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Lymphadenopathy

by James D. Douketis, MD

Lymph nodes are present throughout the body, but particular collections are present in the neck, axillae, and inguinal region; a few small (< 1 cm) nodes often are palpable in those areas in healthy people. Lymphadenopathy is palpable enlargement (> 1 cm) of one or more lymph nodes; it is categorized as localized when present in only 1 body area and as generalized when present in ≥ 2 body areas. Lymphadenopathy with pain and/or signs of inflammation (eg, redness, tenderness) is termed lymphadenitis (see Lymphadenitis). Other symptoms may be present depending on the underlying cause.

Pathophysiology

Some plasma and cells (eg, cancer cells, infectious microorganisms) in the interstitial space, along with certain cellular material, antigens, and foreign particles enter lymphatic vessels, becoming lymphatic fluid. Lymph nodes filter the lymphatic fluid on its way to the central venous circulation, removing cells and other material. The filtering process also presents antigens to the lymphocytes contained within the nodes. The immune response from these lymphocytes involves cellular proliferation, which can cause the nodes to enlarge (reactive lymphadenopathy). Pathogenic microorganisms carried in the lymphatic fluid can directly infect the nodes, causing lymphadenitis (see Lymphadenitis), and cancer cells may lodge in and proliferate in the nodes.

Etiology

Because lymph nodes participate in the body's immune response, a large number of infectious and inflammatory disorders and cancers are potential causes (see Some Causes of Lymphadenopathy). Only the more common causes are discussed here. Causes most likely vary depending on patient age, associated findings, and risk factors, but overall the most common causes are

  • Idiopathic, self-limited

  • Upper respiratory infections (URI)

  • Local soft-tissue infections

The most dangerous causes are cancer, HIV infection, and TB. However, most cases represent benign disorders or clinically obvious local infections. Probably < 1% of undifferentiated cases presenting for primary care involve cancer.

Some Causes of Lymphadenopathy

Cause

Suggestive Findings

Diagnostic Approach

Infections

URI

Cervical adenopathy with only little or no tenderness

Sore throat, runny nose, cough

Clinical evaluation

Oropharyngeal infection (eg, pharyngitis, stomatitis, dental abscess)

Cervical adenopathy only (often tender)

Clinically apparent oropharyngeal infection

Clinical evaluation

Mononucleosis

Symmetric adenopathy, typically cervical but sometimes in axillae and/or inguinal areas

Fever, sore throat, severe fatigue

Often splenomegaly

Typically in adolescents or young adults

Heterophile antibody test

Sometimes Epstein-Barr virus serologic test

TB (extrapulmonary—tuberculous lymphadenitis)

Usually cervical or supraclavicular adenopathy, sometimes inflamed or draining

Often in patients with HIV infection

Tuberculin skin testing or interferon-gamma release assay

Usually node aspiration or biopsy

HIV (primary infection)

Generalized adenopathy

Usually fever, malaise, rash, arthralgia

Often history of HIV exposure or high-risk activity

HIV antibody testing

Sometimes HIV-RNA assay (if early primary infection is suspected)

Sexually transmitted diseases (STDs—particularly herpes simplex, chlamydial infections, and syphilis)

Except for secondary syphilis, only inguinal adenopathy (fluctuant or draining nodes suggest lymphogranuloma venereum)

Often urinary symptoms, urethral or cervical discharge

Sometimes genital lesions

For secondary syphilis, often widespread mucocutaneous lesions, generalized lymphadenopathy

For herpes simplex, culture

For chlamydial infections, nucleic acid-based testing

For syphilis, serologic testing

Skin and soft-tissue infections (eg, cellulitis, abscess, cat-scratch disease), including direct lymph node infection

Usually a visible local lesion (or recent history of a lesion) distal to site of adenopathy

Sometimes only erythema, tenderness of an isolated node (often cervical) without apparent primary site of entry

