Lymphadenopathy

Michael Karpf.

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Definition
Infrequently, patients will note enlarged lymph nodes and present with the chief
complaint of having a nodule, a swollen gland, a "knot," or enlarged lymph nodes;
more commonly, patients do not recognize that they have significantly enlarged
lymph nodes, and the lymphadenopathy is discovered by the physician. Since
lymphadenopathy can be associated with a wide range of disorders spanning
relatively benign medical problems such as streptococcal pharyngitis to life-
threatening diseases such as malignancies, the discovery of enlarged nodes
represents an important physical finding that demands a systematic evaluation.
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Technique
In searching for lymph nodes, one must be gentle; otherwise, lymph nodes that are
only minimally enlarged or embedded in tissue may not be apparent. Particular
attention should be directed to the size, shape, and consistency of enlarged nodes.
Lymph nodes that are smooth and relatively soft, but slightly enlarged, may be
normal and reveal only hyperplasia when biopsied. Enlarged lymph nodes that
have an irregular shape and a rubbery, hard consistency may be infiltrated by
malignant cells. Tender nodes are suggestive of an inflammatory process. Matted
nodes or nodes fixed to underlying structures should raise the question of
malignancy or infection; freely movable nodes are more likely to occur in benign
conditions.
The extent and location of lymphadenopathy are important in determining and
providing diagnostic clues to the cause of lymphadenopathy. All major lymph
node chains should be evaluated in a systematic fashion. Begin with a visual
inspection of the area, looking for asymmetry or erythema. Palpate in a systematic
fashion, encompassing all accessible lymph nodes. For an examination of lymph
nodes of the neck, the patient either sits or stands facing the examiner. The
examiner's right hand explores the left side of the patient's neck and then the left
hand of the examiner explores the right side of the patient's neck. Starting from
the top of the neck and going down, all of the various cervical lymph node chains
should be evaluated including the preauricular, posterior auricular, occipital,
superior cervical, posterior cervical, submaxillary, submental, inferior deep
cervical, and supraclavicular, as noted in Figure 149.1. In the absence of
generalized adenopathy, enlargement of specific cervical lymph node groups can
be helpful diagnostically. For example, posterior auricular adenopathy suggests
rubella, whereas unilateral anterior auricular adenopathy is associated with lesions
of the conjunctiva and eyelids with the resultant oculoglandular syndrome seen in
trachoma, tularemia, cat-scratch fever, tuberculosis, syphilis, epidemic
keratoconjunctivitis, and outbreaks of adenovirus type 3 pharyngoconjunctival
fever. Oropharyngeal and dental infections can also cause cervical adenopathy.
Bilateral cervical adenopathy is also prominent in tuberculosis,
coccidioidomycosis, infectious mononucleosis, toxoplasmosis, sarcoid,
lymphomas, and leukemias. However, a unilateral cervical mass that is firm and
nontender should always raise the question of an undetected nasopharyngeal
carcinoma.

Figure 149.1
Lymph node locations in the neck.
Supraclavicular adenopathy is almost always abnormal. When it is not part of
generalized lymphadenopathy, it is suggestive of a primary malignancy in either
the abdomen or the chest. Right-sided supraclavicular nodes drain parts of the
lung and mediastinum and are signals of intrathoracic lesions, particularly in the
lung and esophagus. Left-sided supraclavicular nodes, which carry the eponym
"Virchow's nodes," are close to the thoracic duct and often signal intra-abdominal
tumors, particularly from the stomach, ovaries, testes, or kidneys. Supraclavicular
nodes are sometimes deep seated, and it is often helpful to have the patient
perform a Valsalva maneuver in order to push the cupola of the lung upward,
thereby bringing these deep-seated nodes to a more accessible position for
palpation. If supraclavicular adenopathy is noted, the patient should also be
closely examined for hilar and mediastinal adenopathy. Although a chest x-ray or
computerized tomography is often needed to verify this type of lymphadenopathy,
dullness to percussion over the manubrium is sometimes suggestive of an anterior
mediastinal mass or mediastinal nodes.
The patient should then be examined for axillary adenopathy. The patient may be
either sitting or supine. The patient's arm, supported by one of the examiner's
hands, should be held in a slightly flexed position and adducted. The examiner's
right hand is used to examine the patient's left axilla, and the left hand for the right
axilla, as shown in Figure 149.2A. The examiner's fingers should be slightly
cuffed and should reach as high into the apex of the axilla as possible. Fingers are
brought down slowly, exerting gentle pressure against the thorax. This maneuver
should be repeated several times in order to examine the lateral group, the medial
group, and the pectoral group of axillary nodes. Axillary adenopathy may be part
of a generalized process or may be localized and secondary to infection in the
limb. Local infection or trauma causing the adenopathy should be searched for
carefully. Concomitant epitrochlear, axillary, and supraclavicular adenopathy
should raise the question of cat-scratch fever. In a female, unilateral axillary nodes
raise the suspicion of an ipsilateral breast carcinoma.

