Lymphadenopathy

See Also

Epidemiology

Incidence of Unexplained Lymphadenopathy in primary care: 0.6%
Cancer risk in unexplained adenopathy (primary care)
1. Overall cancer risk: 1.1%
2. Age over 40 years: 4% cancer risk

Definitions

Lymphadenopathy
1. Lymph Nodes with abnormal size
2. Lymph Nodes with abnormal consistency
3. Lymph Nodes of abnormal number
Lymphadenitis
1. Infectious or inflammatory Lymph Node swelling (Lymphadenopathy)
2. Associated with localized pain, tenderness, edema and skin changes
3. Systemic symptoms such as fever may also be present
Classifications
1. Localized or Regional Lymphadenopathy
  1. Limited to one area of involvement
2. Generalized Lymphadenopathy
  1. Two or more non-contiguous areas

Causes

See Medication Causes of Lymphadenopathy
See Lymphadenopathy in the Febrile Returning Traveler
Generalized Lymphadenopathy (25% of causes, typically systemic illness)
1. See Generalized Lymphadenopathy
Regional Lymphadenopathy
1. See Lymphadenopathy of the Head and Neck
2. See Regional Lymphadenopathy
3. See Hilar Adenopathy
Mnemonic: MIAMI
1. Malignancy (e.g. Leukemia, Lymphoma, metastases, Skin Cancer)
2. Infection (e.g. Skin Infections, Viral Infections, Granulomatous diseases, Syphilis, Tuberculosis, Cat Scratch Disease)
3. Autoimmune Disorders (e.g. Dermatomyositis, RA, SLE, Sarcoidosis)
4. Miscellaneous or unusual causes (e.g. Kawasaki Disease, PFAPA, Castleman disease)
5. Iatrogenic (e.g. medications, Vaccines, Serum Sickness)

History
Exposures

Symptoms suggestive of acute infection
1. Fever, chills, malaise
2. Pharyngitis, cough, congestion
3. Headache, myalgias
4. Nausea or Vomiting
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)
Tick Bite (Lyme Disease or Tularemia)
Tuberculosis exposure
Blood Transfusion history
New medications or Vaccinations
1. See Medication Causes of Lymphadenopathy
Sexually Transmitted Disease exposure
Occupational or hobby exposure
1. Hunters or Trappers (Tularemia)
2. Fish handlers (Erysipeloid)
3. Mining, masonry or metal work (Beryllium or Silicon exposure)
Autoimmune related symptoms (e.g. RA, SLE, Dermatomyositis, Drug Reaction)
1. Arthralgias or Joint Stiffness
2. Muscle Weakness
3. Fever or chills
Substance Use Disorders (infectious or malignancy risk)

History
Travel

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

Risk Factors
Malignant Cause of Lymphadenopathy

Age >40 years old
Lymphadenopathy >4-6 weeks (esp if not returned to baseline by 8-12 weeks)
Generalized Lymphadenopathy (at least 2 regions involved)
Male gender
White race
Supraclavicular Lymphadenopathy
B Symptoms (fever, Night Sweats)
Unintentional Weight Loss (esp. >10 lb or 4.5 kg in last 6-12 months)
Hepatomegaly or Splenomegaly

Symptoms

Isolated Lymphadenopathy <2 weeks or >12 months without change
1. Malignancy unlikely
2. Exception: Low grade or indolent Lymphoma (which have associated systemic symptoms)
Symptoms associated with malignancy (e.g. Leukemia, Lymphoma, solid malignancy metastases)
1. Fever, Night Sweats
2. Unintentional Weight Loss (esp. >10 lb or 4.5 kg in last 6-12 months)
3. Splenomegaly, Hepatomegaly or Bruising
4. Lymphadenopathy >5mm supraclavicular, popliteal or iliac
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

Signs

Anatomy
1. See Lymphatic Anatomy
2. See Regional Lymphadenopathy
Abnormal Lymph Node size criteria (normal Lymph Nodes are typically <0.5 to 1 cm)
1. Epitrochlear, popliteal or iliac Lymphadenopathy >0.5 cm
2. Inguinal Lymphadenopathy >2 cm
3. Isolated Lymphadenopathy in children >1.5 to 2.0 cm
4. Other Lymphadenopathy >1.0 cm
Tenderness to palpation
1. See Tender Regional Lymphadenopathy
2. Tenderness does not differentiate benign from malignant nodes
Lymph Node consistency
1. Rock-hard nodes: Metastatic cancer
2. Firm-Rubbery nodes: Lymphoma
3. Soft nodes: Inflammation or infection
4. Tender, fluctuant, mobile nodes (Lymphadenitis): Bacterial Infections
5. Shotty nodes (multiple small buckshot size): Viral Infections
Matted or Fixed Nodes (connected nodes)
1. Benign causes
2. Malignant causes
  1. Metastatic cancer
  2. Lymphoma
Lymph Node Regions
1. See Regional Lymphadenopathy
2. Classic Lymphadenopathy locations associated with malignancy
  1. Left supraclavicular Node (Virchow's Node)
  2. Left Axillary Node (Irish Node)
  3. Periumbilical Node (Sister Mary Joseph Nodule)
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

