Lymphadenopathy

Department of the Navy
Bureau of Medicine and Surgery

Lymph nodes are lymphoid organs responsible for the processing of antigens, and may become activated by a variety of processes. Antigenic stimulation may result in nodes enlarging to 10 -15 times the normal size within a matter of days. Lymphadenopathy is a manifestation of either stimulation of nodal B or T lymphocytes by antigens or infiltration of the node(s) by a neoplastic process.

Lymphadenopathy may be a reflection of a wide variety of pathologic processes, ranging from mild, self-limited viral infections to life-threatening malignant processes. The key task in the evaluation of the patient with lymphadenopathy is to decide whether the underlying process is benign and can be observed over time, or whether adenopathy represents a more serious entity that requires prompt diagnosis and treatment. Often no single piece of the history or physical is sufficient to make this distinction. However, when combining a number of these clues, a suggested diagnosis may assist in the clinical work-up.

Clinical Pearls

Some useful indicators that will help lead to diagnosis are as follows:

• Is the lymphadenopathy acute or chronic? Enlarged nodes that have been present for days rather than weeks or months are more likely to be secondary to an acute infection, while a longer duration makes other processes increasingly likely.

• Is the adenopathy localized or generalized? Generalized lymphadenopathy may be seen in a number of systemic illnesses, including a variety of infections, immunologic disorders, leukemias and lymphomas. Regional adenopathy, on the other hand is more likely to be due to a localized pyogenic infection. Examples can include a staphylococcal or streptococcal infection of an extremity, a scalp infection, or athlete's foot. However, regional lymphadenopathy is not necessarily trivial, as metastatic malignancy or lymphoma may cause it.

• Does the patient exhibit evidence of systemic illness? While the absence of signs and symptoms such as fatigue, fever, night sweats, weight loss, and anemia certainly does not rule out the possibility of a serious underlying illness, their presence should serve as a red flag to establish a diagnosis.

• What is the nature of the node(s)? Enlarged nodes resulting from infection characteristically are freely moveable, tender, and may cause erythema and even warmth of overlying skin; while nodes infiltrated by lymphoma tend to be rubbery and non tender. Adenopathy caused by metastatic cancers is usually rock-hard, fixed, and frequently matted. It should be pointed out, however, that these are generalities, and their utility to a large degree depends on the experience of the examiner.

• What is the age of the patient? Benign causes of lymph node enlargement are much more common in children than in patients in older life. In contrast, a 45 year old has a statistically higher chance of having neoplastic disease than does a 20 year old. Patients undergoing evaluation for lymphadenopathy that are under the age of 30 have been shown to have a 20 percent incidence of malignant etiologies while patients over the age of 50 have a 60 percent risk of neoplasm. Finally, a careful history with attention to particular items may prove helpful. A thorough sexual history is essential, as generalized lymphadenopathy may be the presenting sign of secondary syphilis as well as hepatitis B. Even more importantly, HIV infection may present in similar fashion, either in the chronic phase of illness (AIDS-related complex), or in acute seroconversion.

• A history of exposure to cats (toxoplasmosis and cat scratch disease), undercooked meat (toxoplasmosis), joint pain and swelling (connective tissue disease and hepatitis B), or medications (particularly Dilantin) may be useful.

Generalized

Infectious

• Viral: Epstein-Barr virus, cytomegalovirus, HIV, rubella, hepatitis B

• Bacterial: Toxoplasmosis, syphilis, tuberculosis, atypical mycobacterial infections, brucellosis, tularemia, leptospirosis

Malignant: leukemias, Hodgkin's disease, non-Hodgkin's lymphoma.

Immunologic: rheumatoid arthritis, systemic lupus erythematosus, serum sickness, drug reactions (Phenytoin, Hydralazine, Allopurinol), angioimmunoblastic lymphadenopathy.

