Lymphadenopathy

Lymphadenopathy is the enlargement and/or change in consistency of one or more lymph nodes. The most common causes are benign, e.g., self-limited upper respiratory tract infections (URTI). Inflamed (reactive) and enlarged lymph nodes with signs of localized or systemic infection are usually caused by bacterial or viral infection. Hard or rubbery nontender lymph nodes that are fixed to the underlying tissue suggest a metastatic cause of lymphadenopathy. A focused history and examination should be performed to assess the duration, onset, exposures (e.g., medication, travel, sexual activity), associated symptoms, and distribution of lymphadenopathy. Diagnostic testing is unnecessary for patients with a local infection or localized nonprogressive lymphadenopathy. Laboratory studies are indicated if an autoimmune or infectious cause is suspected. Lymph node ultrasound and biopsy are used to assess for malignancy.

See also “Cervical lymphadenopathy.”

• Lymphadenopathy: enlargement and/or change in consistency of one or more lymph nodes ^[1]
  • Localized lymphadenopathy involves a single lymph node region.
  • Generalized lymphadenopathy involves two or more noncontiguous lymph node regions.
• Lymphadenitis: lymph node inflammation caused by infection or another inflammatory process (most common cause of lymphadenopathy)
• Buboes: significantly enlarged, tender, and inflamed inguinal and/or axillary lymph nodes characteristic of certain infectious diseases (e.g., lymphogranuloma venereum, syphilis, chancroid) ^[2]

Localized Lymphadenopathy ^[1]

See “Lymph node clusters” for potential causes organized by region.

Infection

• Self-limited viral infections, e.g.:
  • Viral pharyngitis
  • Mumps
  • Rubella (especially postauricular nodes)
  • EBV infection (bilateral cervical lymphadenopathy)
  • CMV infection
• Streptococcal or staphylococcal infections (e.g., skin and soft tissue infections, deep neck infections, GAS tonsillopharyngitis)
• Sexually transmitted infections, e.g.:
  • Genital HSV infection
  • Lymphogranuloma venereum (typically manifests with inguinal buboes)
  • Chancroid
  • Primary syphilis
• Localized cat-scratch disease (typically cervical or axillary lymphadenopathy)
• Tuberculosis (e.g., tuberculous lymphadenitis) ^[3]
• Nontuberculous mycobacteria infection
• Early Lyme disease ^[4]
• Toxoplasmosis (typically cervical lymphadenopathy) ^[5]
• Tularemia
• Sporotrichosis

Malignancy

• Metastatic cancer (e.g., breast cancer, lung cancer, colorectal cancer, skin cancer)
• Lymphoma (i.e., non-Hodgkin lymphoma, Hodgkin lymphoma)

Other

• Residual lymphadenopathy, e.g., after resolution of URTI (especially cervical)
• Kawasaki disease (usually manifests with unilateral cervical lymphadenopathy)
• Sarcoidosis
• Kikuchi-Fujimoto disease
• Silicone breast implants
• Sjogren syndrome ^[6][7]
• Rheumatoid arthritis ^[7][8]

Sarcoidosis and EBV infection typically manifest initially with localized lymphadenopathy that progresses to generalized lymphadenopathy.

Generalized lymphadenopathy ^[1]

Generalized lymphadenopathy is often caused by systemic disease (e.g., infection, autoimmune disease, or malignancy) or medications.

Infection

• Viral
  • Self-limited viral infections, e.g.:
    • EBV infection
    • CMV infection
    • Influenza
    • Mumps
    • Measles
    • Rubella
  • HIV infection
  • Shingles
• Bacterial
  • Tuberculosis
  • Secondary syphilis ^[9]
  • Scrub typhus ^[10]
  • Brucellosis
  • Tularemia
• Fungal
  • Histoplasmosis
  • Coccidioidomycosis
  • Aspergillosis
  • Candidiasis
  • Cryptococcus
• Parasitic
  • Protozoal, e.g.:
    • Toxoplasmosis
    • Visceral leishmaniasis
    • Chagas disease
  • Helminthic, e.g.:
    • Schistosomiasis
    • Lymphatic filariasis

