Step-by-step diagnostic approach

The history may be diagnostic, suggestive, or non-diagnostic of the cause of lymphadenopathy. The physician should determine whether the lymphadenopathy is localised or generalised, and the size, mobility and consistency of the lymph nodes. [1] [12] If localised lymphadenopathy is present, the regions drained by the nodes should be examined for evidence of infection, skin lesions or neoplasms. In a primary care setting, roughly three quarters of patients will present with localised lymphadenopathy, compared with one quarter with generalised lymph node enlargement. [12] When the history and physical signs are diagnostic for a specific disorder, such as a localised skin infection or pharyngitis, no further testing is indicated and treatment should be initiated.

History

The key aspects of the patient history that aid in the diagnostic work-up and in the differential diagnosis are:

  • Age of the patient: in a study from a referral centre, 79% of biopsies performed on young patients (<30 years old) were benign; however, 60% of biopsies performed on patients older than 50 were found to have a malignant aetiology, mainly of the carcinoma subtype. [13] In a primary care setting, the reported prevalence of malignancy found during lymphadenopathy work-up is probably much lower

  • Symptoms of infection: these include pharyngitis, conjunctivitis, skin ulceration, localised tenderness, genital sores or discharge, fever and night sweats

  • Symptoms of metastatic malignancy: with knowledge of the patterns of regional lymph node drainage, constitutional symptoms of malignancy such as weight loss and night sweats may be associated with localised symptoms such as difficulty in swallowing, hoarseness and pain (in head and neck cancer), cough and haemoptysis (in lung cancer)

  • Constitutional or B symptoms: fever, night sweats and/or unexplained weight loss greater than 10% of bodyweight over 6 months are concerning for lymphoma; [14] arthralgias, rash, and myalgias suggest the presence of a collagen vascular disease

  • Epidemiological clues: exposure to pets, occupational exposures, recent travel or high-risk behaviours may suggest specific disorders

  • Medication history: drug hypersensitivity (e.g., to phenytoin) is a common cause of lymphadenopathy.

Duration of lymphadenopathy: persistent lymphadenopathy (more than 4 weeks) is indicative of chronic infection, collagen vascular disease or underlying malignancy, whereas localised lymphadenopathy of brief duration often accompanies some infections (e.g., infectious mononucleosis and bacterial pharyngitis). [12]

Physical examination

The most important physical examination findings are lymph node size, consistency, mobility and distribution:

1. Size: lymph node size varies according to their location. For example, inguinal lymph nodes may be as large as 2 cm in healthy individuals. The significance of enlarged lymph nodes must be viewed in the context of their location, duration and associated symptoms, and the age and gender of the patient. As a general rule, lymph nodes measuring less than 1 cm are rarely of clinical significance. In contrast, lymph nodes greater than 2 cm that are persistent for more than 4 weeks should be thoroughly evaluated [1]

2. Consistency: in general, lymph node consistency should not be used to distinguish between malignant and benign aetiologies. However, rock-hard nodes are seen more commonly with malignancies, whereas tender nodes often suggest an inflammatory disorder [2]

3. Mobility: fixed or matted nodes suggest metastatic carcinoma, whereas freely movable nodes may occur in infections, collagen vascular disease and lymphoma. Evaluation of the mobility of supraclavicular nodes is enhanced by having the patient perform a Valsalva manoeuvre

4. Distribution: in most cases, generalised lymphadenopathy is a sign of systemic disease, especially when associated with splenomegaly. In certain locations, localised lymphadenopathy can provide clues for the possible underlying aetiology. Inguinal lymph nodes may occasionally be enlarged in healthy individuals, whereas enlarged supraclavicular lymph nodes are concerning for underlying malignancy or infection. The distribution of lymphadenopathy may be localised (enlarged lymph nodes in one region); regional (enlarged lymph nodes in 2 or more contiguous regions); or generalised (enlarged lymph nodes in 2 or more non-contiguous regions). [1]

  • Cervical lymphadenopathy: the cervical lymph nodes drain the scalp, skin, oral cavity, larynx, and neck. The most common causes of cervical lymphadenopathy include:

    • Infection

    • Malignancy

    • Bacterial pharyngitis

    • Dental abscess

    • Ear infections

    • Infectious mononucleosis

    • Head and neck cancer (older patients with history of smoking)

    • Thyroid cancer

    • Lymphoma

    • Tuberculosis.

  • Supraclavicular lymphadenopathy: this group of lymph nodes drains the gastrointestinal tract, genitourinary tract and the lungs. Enlarged supraclavicular nodes raise a strong suspicion for malignancy. [15] The prevalence of malignancy in the presence of supraclavicular lymphadenopathy is reported to be in the range of 54% to 85%. [13] [16] [17] Virchow's node (pathological enlargement of one of the left supraclavicular lymph nodes) is associated with the presence of an abdominal or thoracic neoplasm. [18] Other common causes of supraclavicular lymphadenopathy include:

    • Hodgkin's lymphoma

    • Non-Hodgkin's lymphoma

    • Bronchogenic carcinoma

    • Breast carcinoma

    • Infection.

