Lymphadenopathy

Lymphadenopathy is lymph node enlargement (> 1 cm) and is benign and self-limited in most patients. Etiologies include malignancy, infection, and autoimmune disorders, as well as iatrogenic causes such as the use of certain medications. Generalized lymphadenopathy often indicates underlying systemic disease. Diagnosis relies on a thorough medical history and physical examination, which usually identify the underlying cause. When the cause is unknown, a biopsy may be necessary. Management is directed at the underlying infection, malignancy, or other cause.

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Overview

Definition

Lymphadenopathy is lymph node enlargement of usually > 1 cm. It is considered localized if the enlargement is limited to lymph nodes of 1 anatomic region and generalized when ≥ 2 regions are involved.

Etiology

Most often, lymphadenopathy is a reaction to a local infection. Less frequently, it may be due to a malignant process or chronic, systemic disease. The following conditions include lymphadenopathy in their clinical presentation:

  • Infectious:
    • Viral infections:
      • EBV 
      • CMV 
      • HIV 
      • Childhood diseases: varicella, measles, mumps, rubella
      • HSV-1 and HSV-2
      • Hepatitis A, B, and C
    • Bacterial infections:
      • Staphylococcus aureus 
      • Streptococcus pyogenes
      • Treponema pallidum (causes syphilis)
      • Mycobacterium tuberculosis in patients with exposure or risk factors
      • M. avium-intracellulare in immunocompromised patients
      • M. marinum in fishermen
    • Fungal infections:
      • Coccidioidomycosis in patients with recent travel to endemic areas
      • Histoplasmosis
      • Cryptococcosis
      • Sporotrichosis in gardeners
    • Parasitic infections:
      • Toxoplasmosis
      • Histoplasmosis
      • Chagas disease 
      • Leishmaniasis
  • Malignancies:
    • Primary hematologic:
      • ALL
      • Hodgkin lymphoma (HL)
      • Non-Hodgkin lymphoma (NHL)
    • Metastatic cancers:
      • Breast cancer
      • Lung cancer
      • Thyroid cancer 
  • Autoimmune disorders: 
    • Systemic lupus erythematosus (SLE)
    • Juvenile idiopathic arthritis (JIA)
  • Endocrinopathy: primary adrenal insufficiency (Addison’s disease)
  • Iatrogenic causes: medications
    • Anticonvulsants: 
      • Carbamazepine
      • Phenytoin 
      • Lamotrigine
    • Antibiotics: 
      • Penicillin 
      • Cephalosporins 
      • Pyrimethamine
    • Others:
      • Sulfonamides
      • Sulindac
      • Allopurinol
  • Inborn errors of metabolism: 
    • Niemann-Pick disease
    • Gaucher disease
    • Fabry disease 

Mnemonic

To recall the various causes of lymphadenopathy, remember MIAMI:

  • Malignancy
  • Infection 
  • Autoimmune 
  • Inborn errors of Metabolism
  • Iatrogenic 

Pathophysiology

The immune and lymphatic systems are highly interrelated. Lymphocytes are transported via the lymphatic vessels to lymph nodes. Humans have about 500–600 lymph nodes throughout the body. Lymphadenopathy, or swelling of lymph nodes, may occur in response to infection, malignancy, or chronic disease.

Distribution of lymph nodes

  • Lymph nodes that drain from the head and neck:
    • Anterior: preauricular, parotid, tonsillar, submandibular, and submental
    • Posterior: posterior auricular, occipital, and superficial and deep cervical
  • Lymph nodes that drain from the rest of the body: 
    • Supraclavicular
    • Deltopectoral
    • Axillary
    • Epitrochlear
    • Inguinal
    • Popliteal
  • Secondary lymphoid organs play a role in the active immune response:
    • Lymph nodes remove debris and pathogens from the lymph.
    • Spleen
    • Lymphoid nodules:
      • Tonsils
      • MALT
      • Bronchus-associated lymphoid tissue (BALT)

Pathogenic mechanisms

Cells, plasma, and foreign particles in the interstitial space become lymphatic fluid upon entering the lymphatic vessels. Within the lymph nodes, this fluid is filtered of excess fluid and abnormal cells (e.g., infected, malignant, damaged, presenting antigens). This triggers an immune response that involves cellular proliferation, causing the nodes to enlarge (reactive lymphadenopathy).