Malignancy

• Leukemias (e.g., acute lymphoblastic leukemia)
• Kaposi sarcoma
• Advanced metastatic cancers
• Mycosis fungoides ^[11]

Autoimmune conditions ^[12]

• Systemic lupus erythematosus ^[7]
• Autoimmune lymphoproliferative syndrome
• Still disease
• Mixed connective tissue disease
• Dermatomyositis
• IgG4-related disease
• Sjogren syndrome

Iatrogenic causes

• Medication-induced, e.g.:
  • Atenolol
  • Allopurinol
  • Antibiotics (e.g., cephalosporins, penicillins, trimethoprim/sulfamethoxazole)
  • Antihypertensives (e.g., hydralazine, captopril)
  • Phenytoin
• Vaccine-induced, e.g.: ^[13]
  • Influenza vaccine
  • HPV vaccine

Other

• Sarcoidosis ^[7]
• Langerhans cell histiocytosis ^[14]
• Castleman disease
• Lysosomal storage diseases, e.g.: ^[14]
  • Fabry disease
  • Gaucher disease
  • Niemann-Pick disease
• Hyperthyroidism ^[14]

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

• The pathophysiology of lymph node enlargement varies depending on the cause.
• Enlargement may be due to:
  • Proliferation and accumulation of malignant cells (e.g., lymphoma cells or metastases of solid tumors)
  • Proliferation of immune cells and formation of clusters as a result of localized and/or systemic inflammation
  • Circulating immune complexes (e.g., due to medications or hypersensitivity reactions)
  • Accumulation of metabolites due to storage diseases (e.g., ceramide trihexoside in the case of Fabry disease)

Focused history ^[1][13]

• Specific features
  • Duration and progression of lymphadenopathy ^[1][13]
  • Symptoms of local infection (e.g., URTI, cellulitis)
  • B symptoms
  • Features of underlying rheumatic disease (e.g., joint pain)
  • History of immune deficiency or malignancy
• Exposures
  • Travel history (e.g., to areas with endemic tropical disease)
  • Exposure to zoonotic vectors (e.g., ticks, pets, farm animals) or vehicles (e.g., undercooked meat)
  • Medications associated with lymphadenopathy
  • Recent vaccination
• Risk factors
  • Risk factors for sexually transmitted infections
  • Risk factors for bloodborne diseases

Lymphadenopathy lasting at least 12 months without change in node size or systemic symptoms suggests a nonmalignant cause. ^[1][13]

Focused examination ^[1][12][13]

• Examine lymph nodes in each drainage region.
• Assess for signs of systemic disease (e.g., splenomegaly, hepatomegaly).
• Identify any local inflammatory processes (e.g., viral tonsillitis).

Lymph node palpation

• Instruct the patient to relax the area to be examined to facilitate differentiation of the lymph node from the surrounding tissue (e.g., muscles, tendons).
• Gently palpate lymph nodes in each drainage region using your fingertips.
  • Assess size, consistency, tenderness, and fixation.
  • Assess for red flags for a metastatic cause of lymphadenopathy.

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 preauricular lymph nodes, retroauricular lymph nodes, occipital lymph nodes, and deep cervical lymph nodes.
• Move on to the submandibular lymph nodes and submental lymph nodes while also palpating the parotid glands.
• Move on to the lymph nodes of the posterior triangle of the neck and the supraclavicular lymph nodes.

The most common cause of tender regional lymphadenopathy in the head and neck area is URTI.

A palpable, firm lymph node in the left supraclavicular area is called a Virchow node and is classically associated with gastric cancer.

Palpation of the axillary lymph nodes

• Support the patient's relaxed arm with your own.
• Warn the patient that the examination might be uncomfortable.
• With one hand, palpate high into the axillary region, pressing your fingers against the chest wall behind the pectoralis muscle and slide your hand downward.
• Palpate the apical, posterior, lateral, anterior, and central axillary lymph nodes.
• Palpate the epitrochlear lymph nodes (∼ 3 cm above the elbow).

The central lymph nodes are typically the most palpable axillary lymph nodes.

A common cause of axillary lymphadenopathy is breast cancer.

