03. Lymphadenopathy

Updated by: Luis Rubio, M.D.

Faculty Editor: Brent Kobashi, M.D.

BOTTOM LINE

✔ The initial differential is based on whether lymphadenopathy is local or generalized.

✔ Most causes of lymphadenopathy are benign.

✔  Risk factors for a malignant etiology include age >40 years, size >2 cm, splenomegaly, systemic symptoms, and supraclavicular location.

✔  Inguinal and axillary nodes are least preferred for FNA or biopsy due to low diagnostic yield.

✔  Excisional biopsy is of higher yield than FNA and should be considered with unexplained LAD lasting > 2-4 weeks.


Background

  • Prevalence of unexplained peripheral lymphadenopathy (LAD) in the general population is 0.6%.
  • Prevalence of malignancy in patients with LAD is 0.4% for patients <40 years, and 4% for patients >40 years.
  • Approximately 75% is localized, and 25% is generalized.
  • Localized areas for LAD mostly includes head/neck, axillary, subclavicular, and inguinal

Signs and Symptoms

  • Can be symptomatic or asymptomatic.
  • Ask about constitutional symptoms (viral syndrome, hematologic malignancy), arthralgias/weakness/rash (inflammatory condition).

Differential Diagnosis

The initial differential is based on whether LAD is localized or generalized. Broad categories of causes of LAD are similar to fever of unknown origin and includes infectious, inflammatory, malignancy and medication effect.

Differential Diagnosis by region of LAD

  • Cervical: drains head/neck. Infection > malignancy. Infections: bacterial pharyngitis, dental abscess, otitis media/externa, infectious monomucleosis, gonococcal pharyngitis, CMV, toxoplasmosis, hepatitis, adenovirus. Malignancies: non-Hodgkin lymphoma, Hodgkin disease, squamous cell cancers of the head and neck.
  • Supraclavicular: Up to 50% risk of malignancy. Drains chest/abdomen (left: abdomen, testes, ovaries right: mediastinum and lungs). Virchow node (left) highly concerning for abdominal or thoracic malignancy.
  • Axillary: drains lower neck, upper extremity, lateral breast, chest wall. Similar differential to cervical LAD, though with higher malignancy risk. Also consider staph/strep infection of arm, cat-scratch disease, tularemia, and sporotrichosis.
  • Epitrochlear: Never physiologic. Drains upper extremity below elbow. Lymphoma, CLL, infectious mononucleosis, sarcoidosis, HIV, dermatologic or connective tissue disease. Also consider secondary syphilis, leprosy, leishmaniasis, rubella.
  • Inguinal: drains lower extremity, anogenital region, abdominal wall below umbilicus. Usually benign/reactive. Malignant etiologies include non-Hodgkin lymphoma, Hodgkin disease, malignant melanoma, squamous cell cancer of penis or vulva.
  • Popliteal: drains lower extremity below the knee. Foot/leg infections.
  • Generalized: hematologic malignancy, infection (EBV, CMV, HIV, TB, toxoplasmosis, histoplasmosis, coccidiodomycosis, brucellosis), inflammatory (rheumatoid arthritis, lupus), sarcoidosis, medications.
    • Medications: phenytoin, carbamazepine, cephalosporins, penicillin, sulfonamides (e.g., TMP/SMX, sulfonylureas, thiazides), pyrimethamine, atenolol, captopril, hydralazine, allopurinol, quinidine, primidone, sulindac.
  • Miscellaneous: tick-borne lymphadenopathy, tattoo lymphadenopathy, silicosis/berylliosis, histiocytic necrotizing lymphadenitis (“Kikuchi’s disease”), sinus histocytosis with massive lymphadenopathy (“Rosai-Dorfman disease”).

Evaluation

A. History:   

  • Location and Duration: location may suggest infection or malignancy in specific site; >2 weeks and <1 year increases suspicion for malignancy.
  • Constitutional symptoms: may suggest malignancy, chronic infection (e.g., TB, HIV), and rheumatologic causes.
  • Exposures: occupational, TB risk factors, radiation, animals, ticks, tattoos, travel.
  • Other: New medications for drug hypersensitivity reactions; sexual history for STIs; past medical history for prior malignancy or infection; family history of cancer.