Figure 149.2
(A) Technique for palpation of axillary nodes. (B) Technique for palpation of
epitrochlear lymph nodes. (From judge RD, Zuidema GD, eds. Physical diagnosis:
a physiologic approach. Boston: Little, Brown, 1963; 225.)
Next, the patient should be evaluated for the possibility of epitrochlear nodes.
Often, these nodes are overlooked, or inadequate techniques are employed to
examine them. Epitrochlear nodes are best sought with the patient's elbow flexed
to about 90°. The right epitrochlear area is approached by inserting the examiner's
left hand from behind the patient's elbow while the examiner's right hand grasps
the right wrist of the patient, supporting the forearm, as in Figure 149.2B. The
fourth and fifth finger should fall just above the medial epicondyle of the humerus
and then the other fingers will overlie the area where epitrochlear nodes are
usually found. Examination of the left epitrochlear area is just the reverse of the
right. Epitrochlear nodes are usually enlarged secondary to infections of the hand
and forearm. Occasionally, neoplastic processes will present with isolated
epitrochlear adenopathy. Enlarged epitrochlear nodes occur frequently in
mononucleosis. In the past, epitrochlear lymphadenopathy was considered a
diagnostically important sign of secondary syphilis, but now it is more commonly
due to recurrent hand injury or infections in people who do manual labor.
Occasionally, lymph nodes can be found in the vicinity of the umbilicus. These
nodes have the eponym "the node of Sister Mary Joseph" and are a signal of
significant intra-abdominal lymphadenopathy, usually associated with malignant
processes.
The inguinal region should be carefully evaluated for significant
lymphadenopathy. It is not uncommon for adults to have what has been termed
"shotty" nodes in the inguinal region. These shotty nodes are usually firm, not
fixed, and are less than a centimeter in diameter. They result from recurrent
infections and insults to the feet and legs. Significantly enlarged and tender nodes
in the inguinal region that are not part of generalized lymphadenopathy should
suggest a variety of conditions including syphilis, chancroid, and
lymphogranuloma venereum. Unilateral inguinal lymphadenopathy is usually a
response to infection of an ipsilateral lower extremity. Inguinal adenopathy can
also be part of systemic processes such as lymphoma or leukemia.
Femoral adenopathy is usually located in the femoral triangle in the area of the
node of Cloquet. Although femoral adenopathy can also be secondary to chronic
infection and trauma, it is much more commonly of pathologic significance than
is inguinal adenopathy.
Occasionally lymphadenopathy can be found in the popliteal fossa. This
adenopathy can be part of a generalized process or can be localized secondary to
infection or trauma of the lower extremity.
Many important lymph node groups cannot be evaluated by the physical
examination. Whenever there is evidence of generalized adenopathy, these groups
should be evaluated carefully. Hilar and mediastinal adenopathy can compromise
regional structures such as the superior vena cava or trachea and potentially cause
a life-threatening complication.
There are multiple lymph node groupings in the abdomen, including mesenteric,
paraaortic, celiac, and retrogastric. Bulky abdominal adenopathy can also
compromise structures, including the ureters and inferior vena cava, and can cause
complications such as renal failure. Abdominal adenopathy is usually evaluated
by computerized abdominal tomography, gallium scanning, ultrasonography, or
lymphangiography.
The spleen is part of the lymphatic system and should be carefully evaluated in
any patient in whom other lymphadenopathy is present.
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Basic Science
There are over 500 lymph nodes gathered in a variety of groupings throughout the
body. These nodes represent an integral part of both the immunologic and
reticuloendothelial systems. Individual lymph nodes consist of lymphocytes
clustered in lymphoid follicles and reticuloendothelial cells lining nodal sinuses.
Each follicle contains a germinal center populated by rapidly proliferating B cells
and macrophages. The germinal center is surrounded by densely packed small
lymphocyte T cells that replicate at a slower rate. Both B and T cells function in
the recognition of, and response to, antigenic stimulation. B cells are the principal
effector cells of the humoral arm of the immune system, whereas T cells are the
principal effector cells of the cellular arm of the immune system. Macrophages
and cells of the reticuloendothelial system are also part of the immunologic
system, but function in the phagocytosis of cellular debris or foreign substances
such as viruses and bacteria that have gained access to the node from the area
being drained. The reticuloendothelial system also clears some excess metabolites
from the circulation.
The enlargement of lymph nodes, either localized or generalized, can be the
consequence of several different pathologic mechanisms. Lymphadenopathy may
represent an increase in the number and size of lymphoid follicles with
proliferation of lymphocytes as a response to a new antigen. There can be
enlargement of lymph nodes with infiltration of the node by cells normally not
present, such as metastatic tumor or leukemic cells. Lymphadenopathy can occur
secondary to unknown stimuli that cause normal cells to become transformed to
lymphoma cells and to proliferate autonomously. Lymph nodes can be infiltrated
by polymorphonuclear cells, a condition called lymphadenitis, or lymph nodes can
be infiltrated by macrophages laden with metabolites, as in lipid storage diseases.
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Clinical Significance
Given the mechanisms by which lymph nodes enlarge, it is clear that the
differential diagnosis of lymphadenopathy involves infectious processes,
immunologic conditions, malignant processes, storage diseases, and a variety of
miscellaneous disorders (Table 149.1).

