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Clinical Pediatrics
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Lymphadenopathy in Children: When and How to Evaluate
Linda S. Nield and Deepak Kamat
Clin Pediatr (Phila) 2004; 43; 25
DOI: 10.1177/000992280404300104
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Lymphadenopathy in Children:
When and How to Evaluate
Linda S. Nield, MD1
Deepak Kamat, MD, PhD
Introduction
I
t is not uncommon for parents to bring their child to the
pediatrician’s office because
they found a lump in their child’s
neck, axillae, or groin. They are
worried and ask if it is a cancer. Many times parents want a
second or third opinion because
the lump is not getting smaller
even after weeks or months and
even though their primary care
provider has told them that the
child does not have a serious illness. They want a specific diagnosis and want to know when is it going to go away. As primary care
providers, it is our responsibility
to evaluate this lump and tell parents what it is and treat it appropriately. So really, when are these
lumps significant and when does
one need to worry? This article is
a review of childhood lymphadenopathy that is based on
the review of current literature
and our clinical experience and
offers guidance about the evaluation of this common pediatric
problem.
Lymph Nodes in
Healthy Children
How extensive should the evaluation of a child with palpable
lymph nodes be? This is a difficult
question to answer, but knowing
the prevalence and typical size of
palpable nodes in the otherwise
healthy child can aid the clinician
in the decision making. Bamji and
colleagues examined healthy children from birth to twelve months
of age to determine the presence
of cervical, inguinal, axillary, and
surpacalvicular nodes greater
than 0.3 cm in diameter.1 Palpable nodes were found in 34% of
neonates and 57% of children age
1 to 12 months old. Nodes were
even palpated in a 2-hour-old
baby. In neonates, the inguinal
area was the most common site
(24% of neonates) at which nodes
were palpable, whereas in infants
the cer vical area was the most
common site, palpable in 41% of
infants. Cer vical and axillar y
nodes were palpated in 17% and
6.5% of neonates respectively
while inguinal and axillary nodes
Clin Pediatr. 2004;43:25-33
1Department
of Pediatrics, West Virginia University, Morgantown, West Virginia.
Reprint requests and correspondence to: Deepak Kamat, MD, PhD, Children’s Hospital of
Michigan, 3901 Beaubien Blvd., Detroit, MI 48201.
© 2004 Westminster Publications, Inc., 708 Glen Cove Avenue, Glen Head, NY 11545, U.S.A.
were palpated in 29% and 10% of
infants, respectively. The nodes
did not exceed 1.2 cm in diameter
in newbor ns or 1.6 cm in
infants. Supraclavicular nodes
were not palpable at all in these
healthy children and other peripheral lymph node regions were
not mentioned in this study.
Herzog studied the prevalence of cervical, submandibular,
post-auricular, and occipital
nodes of 0.5 cm diameter or
larger in children 3 weeks to 6
years old.2 Forty-five percent of
healthy children had palpable
nodes with the descending order
of prevalence at cervical, occipital, submandibular, and post-auricular sites. Younger children
and infants commonly had occipital and post-auricular adenopathy, while older children had cervical and submandibular nodes
that were palpable. Baptist and
Villalba assert that facial lymph
nodes, particularly those located
in the mandibular and maxillary
areas, may be palpated in the otherwise healthy child.3
In summary, throughout all of
childhood, cervical, inguinal and
axillary nodes of less than 1.6 cm
are commonly found in the otherwise normal individuals. Pediatric
textbooks refer to nodes being enlarged if their diameter exceeds
1.0 cm for cer vical or axillar y
nodes and 1.5 cm for inguinal
nodes.4 Occipital, preauricular,
submaxillar y, submental, pop-
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25
Nield, Kamat
liteal, and epitrochlear nodes
also may be palpable but are typically present when there is a local infection or inflammator y
process.2,5 In particular, many of
the other wise healthy children
with palpable occipital and postauricular nodes had dermatologic conditions of the face and
scalp such as sebor rhea or
eczema.2 Supraclavicular nodes
are not normally palpable and