Lymphadenopathy results from 1 of the pathologic processes:

  • Immune cell proliferation (infection)
  • Malignant proliferation:
    • Hematologic malignancies 
    • Metastasis 
  • Accumulation of metabolites

Clinical Presentation

The signs and symptoms associated with lymphadenopathy will depend on the cause and the type (localized versus generalized).

Localized lymphadenopathy

  • Anterior cervical lymphadenopathy caused by viral or bacterial infections: 
    • Streptococcal pharyngitis
    • Mononucleosis
    • Otitis media
    • Sinusitis
    • Facial cellulitis
    • Dental infections
  • Anterior cervical lymphadenopathy caused by noninfectious conditions:
    • Head and neck malignancies
    • Lymphoma
    • Allergic rhinitis/postnasal drip
  • Posterior cervical:
    • Infections such as EBV in mononucleosis, tuberculosis, lymphoma
    • Scalp dermatologic conditions such as psoriasis or seborrheic dermatitis
    • Malignancies such as lymphoma or metastatic squamous cell carcinoma
  • Supraclavicular:
    • Right supraclavicular adenopathy is associated with cancer in the mediastinum, lungs, or esophagus.
    • Left supraclavicular adenopathy (Virchow’s node): associated with abdominal or pelvic malignancy from the stomach, gallbladder, pancreas, kidneys, testicles, ovaries, lymphoma, or prostate
  • Axillary:
    • Infections such as cat scratch disease due to Bartonella henselae
    • Breast cancer
  • Epitrochlear: Palpable epitrochlear nodes are always pathologic.
    • Infections of the forearm or hand
    • Lymphoma
    • Sarcoidosis
    • Tularemia
    • Secondary syphilis
  • Inguinal: often seen in healthy people, as chronic trauma and infection are common in the lower extremities
    • Not always considered pathologic
    • Can be due to pelvic or genitourinary malignancies
    • Sexually transmitted infections such as chancroid, syphilis, lymphogranuloma venereum, or genital herpes

Generalized lymphadenopathy

  • Primary HIV disease: nontender cervical and axillary nodes develop in the majority of patients during the 2nd week of acute symptomatic HIV infection due to the emergence of an immune response.
  • Mycobacterium tuberculosis
  • Autoimmune disease: SLE
  • Sarcoidosis
  • Malignancies:
    • Hodgkin disease
    • NHL
    • ALL or CLL
    • Plasma cell disorders 
    • POEMS syndrome (Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal protein, Skin changes)
    • Waldenström’s macroglobulinemia (also called lymphoplasmacytic lymphoma)
  • Rare systemic diseases

Diagnosis and Management

Diagnosis

History:

  • Onset: rapid onset versus slow-growing
  • Symptoms: painful versus painless
  • Location: 1 area or multiple areas
  • Associated symptoms:
    • Fever
    • Night sweats
    • Weight loss
    • Fatigue
    • Cough
    • Rash
    • Genital symptoms
  • Medical history:
    • Sexual history
    • Smoking
    • Recent travel
    • Animal contact (e.g., cats, rabbits)
    • IV drug use
    • Recent tick bites
    • Autoimmune disease
    • Previous malignancy
  • Risk factors for malignancy include:
    • Age > 40 years
    • Supraclavicular location of the nodes
    • Presence of systemic symptoms such as:
      • Fever
      • Night sweats
      • Unexplained weight loss

Physical examination:

  • Check for signs of local or systemic disease or infection.
  • Clinical features of lymphadenopathy:
    • Benign or infectious etiologies tend to cause:
      • Tenderness
      • Warmth to palpation
      • Fluctuance
      • Mobility
      • Rapid onset
    • Favor malignant/mycobacterial causes:
      • Nontender
      • Solid or firm
      • Fixed
      • Slow-growing
  • Associated findings:
    • Skin rash
    • Splenomegaly
    • Joint abnormalities
    • Abnormal cardiac findings

