Lymphadenopathy

Lymphadenopathy is the enlargement of lymph nodes and most commonly occurs during benign, inflammatory processes. In pediatric patients, lymphadenopathy is usually caused by upper respiratory tract infections (see “Cervical lymphadenopathy”). Painful, enlarged lymph nodes in adults, paired with signs of localized or systemic infection, are generally caused by some type of bacterial or viral infection. Malignancy must be considered in the case of painless, progressive lymph node swelling in the absence of signs of infection, in which case further diagnostic testing (e.g., serology, imaging, biopsy, and histological analysis) is necessary in order to make the diagnosis.

• Infections
  • Bacterial
    • Tuberculosis
    • Syphilis
    • Lymphogranuloma venereum
    • Staphylococcal/streptococcal skin infections
    • Lyme disease
    • Typhoid fever
    • Cat-scratch disease
    • Brucellosis
    • Tularemia
    • Rickettsial scrub typhus
  • Viral
    • HIV
    • Epstein-Barr Virus (EBV)
    • Cytomegalovirus (CMV)
    • Adenovirus
    • Herpes zoster
    • Rubella
  • Fungal: aspergillosis, candidiasis, cryptococcus
  • Parasitic
    • Helminthic: schistosomiasis, lymphatic filariasis
    • Protozoal: toxoplasmosis, malaria, visceral leishmaniosis
• Malignancies
  • Leukemias (e.g., acute lymphoblastic leukemia)
  • Lymphomas (e.g., Hodgkin lymphoma)
  • Kaposi sarcoma
  • Metastases
• Autoimmune conditions
  • Systemic lupus erythematosus
  • Rheumatoid arthritis, Still disease
  • Sjogren syndrome
  • Dermatomyositis
• Medication
  • Allopurinol
  • Antibiotics (e.g., penicillins, trimethoprim/sulfamethoxazole)
  • Antihypertensives (e.g., hydralazine, captopril)
• Other: Kawasaki disease, histiocytosis X, sarcoidosis, Castleman disease

References:^[1]

• Lymph node structure and function: See “Lymph nodes” in “Lymphatic system.”
• Pathophysiology of lymph node enlargement
  • Lymphadenitis: proliferation and formation of immune cell clusters as a result of localized/systemic inflammation (most common cause of lymphadenopathy)
  • Malignant proliferation of cells that have settled in the affected lymph node (e.g., lymphoma cells or metastases of solid tumors)
  • Storage diseases: accumulation of metabolites (e.g., ceramide trihexoside in the case of Fabry disease)
  • Drug-induced: Certain drugs such as phenytoin, allopurinol, atenolol, hydralazine, and antibiotics such as penicillin or cephalosporins can induce generalized lymphadenopathy. ^[2]

To remember the different causes of lymphadenopathy, think “MIAMI”: Malignancy (e.g., lymphomas), Infection (e.g., TB), Autoimmune disease (e.g., SLE), Miscellaneous (e.g., sarcoidosis), and Iatrogenic (medications).

References:^[3]

Medical history

• Duration of lymph node swelling
• Symptoms:
  • Pain or tenderness: suggests benign inflammatory process
  • Acute fever, skin changes (common in viral infections)
  • Signs of inflammation in the lymph node drainage area
  • B symptoms
• Underlying diseases
• Medications
• Travel history
• Social and sexual history
• Animal contacts