should be considered pathologic
unless proven otherwise because
of their association with mediastinal disease.2,6
Causes of Lymph Node
Enlargement
The lymph nodes enlarge due
to proliferation of the lymphocytes in the lymph nodes in response to infection or due to lymphoproliferative disorder, and
also due to infiltration of lymph
nodes by inflammatory or malignant cells. Infection is the most
common trigger for lymph node
enlargement in children. To simplify the evaluation and management of the child with lymphadenopathy, one can approach
this issue by dividing it into the
following categories: acute infective lymphadenitis, acute lymphadenopathy, and chronic lymphadenopathy. Lymphadenopath
y can be defined as acute if it lasts
less than 3 weeks or chronic if it
lasts longer than 6 weeks.7
tis is usually unilateral and often associated with infection in the region drained by that group of
lymph nodes (Figure 1). Bacterial
lymphadenitis is caused mainly by
Staphylococcus aureus and group A
beta hemolytic streptococci.8,9 Barton and Feigin found S. aureus,
group A beta hemolytic strep,
peptostreptococci, Gram-negative
rods, atypical mycobacteria, and
Francisella tularensis in their patients with lymphadenitis.8 Lane
and colleagues found that the 3
most common causes of lymphadenitis in their pediatric patients that experienced symptoms
from less than 2 days to more than
1 month were S. aureus, group A
beta hemolytic streptococcus, and
mycobacteria.9 Atypical mycobacteria are more likely cause in children, and tuberculous adenitis is
more likely in adults.10
Acute Reactive
Lymphadenitis
Another relatively simple patient to evaluate and treat is one
with acute reactive lymphadenopathy to infections in the
head or neck regions. The patient
will display obvious abnormalities
of the ear, nose, throat, teeth, or
symptoms of upper respirator y
tract infections (URIs). URIs
caused by influenza and adenoviruses are associated with bilateral cervical lymphadenitis. Infections with Epstein Bar r vir us
(EBV) and cytomegalovir us
(CMV) are commonly associated
with generalized lymphadenopathy, but can also cause acute bilateral cervical lymphadenitis. Mucocutaneous lymph node
syndrome of unknown etiology,
or Kawasaki disease, is a wellknown cause of acute lymph node
enlargement, typically of a single
cervical node.
Chronic
Lymphadenopathy
Known causes of chronic lymphadenopathy are the infections
and conditions listed in Table
1. The majority of patients with a
Acute Infective
Lymphadenitis
A common presentation for
acute bacterial lymphadenitis is
the febrile child with an acute
tender, fluctuant lymph node
with overlying er ythematous
skin. Acute bacterial lymphadeni-
26
Figure 1. A 1-year-old with acute unilateral cervical lymphadenitis.
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L ymphadenopathy in Children
Table 1
CAUSES OF CHRONIC LYMPHADENOPATHY
Granulomatous diseases:
Cat Scratch disease
Atypical mycobacterium
Mycobacterium tuberculosis
Sarcoid
Neoplastic:
Lymphoma (Hodgkin’s and Non-Hodgkin’s)
Leukemia
Histiocytosis
Neuroblastoma
Rhabdomyosarcoma
Infections
EBV
CMV
HIV
Toxoplasmosis
Tularemia
Yersinia
Histoplasmosis
Coccidiomycosis
Miscellaneous
Autoimmune diseases
Storage diseases
Castleman’s disease
Kikuchi’s
Post-vaccination
Medications
persistently enlarged node will not
have a specific known cause, but
will be classified as having “nondiagnostic,” “nonspecific,” or “reactive” hyperplasia based on biopsy
and fine needle aspiration results.6,11-14 If a definitive diagnosis
is determined, it will most likely
be granulomatous lymphadenitis
caused by infections with atypical
mycobacteria and Bartonella heneselae (cause of cat scratch disease)
or by malignant neoplasm such as
Hodgkin’s lymphoma.6,11 Other
causes for persistent lymphadenopathy in children are tuberculosis, toxoplasmosis and
sarcoidosis, non-Hodgkin’s lym-
phoma, acute lymphocytic leukemia, rhabdomyosarcoma, and
neuroblastoma. Knight et al
found that the mean duration of
adenopathy by history was significantly longer for reactive lymphadenopathy than for granulomatous or neoplastic nodes.6 The
mean duration of reactive nodes
was 9.2 ± 13.6 months versus 2.3 ±
2.8 months for granulomatous
nodes. Since duration of lymphadenopathy for each pathologic cause overlapped so much,
it was not a reliable factor in determining the etiology.