Table 149.1
Conditions Causing Lymphadenopathy.
Information from the clinical history is invaluable in the diagnostic management
of the patient with lymphadenopathy, and frequently leads to an accurate
diagnosis without the need for extensive diagnostic testing. The age of the patient
is quite important. Dramatic enlargement of lymph nodes and other lymphoid
tissue such as the adenoids and tonsils is often a normal response to a variety of
relatively weak antigenic stimuli such as mild viral and bacterial infections or
vaccinations in infants and children, whereas in adults these antigens will not
elicit a generalized response. This age difference in the expression of
lymphadenopathy is of such importance as to warrant an almost totally different
diagnostic approach to patients before and after puberty.
Specific inquiries should be made about drugs, allergies, animal exposures,
hobbies, and occupation. Lymphadenopathy as an adverse response to drugs and
allergies is well recognized. Exposure to cats may raise a question of cat-scratch
fever in a patient who presents with unilateral lymphadenopathy of an extremity.
Enlarged, nontender lymph nodes in the epitrochlear, axillary, femoral, and
inguinal areas are often seen in patients with occupations in which recurrent,
usually minor, injuries to extremities occur. Generalized lymphadenopathy also
can occur in patients with such chronic dermatologic disorders as eczema. If
acquired immune deficiency syndrome (AIDS) is suspected, information must be
obtained concerning potential risk factors for this disorder: sexual preference,
contact with individuals with the disorder, transfusion of blood products, etc.
Information must also be obtained about the lymphadenopathy itself. Tender,
painful nodes that appear and enlarge within a few days to a few weeks are most
often secondary to an inflammatory process in the area drained by the lymph
nodes. Occasionally a patient with tender, rapidly enlarging lymphadenopathy
will have lymphoma or leukemia. However, slowly growing, nontender nodes
may be indicative of either local or generalized malignancy.
A careful history must be taken regarding constitutional symptoms including
fever, night sweats, weight loss, pruritus, and generalized malaise. These
symptoms can be associated with either malignancies or infectious processes such
as tuberculosis or hepatitis.
Specific symptoms such as cough may raise the question of tuberculosis or fungal
pulmonary infection; a history of jaundice or clay-colored stools should raise the
question of hepatitis. Usually any diagnosis or condition suggested by the history
requires corroboration by data from the physical examination and appropriate
laboratory tests or lymph node biopsy. Infectious processes can be localized, as in
a response to a local abscess or to cellulitis. When the infection is systemic in
nature, the lymphadenopathy is also usually generalized, as in tuberculosis,
brucellosis, infectious mononucleosis, hepatitis, fungal infections, and
toxoplasmosis.
Immunologic conditions that cause lymphadenopathy can be secondary to clearly
identified antigens, as in serum sickness, or a response to an insect bite, or the
lymphadenopathy may be secondary to antigenic stimulation in conditions where
the antigen has not been identified. Examples of the latter include the connective
