Lymphadenopathy
Background
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:
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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.
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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.
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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.
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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.
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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.
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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.
Differential Diagnosis
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.
Hilar adenopathy
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.
When to refer
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.
Written and reviewed by CDR James C. Pile, MC, USN, Department of Infectious
Disease, National Naval
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Preface
· Administrative Section
· Clinical Section
The
General Medical Officer Manual , NAVMEDPUB 5134, January 1, 2000
Bureau
of Medicine and Surgery, Department of the Navy, 2300 E Street NW, Washington, D.C.,
20372-5300
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