It is worth discussing the relatively common (EBV, cat scratch
disease) and some more serious
entities human immunodef iciency virus (HIV) that cause
chronic lymphadenopathy. Infectious mononucleosis, secondary
to EBV, is a well-known illness associated with lymphadenopathy. Because this diagnosis can
usually be conf ir med by heterophile antibody test (e.g.,
Monospot) in children older than
4 years old, or EBV serology in
younger individuals,15 biopsy isn’t
usually needed to establish this
diagnosis. Children infected with
EBV may display a spectrum of
severity from being asymptomatic to being critically ill. Rea
and colleagues found that most
of their patients age 16 years and
older initially presented with anterior and posterior lymphadenopathy and phar yngeal
inflammation, and the lymphadenopathy and phar yngitis
were still evident in approximately one fourth of participants
even at 6 months follow-up.16
Uncomplicated cat scratch
disease develops 1 to 2 weeks after
a cat scratch or bite. The nodes
enlarge for 2 to 3 weeks and
regress over the next 1 to 2
months, but may become extremely enlarged and last several
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27
Nield, Kamat
months. 17 The presence of enlarged nodes in areas such as the
axillary, inguinal and epitrochlear regions, which drain extremities, correlated by histor y and
histopathology with the diagnosis
of cat scratch disease. 11 Cat
scratch disease can present more
seriously with prolonged fever, hepatosplenomegaly, and encephalitis. 18 Diagnosis of cat
scratch disease is established by
detecting antibodies to B. heneselae. Treatment of this disease is
primarily supportive because it is
typically self-limited. Painful, supprative nodes can be treated with
needle aspiration for symptomatic relief and surgical excision is
usually unnecessary. The Red Book
(American Academy of Pediatrics)
states that antibiotic treatment may
be considered for acutely ill patients with hepatosplenomegaly,
large and painful adenopathy and
immunodeficiency. 15 Rifampin,
trimethoprim-sulfamethoxazole,
azithromycin and ciprofloxacin
may be effective, although adequate
efficacy data was not available.
Spira and colleagues found
that failure-to-thrive and persistent lymphadenopathy (lymph
nodes greater than or equal to 0.5
cm and present in two or more
sites other than inguinal region)
were the initial clinical signs that
occurred most frequently in their
pediatric patients infected with
HIV; however, 63% presented
with only one sign or symptom.19
There are several unusual
causes that have been described
in both children and adults that
can lead to chronic adenopathy. A
non-exhaustive list includes fungal infections, autoimmune diseases, storage diseases, Castleman’s disease, and Kikuchi’s
lymphadenitis. Kikuchi’s disease,
a histiocytic necrotizing lymphadenitis of possible autoimmune or viral etiology, has been
28
reported rarely in children and
manifests most frequently with local or generalized lymphadenopathy, but can be associated with serious systemic symptoms such as
malaise, arthralgia, and abdominal pain. 20 Vaccines such as
BCG, 21 MMR, 22 and varicella 23
and several medications14 including anticonvulsants and antibiotics, have also been associated
with persistent lymphadenopathy.
Evaluation of
Lymphadenopathy
A thorough history and physical examination alone (as described in detail in the subsequent Histor y and Physical
Examination sections) may provide enough information to determine the cause of acute infective lymphadenitis and acute
reactive lymphadenitis. Infections
are the most common cause and
proper treatment and tincture of
time should result in prompt resolution of the problem. To establish Kawasaki disease as the cause
of the acute lymph node enlargement, the specific criteria of this
entity needs to be fulfilled. Unfortunately, it is not so simple when
one tries to determine the cause
of lymph node enlargement of
long duration. One has to proceed in a very organized manner
to determine the cause, and Table
2 and Figure 2 outline this approach. The diagnostic process
begins with the detailed history
and physical examination.
History
Because infections are the
most common cause of acute or
chronic lymphadenopathy, the
history should be focused on exploring the presence of infections
or exposures to infections. Inquire about symptoms suggestive
of upper respiratory infections
such as sore throat, dental problems, skin infections, insect bites,
and pet scratches. Ask about exposure to infectious mononucleosis, tuberculosis, HIV, and animals
(especially cats) and birds. Document the presence or absence of
systemic symptoms such as persistent fever, weight loss, arthralgias,
chronic cough, rash, fatigue,
night sweats, and neurologic deterioration. Remember to inquire
about international travel especially to developing countries and
exposure to medications.