Usually clinical evaluation

For cat scratch disease, serum antibody titers

Toxoplasmosis

Bilateral, nontender cervical or axillary adenopathy

Sometimes a flu-like syndrome, hepatosplenomegaly

Often history of exposure to cat feces

Serologic testing

Other infections (eg, brucellosis, cytomegalovirus infection, histoplasmosis, paracoccidioidomycosis, plague, rat bite fever, tularemia)

Vary

Often risk factors (eg, geographic location, exposure)

Varies

Cancers

Leukemias (typically chronic and sometimes acute lymphocytic leukemia)

Fatigue, fever, weight loss, splenomegaly

With acute leukemia, often easy bruising and/or bleeding

CBC, peripheral smear

Bone marrow examination

Lymphomas

Painless adenopathy (local or generalized), often rubbery, sometimes matted

Often fever, night sweats, weight loss, splenomegaly

Lymph node biopsy

Metastatic cancers (often head and neck, thyroid, breast, or lung)

One or several painless local nodes

Nodes often hard, sometimes fixed to adjacent tissue

Usually evaluation to identify the primary tumor

Connective tissue disorders

Systemic lupus erythematosus (SLE)

Generalized adenopathy

Typically arthritis or arthralgias

Sometimes malar rash, other skin lesions

Clinical criteria, antibody testing

Sarcoidosis

Painless adenopathy (local or generalized)

Often cough and/or dyspnea, fever, malaise, muscle weakness, weight loss, joint pains

Chest imaging (plain x-ray or CT)

If imaging results are positive, node biopsy

Kawasaki disease

Tender cervical adenopathy in children

Fever (usually > 39° C), truncal rash, strawberry tongue, periungual, palmar and plantar desquamation

Clinical criteria

Other connective tissue disorders (eg, juvenile idiopathic arthritis, Kikuchi lymphadenopathy, RA, Sjögren syndrome)

Vary

Varies

Other conditions

Drugs such as allopurinol, antibiotics (eg, cephalosporins, penicillin, sulfonamides), atenolol, captopril, carbamazepine, phenytoin, pyrimethamine, and quinidine

History of using a causative drug

Except for phenytoin, a serum sickness-type reaction (eg, rash, arthritis and/or arthralgias, myalgia, fever)

Clinical evaluation

Silicone breast implants

Localized adenopathy in patients with breast implants

Exclusion of other causes of adenopathy

Evaluation

Adenopathy may be the patient's reason for presenting or be discovered during evaluation for another complaint.

History

History of present illness should determine the location and duration of adenopathy and whether it is accompanied by pain. Recent cutaneous injuries (particularly cat scratches and rat bites) and infections in the area drained by affected nodes are noted.

Review of systems should seek symptoms of possible causes, including runny, congested nose (URI); sore throat (pharyngitis, mononucleosis); mouth, gum, or tooth pain (oral-dental infection); cough and/or dyspnea (sarcoidosis, lung cancer, TB, some fungal infections); fever, fatigue, and malaise (mononucleosis and many other  infections, cancers, and connective tissue disorders); genital lesions or discharge (herpes simplex, chlamydia, syphilis); joint pain and/or swelling (SLE or other connective tissue disorders); easy bleeding and/or bruising (leukemia); and dry, irritated eyes (Sjögren syndrome).

Past medical history should identify risk factors for (or known) TB or HIV infection, and cancer (particularly use of alcohol and/or tobacco). Patients are queried about travel history to areas of endemic infections (eg, Middle East for brucellosis, American Southwest for plague) and possible exposures (eg, cat feces for toxoplasmosis, farm animals for brucellosis, wild animals for tularemia). Drug history is reviewed for specific known causative agents.

Physical examination

Vital signs are reviewed for fever. Areas of particular lymph node concentration in the neck (including occipital and supraclavicular areas), axillae, and inguinal region are palpated. Node size, tenderness, and consistency are noted as well as whether the nodes are freely mobile or fixed to adjacent tissue.