Endocrine: hyperthyroidism

Localized

May include all of the above plus: streptococcal/staphylococcal infections, cat-scratch disease, lymphogranuloma venereum, herpes simplex virus, dermatopathic lymphadenitis, metastatic cancers, and sarcoid.

Hilar

Sarcoid, histoplasmosis, coccidiomycosis, lymphoma, tuberculosis, bronchogenic carcinoma

Active Duty Population

The above list, while clearly not exhaustive, may still appear somewhat daunting when one is faced with evaluation of the patient with lymphadenopathy. Fortunately, a relatively small number of disease processes make up the bulk of patients seen with adenopathy. By far the most common cause of generalized lymphadenopathy in the younger active duty population is the infectious mononucleosis syndrome, or "mono." Typically caused by the Epstein-Barr virus, adenopathy is most prominent in the cervical distribution, and usually accompanied by pharyngitis (usually exudative), fever, fatigue, and frequently splenomegaly and elevated liver-associated enzymes. Disease is suggested by atypical lymphocytosis on peripheral smear, and essentially ruled-in by a positive Monospot test, with the caveat that the Monospot may be negative initially but positive on repeat testing. It is important to realize that cytomegalovirus and toxoplasmosis can present in identical fashion (although pharyngitis tends to be a less prominent complaint), and serologies for these diseases should be sent in heterophile-negative infectious mono syndromes.

HIV infection should always be kept in mind when faced with a sexually active patient with lymphadenopathy, in particular the acute seroconverting illness as previously mentioned. This syndrome occurs on average 6 weeks after exposure in about half of all individuals infected with HIV. Symptoms often consist of pharyngitis, fever, diarrhea, maculopapular, truncal rash, and mucocutaneous ulcers in addition to lymphadenopathy. Of critical importance, these individuals will typically test negative for HIV at the time of illness, and so it is essential to send a p24 antigen if possible, and to retest for HIV 44 weeks later.

As alluded to earlier, syphilis as well as hepatitis B need to be kept in mind as possibilities in the active duty population. Localized adenopathy in most cases will be caused by a local strep or staph infection, but cat scratch disease should be kept in mind, particularly if there is a history of recent exposure to cats. Finally, although malignancies are fortunately not common in the active duty population, they do occur regularly, and should always be kept in mind in the differential of both localized and general lymphadenopathy.

Bilateral hilar adenopathy in an asymptomatic individual, especially if African-American, strongly points to sarcoid as the diagnosis. Bilateral hilar adenopathy in a symptomatic patient, or the presence of enlarged unilateral hilar nodes, raises the possibility of lymphoma, bronchogenic lung cancer, or tuberculosis.

Laboratory Studies

Laboratory studies may be very useful in the investigation of lymphadenopathy. A CBC with differential should always be performed if any doubt exists as to the etiology. A left shift suggests a bacterial process, atypical lymphocytes point toward infectious mononucleosis, or other viral diseases, and eosinophils raise the possibility of a drug reaction. Other studies that may be useful include syphilis serologies, Monospot, hepatitis serologies,  toxoplasmosis titer, LDH (nonspecific, but substantial elevation suggests lymphoma), ANA, rheumatoid factor, and PPD. A chest x-ray may be useful also. With peripheral lymphadenopathy and an abnormal chest film there is a likelihood of a serious systemic illness.

If a diagnosis is not apparent after appropriate initial work-up, consideration should be given to referral of the patient to a higher level of care for further evaluation and/or a biopsy. While it is difficult to give definite guidelines regarding whom and when to refer to, certain factors should prompt early referral. These include a history of fever or night sweats, node(s) greater than 2 centimeters in size, an abnormal CXR, anemia, and any enlarged supraclavicular node. Unfortunately, even when biopsy is performed, not infrequently the pathology is non-diagnostic. It is essential to remember that anywhere from 15 to 25 percent of these patients, when followed over time, will prove to have a definable cause for their lymphadenopathy. Most often this proves to be lymphoma, pointing out the importance of continued re-evaluation after a non-diagnostic biopsy.