Evaluation
Initial Tests

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
Indications
1. Specific indications based on location and exposures
2. Generalized Lymphadenopathy
Tests
1. Complete Blood Count with manual differential
2. Monospot (Mononucleosis Serology)
3. Group A Streptococcal PCR
Management
1. Avoid Corticosteroids until definitive diagnosis made (may mask Lymphoma or Leukemia diagnosis)
2. Consider Antibiotics for persistent acute anterior cervical Lymphadenitis with systemic symptoms in children
  1. Indicated in Bacterial Lymphadenitis (unilateral, tender nodes with skin erythema) or nodes >2-3 cm
  2. Empiric first line Antibiotics target MSSA, Group A Streptococcus
    1. Amoxicillin-Clavulanate (Augmentin)
    2. Cephalexin (Keflex)
  3. Empiric MRSA coverage
    1. Trimethoprim-sulfamethoxazole (Bactrim, Septra)
    2. Doxycycline (age >8 years)
    3. Clindamycin (risk of induced resistance)
  4. Suspected Cat Scratch Disease
    1. Azithromycin

Evaluation
Second-line Tests

Indications
1. Specific indications and normal initial tests
2. Persistent Generalized Lymphadenopathy >4 weeks
Labs: General
1. Complete Blood Count with manual differential (if not already performed above)
2. C-Reactive Protein (cRP)
3. Erythrocyte Sedimentation Rate (ESR)
4. Lactate Dehydrogenase (if suspected Lymphoma or Leukemia)
Labs: Autoimmune
1. Anticyclic Citrullinated Peptide Antibody
2. Rheumatoid Factor
3. Antinuclear Antibody (ANA)
4. Other labs
  1. Complement Levels
  2. dsDNA Antibody
Labs: Infectious
1. Monospot (if not already performed above)
2. Epstein Barr Virus Serology
3. Cytomegalovirus PCR
4. Tuberculin Skin Test (Purified Protein Derivative) or IFN-Gamma Release Assay (Quantiferon-TB)
5. Rapid Plasma Reagin (RPR) or other Treponemal Antibody
6. Chlamydia PCR
7. Gonorrhea PCR
8. Hepatitis B Serology (HBsAg)
9. HIV Test
Imaging
1. Chest XRay
  1. Mediastinal Widening (Lymphoma, Sarcoidosis)
  2. Mediastinal Lymphadenopathy
  3. Hilar Lymphadenopathy
2. Head and neck imaging (as indicated)
  1. Ultrasound (preferred in children <14 years old)
  2. CT soft tissue neck (age >14 years old or adults)
3. Imaging of other regions as indicated
  1. Start with Ultrasound or XRay in age <14 years
  2. Consider CT chest Abdomen and Pelvis with contrast in age >14 years with suspected malignancy

Evaluation
Third-line Tests (Biopsy)

Indications
1. Persistent Lymphadenopathy for more than 4 weeks with no other cause identified
2. Malignancy or serious disease suspected
Biopsy: Lymph Node biopsy of most abnormal or largest node
1. Fine needle aspirate (FNA)
  1. Refer to Interventional Radiology
  2. Preferred if a small needle is needed due to node location
  3. Preferred first-line test for Cervical Lymphadenopathy (followed by Excisional Biopsy)
    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
  1. Refer to Interventional Radiology
  2. Preferred if Lymph Node is clearly visible on imaging and easily accessible
  3. Better initial test than FNA (esp. for Lymphoma)
    1. Maintains tissue architecture (distorted by FNA)
    2. Less prone to sampling error than FNA
    3. May be combined with immunohistochemical and molecular techniques for greater efficacy
3. Excisional Biopsy
  1. Typically follows positive or indeterminate FNA or core needle biopsy
  2. Refer to surgery
Efficacy
1. Highest yield site: Supraclavicular nodes
2. Lowest yield site: Inguinal nodes
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%)

References

Dornbland (1992) Adult Ambulatory Care, p. 662-7
Lee (1999) Wintrobe's Hematology, p. 1826-30
Wilson (1991) Harrison's Internal Medicine, p. 354-6
Ali (2022) Cureus 14(10): e30623 [PubMed]
Falk (2025) Am Fam Physician 112(3): 286-93 [PubMed]
Ferrer (1998) Am Fam Physician 58(6): 1313-2 [PubMed]
Gaddey (2016) Am Fam Physician 94(11): 896-903 [PubMed]
Habermann (2000) Mayo Clin Proc 75:728 [PubMed]
Libman (1987) J Gen Intern Med 2(1):48-58 [PubMed]
Meier (2014) Am Fam Physician 89(5): 353-8 [PubMed]