  • Axillary lymphadenopathy: this group of lymph nodes drains the upper extremities, breast and thorax. Causes of axillary lymphadenopathy include:

    • Cat scratch disease [19]

    • Streptococcal or staphylococcal skin infection

    • Metastatic breast carcinoma

    • Metastatic melanoma.

  • Epitrochlear lymphadenopathy: this group of lymph nodes drains the ulna, forearm and hand. Epitrochlear lymphadenopathy is a rare finding in healthy people. [20] Causes of epitrochlear lymphadenopathy include:

    • Lymphoma

    • Chronic lymphocytic leukaemia (CLL)

    • Infectious mononucleosis

    • Local upper extremity infections

    • Sarcoidosis

    • Secondary syphilis

    • HIV.

  • Inguinal lymphadenopathy: this group of lymph nodes drains the lower abdomen, external genitalia (skin), anal canal, lower third of the vagina and lower extremities. Enlargement of inguinal lymph nodes up to 1 to 2 cm in size can be found in healthy adults. [2] In a diagnostic work-up, biopsy of inguinal lymph nodes has been shown to offer the lowest diagnostic yield. [16] Causes of inguinal lymphadenopathy include:

    • Cellulitis

    • Venereal disease

    • Hodgkin's lymphoma

    • Non-Hodgkin's lymphoma

    • Metastatic melanoma

    • Squamous cell carcinoma (metastatic from the penile or vulvar regions).

  • Mediastinal lymphadenopathy: the differential is extensive. Unilateral mediastinal lymphadenopathy can be secondary to infectious or malignant aetiologies. Bilateral mediastinal lymphadenopathy may be caused by sarcoidosis or chronic granulomatous disease and by several malignant conditions. Calcified lymph nodes in this location may be due to tuberculosis, histoplasmosis, or silicosis. Evaluation of mediastinal lymph node enlargement may require invasive procedures such as mediastinoscopy. Endobronchial ultrasound-guided transbronchial needle biopsy is emerging as a less invasive, alternative approach for evaluation of mediastinal (and hilar) lymphadenopathy. [21]

  • Abdominal lymphadenopathy: lymphadenopathy limited to the mesenteric or retroperitoneal space is highly suspicious for underlying malignant disease. Periumbilical enlarged lymph nodes (which also include metastatic tumour deposits) are known as Sister (Mary) Joseph's nodes, and are a classic sign of gastric adenocarcinoma.

  • Splenomegaly: may be associated with lymphadenopathy in the following conditions:

    • Infectious mononucleosis

    • Some haematological malignancies

    • Lymphoma

    • Tuberculosis

    • HIV

    • Collagen vascular disease.

Investigations

If the history and physical examination are suggestive but not diagnostic for a specific disorder, further testing is required. Initial investigations include:

  • FBC with WBC differential

  • Throat culture

  • Monospot test

  • HIV test

  • Hepatitis serologies

  • PPD placement

  • Chest x-ray.

If the estimated risk for malignancy is low, patients with localised lymphadenopathy and non-diagnostic initial studies are observed for 3 to 4 weeks.

When malignancy is suspected, the first-line investigation is lymph node excision biopsy and histological examination. This is the only way to diagnose and grade Hodgkin's lymphoma and non-Hodgkin's lymphoma. Indications for excision biopsy and histological examination include:

  • Patients with generalised lymphadenopathy in whom the initial studies are non-diagnostic

  • Patients with localised persistent lymphadenopathy, non-diagnostic initial studies and a high risk for malignancy.

Important considerations for histological diagnosis:

  • In general, excisional lymph node biopsies are preferred, particularly if lymphoma is suspected

  • Fine needle aspiration (FNA) of a lymph node is occasionally useful for the diagnosis of underlying carcinomas or recurrent malignancy

  • Biopsies should be obtained at the most abnormal or largest lymph node site

  • Inguinal node biopsy should be avoided, since the diagnostic yield at this site is often low [1]

  • Empiric therapy with corticosteroids or antibiotics should be avoided in patients with non-diagnostic work-ups as they may confound the results of a lymph node biopsy due to their lympholytic effect

  • Biopsies that are interpreted by the pathologist as atypical lymphoid hyperplasia should be considered non-diagnostic rather than negative for a malignancy, and these patients should be carefully followed and an additional lymph node biopsy strongly considered

  • For patients in whom suspicion for an underlying malignancy is high, an unrevealing lymph node biopsy should be considered non-diagnostic rather than negative for malignancy, and further work-up should be pursued.

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