Physical examination

• General: assess for both local inflammatory processes (e.g., enlarged neck lymph nodes due to tonsillitis) and signs of systemic disease (e.g., hepatomegaly and splenomegaly)
• Peripheral lymph node examination:
  • Inspection
    • Visible enlargement: Lymph nodes should not be visible in healthy individuals, as they are only a few millimeters in diameter.
    • Local erythema, swelling, or lesion
  • Palpation
    • Gentle palpation using fingertips
    • The area to be examined should be relaxed to facilitate differentiation of the lymph node from the surrounding tissue (e.g., muscles, tendons).
    • Evaluation of size and level of pain consistency, and fixation.
    • Conduct the following :
      • Palpation of head and neck lymph nodes
        • Instruct the patient to keep the neck relaxed and slightly flexed. Palpate bilaterally with one hand on each side.
        • Palpate the periauricular, occipital, and deep cervical lymph nodes.
        • Move on to the submandibular and submental lymph nodes while also palpating for the parotid glands.
        • Move on to the lymph nodes of the posterior triangle of the neck and the periclavicular lymph nodes.
        • The most common cause of tender regional lymphadenopathy in the head/neck area is upper respiratory tract infection.
      • Palpation of the axillary lymph nodes
        • Support the patient's relaxed arm with your own. Warn the patient that the exam might be uncomfortable.
        • With one hand, palpate high into the axillary region, pressing your fingers against the chest wall behind the pectoralis muscle and sliding downward.
        • Palpate the subclavicular, lateral, pectoral, and central lymph nodes. The central lymph nodes are typically the most palpable.
        • Move on to palpate the supratrochlear nodes, which are located 3 cm above the elbow.
        • A common cause of axillary lymphadenopathy is breast cancer.
      • Palpation of the inguinal lymph nodes
        • Instruct the patient to lay supine.
        • Palpate the nodes below the inguinal ligament and medial to the femoral artery.
        • A common cause of enlarged superficial inguinal lymph nodes are STIs such as chancroid or genital herpes.

Soft, mobile, and tender lymph nodes are likely benign. Hard, nonmobile, nontender lymph nodes should raise concern for malignancy. Firm, nontender lymph nodes in patients with sarcoidosis or tuberculosis are exceptions.A palpable, firm lymph node in the left supraclavicular area is called a Virchow node and is classically associated with gastric carcinoma.

Further diagnostic testing

• Acute, painful (localized or systemic) lymph node enlargement potentially associated with localized inflammation or infection (e.g., herpes labialis, pharyngitis).
  • In general, no further diagnostic testing is necessary.
  • If diagnosis and treatment decision is unclear, test for:
    • Inflammatory markers (e.g., CRP, ESR) in the case of severe inflammatory processes
    • If systemic infection is suspected: detection of pathogen (e.g., Monospot test in EBV, RPR/VDRL in syphilis, ELISA in HIV)
• Chronic, localized, nonprogressive lymph node enlargement: In general, no further diagnostic testing is necessary.
• Painless, slowly progressing lymph node enlargement (generalized or localized) or in any other case of unexplained lymph node enlargement suggestive of malignant disease
  • Laboratory tests:
    • CBC, liver function tests and BUN/creatinine
    • Blood smear, LDH, uric acid
    • If suspected, diagnostic tests for tuberculosis
  • Imaging
    • Sonography: can help to characterize lymphadenopathy
      • Physiological lymph nodes or lymph node changes due to inflammation: sharply delimited, oval shape, presence of fatty hilum
      • Malignant lymph nodes: round , irregular, blurred margins, loss of fatty hilum
      • Allows for differentiation from other pathologic conditions (e.g., abscesses, cysts)
    • Chest x-ray: unexplained generalized lymphadenopathy requires evaluation of the hilar and mediastinal lymph nodes, especially if tuberculosis is suspected
    • If necessary, CT/MRI may be performed to better visualize lymph nodes.
  • Lymph node biopsy and histological analysis: if cancer is suspected or localized or generalized lymphadenopathy does not resolve in 3–4 weeks and imaging has been inconclusive

References:^[3][4][5]

Differential diagnoses according to characteristics of enlarged lymph nodes ^[2]

Generalized lymphadenopathy is defined as the enlargement of more than two noncontiguous lymph node groups.

Differential diagnoses according to location of enlarged lymph nodes

See “Lymph node clusters” in “Lymphatic system.”

The differential diagnoses listed here are not exhaustive.