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Jen,

Although the finding of lymphadenopathy sometimes raises fears about serious illness, it is, in patients seen in primary care settings, usually a result of benign infectious causes. Most patients can be diagnosed on the basis of a careful history and physical examination. In general, lymph nodes greater than 1 cm in diameter are considered to be abnormal. Supraclavicular nodes are the most worrisome for malignancy. Generalized adenopathy should always prompt further clinical investigation. When a node biopsy is indicated, excisional biopsy of the most abnormal node will best enable the pathologist to determine a diagnosis.

Lymphadenopathy may be the only clinical finding or one of several nonspecific findings, and the discovery of swollen lymph nodes will often raise the specter of serious illness such as lymphoma, acquired immunodeficiency syndrome or metastatic cancer.

Generalized lymphadenopathy is defined as two or more sites with abnormal lymph nodes.

The body has approximately 600 lymph nodes, but only those in the submandibular, axillary or inguinal regions may normally be palpable in healthy people. Lymphadenopathy refers to nodes that are abnormal in either size, consistency or number. There are various classifications of lymphadenopathy, but a simple and clinically useful system is to classify lymphadenopathy as "generalized" if lymph nodes are enlarged in two or more noncontiguous areas or "localized" if only one area is involved. Distinguishing between localized and generalized lymphadenopathy is important in formulating a differential diagnosis.


In most cases, a careful history and physical examination will identify a readily diagnosable cause of the lymphadenopathy, such as upper respiratory tract infection, pharyngitis, periodontal disease, conjunctivitis, lymphadenitis, tinea, insect bites, recent immunization, cat-scratch disease or dermatitis, and no further assessment is necessary

In patients with unexplained localized lymphadenopathy and a reassuring clinical picture, a three- to four-week period of observation is appropriate before biopsy. Patients with localized lymphadenopathy and a worrisome clinical picture or patients with generalized lymphadenopathy will need further diagnostic evaluation that often includes biopsy.
Fine-needle aspiration is occasionally considered an alternative to excisional biopsy but often yields a high number of nondiagnostic results because of the small amount of tissue obtained and the inability to examine the architecture of the gland.

History
The physician should consider four key points when compiling a patient's history. First, are there localizing symptoms or signs to suggest infection or neoplasm in a specific site? Second, are there constitutional symptoms such as fever, weight loss, fatigue or night sweats to suggest disorders such as tuberculosis, lymphoma, collagen vascular diseases, unrecognized infection or malignancy? Third, are there epidemiologic clues such as occupational exposures, recent travel or high-risk behaviors that suggest specific disorders? Fourth, is the patient taking a medication that may cause lymphadenopathy? Some medications are known to specifically cause lymphadenopathy (e.g., phenytoin [Dilantin]), while others, such as cephalosporins, penicillins or sulfonamides, are more likely to cause a serum sickness-like syndrome with fever, arthralgias and rash in addition to lymphadenopathy.


Epidemiologic Clues to the Diagnosis of Lymphadenopathy

Undercooked meat
Tick bite
Tuberculosis
Recent blood transfusion or transplant
High-risk sexual behavior
Intravenous drug use
Cat-scratch disease
Toxoplasmosis
Lyme disease, tularemia
Tuberculous adenitis
Cytomegalovirus, HIV

Fine-needle aspiration is occasionally considered an alternative to excisional biopsy but is often unhelpful.

Size. Nodes are generally considered to be normal if they are up to 1 cm in diameter; however, some authors suggest that epitrochlear nodes larger than 0.5 cm or inguinal nodes larger than 1.5 cm should be considered abnormal. Little information exists to suggest that a specific diagnosis can be based on node size. However, in one series10 of 213 adults with unexplained lymphadenopathy, no patient with a lymph node smaller than 1 cm2 (1 cm) had cancer, while cancer was present in 8 percent of those with nodes from 1 cm to 2cm

.Pain/Tenderness. When a lymph node rapidly increases in size, its capsule stretches and causes pain. Pain is usually the result of an inflammatory process or suppuration, but pain may also result from hemorrhage into the necrotic center of a malignant node. The presence or absence of tenderness does not reliably differentiate benign from malignant nodes.

