augmentin, Clindamycin)
    3. Avoid Corticosteroids until definitive diagnosis made (may mask Lymphoma or Leukemia diagnosis)

XII. Evaluation: Second-line Tests

  1. Indications
    1. Specific indications and normal initial tests
    2. Persistent Generalized Lymphadenopathy
  2. Tests
    1. Tuberculin Skin Test (Purified Protein Derivative)
    2. Rapid Plasma Reagin (RPR)
    3. Antinuclear Antibody (ANA)
    4. Hepatitis B Serology (HBsAg)
    5. HIV Test
  3. Imaging
    1. Chest XRay
    2. Head and neck imaging (as indicated)
      1. Ultrasound is preferred in children <14 years old
      2. MRI or CT of the neck

XIII. Evaluation: Third-line Tests (Biopsy)

  1. Indications
    1. Persistent Lymphadenopathy for more than 3-4 weeks
    2. Malignancy or serious disease suspected
  2. Biopsy: Lymph Node biopsy of most abnormal or largest node
    1. Fine needle aspirate (FNA)
      1. Fast, accurate, minimally invasive and safe
      2. High accuracy except where Lymph Node architecture needs to be defined (e.g. Lymphoma)
      3. Lioe (1999) Cytopathology 10(5): 291-7 [PubMed]
    2. Core needle biopsy
    3. Excisional Biopsy preferred over FNA or needle biopsy if Lymphoma suspected
  3. Efficacy
    1. Highest yield site: Supraclavicular nodes
    2. Lowest yield site: Inguinal nodes
  4. Most common findings on biopsy
    1. Abnormal but non-specific findings (40%)
    2. Metastatic cancer (25%)
    3. Intrinsic malignancy such as Lymphoma (20%)
    4. Tuberculosis (10%)

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