Palpation of the inguinal lymph nodes

• Instruct the patient to lie supine.
• Palpate the nodes below the inguinal ligament and medial to the femoral artery.

Common causes of enlarged superficial inguinal lymph nodes are STIs such as chancroid or genital herpes.

Features of abnormal lymph nodes

• Lymph node size > 1 cm is usually considered abnormal. ^[1][13]
• Exceptions include the following:
  • Inguinal lymph nodes may be up to 2 cm. ^[12]
  • Epitrochlear lymph nodes > 0.5 cm and any palpable supraclavicular, popliteal, or iliac lymph nodes are considered abnormal. ^[1]

Normal inguinal lymph nodes may be up to 2 cm in diameter. ^[12]

Sarcoidosis and tuberculosis typically manifest with features similar to the lymphadenopathy caused by metastatic disease.

Most cases of lymphadenopathy are benign and idiopathic. ^[1][12]

Approach

• Obtain routine laboratory studies if an atypical infection, malignancy, or autoimmune disease is suspected.
• Consider targeted laboratory studies based on clinical suspicion.
• Lymph node ultrasound may help differentiate between nonmalignant and malignant lymph nodes.
• Consider lymph node biopsy and/or cross-sectional imaging if the diagnosis remains unclear or malignancy is suspected.

Diagnostic testing is not always indicated (e.g., for patients with local infection or localized nonprogressive lymphadenopathy).

Laboratory studies ^[1][12]

• Routine studies
  • CBC with differential
  • BMP
  • Liver chemistries
  • Inflammatory markers: ESR, CRP
• Additional studies
  • Infectious disease testing (e.g., monospot test, HIV serology, tuberculosis testing)
  • Rheumatologic studies (e.g., rheumatoid factor, ANAs)

Lymph node ultrasound ^[7][15]

• Findings suggestive of normal and/or reactive lymph nodes
  • Oval shape ^[15]
  • Hypoechoic, except for the hilum, which appears contiguous (i.e., echogenic) with surrounding tissue
• Findings suggestive of malignant lymph nodes
  • Round
  • Hypoechoic, without an echogenic hilum
  • Demarcated echogenic focus in metastatic nodes with coagulative necrosis
  • Eccentric cortical hypertrophy in nodes with tumor infiltration
  • Reticulation in lymphomatous nodes

Lymph node biopsy ^[1][13]

• Indications
  • Diagnosis remains unclear after laboratory studies and imaging.
  • Malignancy is suspected, e.g.:
    • Localized lymphadenopathy and no improvement after 3–4 weeks of observation ^[1]
    • Generalized lymphadenopathy
• Techniques
  • Fine-needle aspiration biopsy
  • Core needle biopsy
  • Excisional biopsy (preferred method in suspected lymphoma)

Further testing

• Chest x-ray: may reveal hilar and/or mediastinal lymph nodes (e.g., in sarcoidosis)
• CT or MRI with contrast: to better visualize enlarged lymph nodes and/or assess for nonpalpable lymph nodes or other lesions ^[7]
• FDG PET CT: to help differentiate between malignant and nonmalignant lymphadenopathy ^[7]

• Identify and treat the underlying cause.
• Consider empiric antibiotics for patients with suspected infectious causes of lymphadenopathy.
• Review medication history and consider stopping agents known to cause lymphadenopathy.

Infectious causes of lymphadenopathy

Lymphadenopathy due to common infectious causes (especially among children) is often self-limited and resolves within 2 weeks.

Noninfectious causes of lymphadenopathy

• Any lymph node enlargement
  • Simple cyst ^[34]
  • Sebaceous cyst
  • Abscess
  • Insect bite
  • Carbuncle
  • Mesenchymal tumors, e.g.:
    • Lipoma
    • Soft tissue sarcomas (e.g., liposarcoma)
  • Metastatic cancer
• Head and neck lymph nodes
  • Congenital neck masses
  • See also “Differential diagnosis” in “Cervical lymphadenopathy.”
• Axillary lymph nodes
  • Hidradenitis suppurativa
  • Ectopic breast tissue (may enlarge due to hormonal changes)
• Inguinal lymph nodes
  • Inguinal hernia
  • Femoral artery aneurysm