Laboratory testing:

Ordered based on the patient’s relevant history and physical exam findings to confirm the suspected diagnosis:

  • Rapid streptococcal testing or culture
  • EBV serology 
  • CMV serology
  • STI testing
  • CBC and peripheral blood smear
  • ANA
  • QuantiFERON-TB Gold (blood test for TB)
  • Liver and renal function tests
  • Serum tumor markers in selected cases with high suspicion
  • HIV testing

Imaging:

The type of test ordered is guided by history, physical exam, and risk factors.

  • Ultrasonography
  • Chest X-ray
  • CT or MRI

Lymph node biopsy:

  • If no clear diagnosis is made with the testing listed above.

Management

  • Treatment of the underlying cause of lymphadenopathy is the basis of management.
  • Patients with localized lymphadenopathy can be observed for 3–4 weeks if there is nothing else in the history, physical examination, and laboratory screening to suggest malignancy. 
  • Biopsy is appropriate if an abnormal node has not resolved after 4 weeks.

Differential Diagnosis

  • Hodgkin lymphoma (HL): malignancy of B lymphocytes originating in lymph nodes. Hodgkin lymphoma most commonly presents with lymphadenopathy in the neck, as well as night sweats, weight loss, fever, and possible splenomegaly and hepatomegaly. Diagnostic testing includes lymph node histologic analysis showing Hodgkin Reed-Sternberg (HRS) cells (giant multinucleated B cells with eosinophilic inclusions). Hodgkin lymphoma is managed with chemotherapy and radiotherapy. 
  • Non-Hodgkin lymphoma (NHL): diverse group of malignancies of B-cell, T-cell, and natural killer (NK)–cell origin. ⅔ of NHLs involve lymph nodes, and the remainder are extranodal. Like HL, which is distinct because of its clear pathologic features and treatments, NHL uniquely presents with constitutional signs. Management is primarily with chemotherapy. 
  • CLL: hematologic malignancy characterized by excess production of monoclonal B lymphocytes in the peripheral blood. CLL is identical to 1 of the NHLs and is called small lymphocytic lymphoma (SLL) when its involvement is primarily nodal. The disease usually presents in older adults, and symptom progression is slow. The B cells in these patients are functionally incompetent lymphocytes and thus may result in recurrent infections. 
  • Acute leukemias: hematologic malignancies that start in the bone marrow with malignant transformation and uncontrolled proliferation of WBC precursors. ALL may present with painless lymphadenopathy, while palpable lymph nodes are rare in AML. Other symptoms include fatigue, pallor, bleeding, fever, and infection related to anemia, thrombocytopenia, and lack of functional WBCs seen in acute leukemia. Diagnosis is made with peripheral blood smear and bone marrow biopsy. 
  • Kawasaki disease: though an uncommon illness, Kawasaki disease is the most frequent cause of childhood vasculitis. This syndrome is associated with fever, cervical lymphadenopathy, and a variety of other symptoms, including conjunctivitis, mucositis, rash, and coronary artery aneurysm.
  • Amyloidosis: pathogenic accumulation and deposition of amyloid throughout the body. Amyloid can be deposited in lymph nodes and is a rare cause of lymphadenopathy in the absence of amyloid infiltration of other organs. Diagnosis relies on lymph node biopsy.

References

  1. Ferrer, R.L. (2019). Evaluation of peripheral lymphadenopathy in adults. UpToDate. Retrieved April 29, 2021, from https://www.uptodate.com/contents/evaluation-of-peripheral-lymphadenopathy-in-adults
  2. McClain, K.L. (2020). Peripheral lymphadenopathy in children: evaluation and diagnostic approach. UpToDate. Retrieved April 29, 2021, from https://www.uptodate.com/contents/peripheral-lymphadenopathy-in-children-evaluation-and-diagnostic-approach

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