Consistency.
Stony-hard nodes are typically a sign of cancer, usually metastatic. Very firm, rubbery nodes suggest lymphoma. Softer nodes are the result of infections or inflammatory conditions. Suppurant nodes may be fluctuant. The term "shotty" refers to small nodes that feel like buckshot under the skin, as found in the cervical nodes of children with viral illnesses.

Matting. A group of nodes that feels connected and seems to move as a unit is said to be "matted." Nodes that are matted can be either benign (e.g., tuberculosis, sarcoidosis or lymphogranuloma venereum) or malignant (e.g., metastatic carcinoma or lymphomas).

Location. The anatomic location of localized adenopathy will sometimes be helpful in narrowing the differential diagnosis. For example, cat-scratch disease typically causes cervical or axillary adenopathy, infectious mononucleosis causes cervical adenopathy and a number of sexually transmitted diseases are associated with inguinal adenopathy.


Less common causes of lymphadenopathy

Lyme disease*
Measles*
Rubella
Tularemiala*
Brucellosis*
Typhoid fever*
Still's disease*
Dermatomyositis*
Amyloidosis*

Supraclavicular lymphadenopathy has the highest risk of malignancy, estimated as 90 percent in patients older than 40 years and 25 percent in those younger than age 40.
In patients with generalized lymphadenopathy, the physical examination should focus on searching for signs of systemic illness. The most helpful findings are rash, mucous membrane lesions, hepatomegaly, splenomegaly or arthritis .

If Epstein-Barr virus antibodies are absent, other causes of the mononucleosis syndrome should be considered. These include toxoplasmosis, cytomegalovirus infection, streptococcal pharyngitis, hepatitis B infection and acute human immunodeficiency virus (HIV)

Ulceroglandular Syndrome
This syndrome is defined by the presence of a skin lesion with associated regional lymphadenopathy. The classic cause is tularemia, acquired by contact with an infected rabbit or tick; more common causes include streptococcal infection (e.g., impetigo), cat-scratch disease and Lyme disease.

Oculoglandular Syndrome
This syndrome involves the combination of conjunctivitis and associated preauricular nodes. Common causes include viral keratoconjunctivitis and cat-scratch disease resulting from an ocular lesion.

Because generalized lymphadenopathy almost always indicates that a significant systemic disease is present, the clinician should consider and proceed with specific testing as indicated. If a diagnosis cannot be made, the clinician should obtain a biopsy of the node. The diagnostic yield of the biopsy can be maximized by obtaining an excisional biopsy of the largest and most abnormal node (which is not necessarily the most accessible node). If possible, the physician should not select inguinal and axillary nodes for biopsy, since they frequently show only reactive hyperplasia.


If the lymphadenopathy is localized, the decision about when to biopsy is more difficult. Patients with a benign clinical history, an unremarkable physical examination and no constitutional symptoms should be reexamined in three to four weeks to see if the lymph nodes have regressed or disappeared. Patients with unexplained localized lymphadenopathy who have constitutional symptoms or signs, risk factors for malignancy or lymphadenopathy that persists for three to four weeks should undergo a biopsy. Biopsy should be avoided in patients with probable viral illness because lymph node pathology in these patients may sometimes simulate lymphoma and lead to a false-positive diagnosis of malignancy.


Many patients worry about the cause of their abnormal lymph nodes. To adequately address their fears, the physician should ask the patient about his or her concerns and respond to questions about specific diagnoses. When biopsy is deferred, the physician should explain to the patient the rationale for waiting. Patients should be cautioned to remain alert for the reappearance of the nodes because lymphomatous nodes have been known to temporarily regress.


In most patients, lymphadenopathy has a readily diagnosable infectious cause. A diagnosis of less obvious causes can often be made after considering the patient's age, the duration of the lymphadenopathy and whether localizing signs or symptoms, constitutional signs or epidemiologic clues are present. When the cause of the lymphadenopathy remains unexplained, a three- to four-week observation period is appropriate when the clinical setting indicates a high probability of benign disease.





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