tissue disorders including rheumatoid arthritis and systemic lupus erythematosus.
Sarcoidosis is another example of an immunologic process that causes widespread
lymphadenopathy, although the causative antigen has not yet been identified.
A recently recognized viral (HIV) cause of lymphadenopathy is a systemic
infection causing severe immunologic deficiencies in the host. This syndrome has
been labeled the AIDS complex. Unexplained generalized adenopathy should
raise the possibility of AIDS or AIDS-related complex, and the individual should
be carefully evaluated for possible risk factors. Blood samples for viral titers
should also be obtained.
Invasion by malignant cells can cause either regional lymphadenopathy, as in
patients with head and neck tumors, or generalized lymphadenopathy, as in
patients with disseminated carcinomatosis. Lymphoma can also result in either
regional or generalized lymphadenopathy.
Generalized lymphadenopathy may also be the result of a variety of other
conditions, including Gaucher's disease, Graves" disease, and Addison's disease.
In most patients with lymphadenopathy, a diagnosis can be made after a careful
history, physical examination, and appropriate testing including hematologic
parameters, serologic tests, skin tests, and routine x-rays. As in all diagnostic
work-ups, these tests should be performed in a goal-directed manner in order to
evaluate specific hypotheses. If a specific diagnosis cannot be established after
appropriate evaluation, but infection is suspected, cautious observation after
appropriate cultures have been obtained may be warranted. Indiscriminant use of
antibiotics for unsubstantiated infections should not be encouraged. On the other
hand, if the diagnosis cannot be established and a malignancy is a major concern,
biopsy of a lymph node is appropriate and should be done in a timely fashion.
When a biopsy is done, adequate tissue should be obtained for both histologic
examination and appropriate cultures. Occasionally, more than one node may
have to be biopsied in order to determine the appropriate diagnosis. Occasionally,
nodes will reveal only nonspecific lymphoid hyperplasia, whereas a neighboring
node will harbor metastatic tumor. If an inadequate specimen is obtained, the
malignant disease may not be diagnosed.
In conclusion, although the differential diagnosis of lymphadenopathy may be
broad and sometimes initially confusing, the careful gathering of data from the
history, physical, and appropriate laboratory tests will resolve the differential in
the vast majority of patients.
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References

1. Doberneck RC. The diagnostic yield of lymph node biopsy. Arch

Surg. 1983;118:1203–5. [PubMed]
2. Harvey AM, Bordley J. Differential diagnosis. Philadelphia: W.B.
Saunders. 1972;361–64.
3. Nieuwenhuis P, Opsteltew D. Functional anatomy of germinal centers. Am
J Anat. 1984;170:421–35. [PubMed]
4. Solnitzsky OC, Jeghers H. Lymphadenopathy and disorders of the
lymphatic system. In: MacBryde CM. Blacklow RS. Signs and symptoms:
applied pathologic physiology and clinical interpretation. 5th ed.
Philadelphia: J.B. Lippincott, 1970;476–538.
5. Zuelzer WW, Kaplan J. The child with lymphadenopathy. Semin
Hematol. 1975;12:323. [PubMed]