Skin is inspected for rash and lesions, with particular attention to areas drained by the affected nodes. The oropharynx is inspected and palpated for signs of infection and any lesions that may be cancerous. The thyroid gland is palpated for enlargement and nodularity. Breasts (including in males) are palpated for lumps. Lungs are auscultated for crackles (suggesting sarcoidosis or infection). Abdomen is palpated for hepatomegaly and splenomegaly. Genitals are examined for chancres, vesicles, and other lesions, and for urethral discharge. Joints are examined for signs of inflammation.

Red flags

  • Node > 2 cm

  • Node that is draining, hard, or fixed to underlying tissue

  • Supraclavicular node

  • Risk factors for HIV or TB

  • Fever and/or weight loss

  • Splenomegaly

Interpretation of findings

Patients with generalized adenopathy usually have a systemic disorder. However, patients with localized adenopathy may have a local or systemic disorder (including one that often causes generalized adenopathy).

Sometimes, history and physical examination suggest a cause (see Some Causes of Lymphadenopathy) and may be diagnostic in patients with a clear viral URI or with local soft-tissue or dental infection. In other cases, findings (such as the red flag findings) are of concern but do not point to a single cause. Nodes that are hard, markedly enlarged (> 2 to 2.5 cm), and/or fixed to adjacent tissue, particularly nodes in the supraclavicular area or in patients who have had prolonged use of tobacco and/or alcohol, are concerning for cancer. Marked tenderness, erythema, and warmth in a single enlarged node may be due to a suppurative node infection (eg, due to staphylococcus or streptococcus). Fever may occur with many of the infectious, malignant, and connective tissue disorders. Splenomegaly can occur with mononucleosis, toxoplasmosis, leukemia, and lymphoma. Weight loss occurs with TB and cancer. Risk factors and travel and exposure history are at best suggestive. Finally, adenopathy sometimes has a serious cause in patients who have no other manifestations of illness.

Testing

If a specific disorder is suspected (eg, mononucleosis in a young patient with fever, sore throat, and splenomegaly), initial testing is directed at that condition (see Some Causes of Lymphadenopathy).

If history and physical examination do not show a likely cause, further evaluation depends on the nodes involved and the other findings present.

Patients with red flag findings and those with generalized adenopathy should have a CBC and chest x-ray. For generalized adenopathy, most clinicians would also do a tuberculin skin test (or interferon-gamma release assay) and serologic tests for HIV, mononucleosis, and perhaps toxoplasmosis and syphilis. Patients with joint symptoms or rash should have antinuclear antibody testing for SLE. Most clinicians believe patients with localized adenopathy and no other findings can safely be observed for 3 to 4 wk, unless cancer is suspected. If cancer is suspected, patients typically should have node biopsy (those with a neck mass require a more extensive evaluation prior to biopsy—see Neck Mass). Biopsy is also done if isolated or generalized adenopathy does not resolve in 3 to 4 wk.

Treatment

Primary treatment is directed at the cause; adenopathy itself is not treated. A trial of corticosteroids is not done for adenopathy of unknown etiology because corticosteroids can reduce adenopathy caused by leukemia and lymphoma and thus delay diagnosis, and corticosteroids can exacerbate TB. A trial of antibiotics is also not indicated, except when a suppurative lymph node infection is suspected.

Key Points

  • Most cases are idiopathic and self limited, or result from clinically apparent local causes

  • Initial testing should be done if there are red flag findings, if other manifestations or risk factors suggest a specific disorder, or when generalized adenopathy has no apparent cause.

  • Patients with acute localized lymphadenopathy and no other findings can be observed for 3 to 4 wk, after which time biopsy should be considered.

Resources In This Article

Drugs Mentioned In This Article

  • Drug Name
    Select Trade
  • DARAPRIM
  • TENORMIN
  • ZYLOPRIM
  • CAPOTEN
  • DILANTIN
  • No US brand name
  • TEGRETOL

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