B. Physical exam:

  • Localized vs. generalized: perform a complete, careful physical exam (cervical, axillary, inguinal, supraclavicular) to avoid missing generalized LAD.
    • Gentle palpation so as not to miss smaller enlarged lymph nodes.
    • Vasalva’s maneuver may increase chance of palpating nodes insupravlavicular fossa
  • Size: > 1 cm considered enlarged, however normal ininguinal nodes may be up to 1.5 cm. >2 cm are more concerning for malignancy or granulomatous process (i.e, tuberculosis, sarcoidosis, cat-scratch disease).
  • Consistency: Firm, hard, fixed nodes suggest metastatic solid tumor. Firm, rubbery nodes suggests lymphoma. Softer nodes more likely to be inflammatory or infectious.
  • Tenderness: inflammatory process, or necrosis from malignancy.
  • Concurrent splenomegaly: suggests mononucleosis, leukemia, or lymphoma.
  • Site: supraclavicular, axillary, and epitrochlear nodes are more concerning for malignancy. Paraumbilical “Sister Mary Joseph’s node” suggests pelvic or abdominal malignancy. Supraclavicular nodes are malignant in 90% of patients >40 years.
  • Patients with generalized LAD should have thorough physical exam focusing on systemic processes such as rash, mucous membrane lesions, organomegaly or arthritis.

C. Diagnostic studies:

Further evaluation is merited if cause of LAD is unknown after thorough history and physical, yet persists >2-4 weeks. Consider expedited work-up ith the patient has constitutional symptoms or has LAD in high risk site

  • Initial studies should include CBC with differential, peripheral smear, metabolic panel including LFTs, chest X-ray, acute HIV testing
  • Additional studies may be considered based on history or suspicion for malignancy: herpesviridae serologies (CMV, EBV, HSV), LDH, SPEP, immunoglobulin levels, heterophile antibody, RPR, PPD/IGRA, ANA, and RF.
  • ESR, CRP, and fibrinogen are of low yield because of lack of specificity
  • Imaging: US usually will not rule out malignancy but can be useful for peripheral LAD evaluation of number, size, site, shape, margins, etc., CT and MRI more useful in thoracic and abdominopelvic cavities Imaging is likely to have inconclusive results and does not replace biopsy/
  • Tissue diagnosis should be performed immediately if clinical suspicion for malignancy is high.
    • In general, excisional biopsy is preferred over fine needle aspiration (FNA) unless the patient is very frail or unstable to improve diagnostic yield. Excisional biopsy is particularly important for hematologic malignancies, especially lymphoma, because it preserves nodal architecture.
    • Inguinal and axillary nodes are the lowest diagnostic yield sites.

Treatment

  • Treat the underlying cause (if found).
  • In general, avoid empiric treatment with antibiotics or corticosteroids.
  • For localized LAD and a benign clinical picture, a 2-4-week observation period is reasonable.

When to Refer

  • Consider referral to surgical subspecialty for excisional biopsy if no clear reason for LAD is found and suspicion for malignancy is high

References

1. Bazemore AW, Smucker DR. Lymphadenopathy and malignancy. Am Fam Physician. 2002; 66(11):2103-2110.

2. Ferrer R. Lymphadenopathy: differential diagnosis and evaluation. American Family Physician. 1998; 58:1313-20.

3. Habermann TM, Steensma DP. Lymphadenopathy. Mayo Clin Proc. 2000; 75:723-32.

4. Mohseni S, Shojaiefard A, Khorgami Z, Alinejad S, Ghorbani A, Ghafouri A. Peripheral lymphadenopathy: approach and diagnostic tools. Iran J Med Sci. 2014;39(2 Suppl):158-70.5. Motyckova G, Steensma DP. Why does my patient have lymphadenopathy or splenomegaly? Hematol Oncol Clin N Am. 2012; 26:395-408.

5. Richner S, Laifer G. Peripheral lymphadenopathy in immunocompetent adults. Swiss Med Wkly. 2010; 140:98-104.