Physical Examination
The physical examination begins with measuring temperature
and plotting the weight and
height on the growth chart. The
enlarged group of lymph nodes
should be palpated and information as to the size, location, number of lymph nodes enlarged,
consistency, mobility, and tenderness should be recorded. The size
is helpful because larger size may
indicate more serious pathology. Slap and colleagues reported
that lymph nodes greater than 2.0
cm in diameter were predictive of
tuberculosis, cat-scratch disease,
sarcoid, and malignancy in the
child with an abnormal chest radiograph and without obvious
pathology in ears, nose, oral cavity, and phar ynx. 12 In an adult
population, 8% of patients with
unexplained lymphadenopathy
with nodes in the 1.0 to 2.25 cm
range were found to have malignancy as the cause.14 It is worth
emphasizing that the most worrisome location for a lymph node
to be palpated is in the supraclavicular region, which may be reflective of mediastinal disease. Lake
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L ymphadenopathy in Children
Table 2
SUMMARY OF WORK-UP FOR CHRONIC LYMPHADENOPATHY
History
Exposures to infections
Eyes, ears, nose, throat and teeth complaints
Dermatologic complaints
Systemic complaints
Animal exposures
International travel
other areas of the body should be
palpated and the same information should be recorded. The skin
should be examined for presence
of impetigo, eczema or seborrhea, rashes, and petechiae. Eyes,
ears, oral cavity, and nose should
be examined for the presence of
infection. The pharynx should be
examined for evidence of infection as well as enlargement and
asymmetr y of tonsils. The abdomen should be examined to
deter mine if the child has
hepatosplenomegaly.
Medications
Immunizations
Antibiotic Trial Before
Further Evaluation
Physical examination
Laboratory investigations
Basic screen for systemic illness
CBC with differential
Peripheral blood smear
ESR
Serum LDH level
Serum uric acid level
Liver enzymes
Screen for specific infectious agents
Bartonella henselae
EBV
CMV
Toxoplasmosis
HIV
PPD placement
Chest radiograph
Less invasive procedures
Ultrasound
Even if inadequate evidence is
obtained from the histor y and
physical examination to arrive at a
definitive diagnosis, it is worthwhile to treat with antibiotics that
provide adequate staphylococcal
and streptococcal coverage due to
the high incidence of these bacteria triggering lymph node enlargement. A second course of antibiotics that provide adequate
B. henselae coverage, such as
azithromycin, may also be tried if
the first trial is unhelpful. If the
history and physical examination
findings do not direct the practitioner in the direction of an obvious diagnosis and the antibiotic
trials have failed to resolve the
problem, a more aggressive
workup needs to undertaken, beginning with laboratory studies.
Needle aspiration
Laboratory Investigation
Biopsy
and Oski found that all of the patients in their study with palpable
supraclavicular nodes had mediastinal disease of lymphoma, tuberculosis, atypical mycobacterial
infection, or sarcoid.11 A description of the nodal consistency as
rubbery or firm or fluctuant may
aid in the diagnostic decision
making. Lymph nodes in the
Whether or not the laboratory
workup for the lymphadenopathy
should be initiated simultaneously or after completion and failure of the antibiotic trial is dependant on the individual
patient’s circumstances. This
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29
Nield, Kamat
Figure 2. Algorithm depicting workup of enlarged lymph node.
30
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L ymphadenopathy in Children
work-up can be quite extensive
and may be of limited value in
most instances, but needs to be
undertaken to aid in the diagnosis. Complete blood cell (CBC)
count with differential count, peripheral smear, erythrocyte sedimentation rate (ESR), serum lactate dehydrogenase (LDH), uric
acid and liver enzyme levels are a
basic screen for serious systemic
conditions such as malignancy or
autoimmune disease. An elevated
total white blood cell count or
pancytopenia may suggest infection. The presence of atypical
lymphocytes may be reflective of
infectious mononucleosis, however atypical lymphocytes in the
presence of high white cell count
or pancytopenia could be indicative of leukemia as well. An elevated ESR is a nonspecific marker
for inflammation or malignancy. Lymphoproliferative diseases such as leukemia and lymphoma can be revealed by the
presence of elevated LDH or uric
acid levels. Abnor mal liver
transaminases signal the presence
of hepatitis and therefore should
spark the clinician to focus on the
possible causes of the hepatitis,
such as the multiple viral etiologies. EBV, CMV, toxoplasmosis,
HIV and B. henselae titers also may
be determined depending on the
clinical situation. Chest radiography is also recommended in cases
of unexplained lymphadenopathy because of the possible existence of mediastinal disease in
the otherwise asymptomatic patient. There is a strong association
between an abnormal chest radiograph and granulomatous or
malignant lymphadenopathy. 12
Skin test with purified protein derivative (PPD) should be done in
cases of suspected mycobacterial
infections.
If this initial laboratory evaluation is normal and the patient
continues to have lymphadenopathy or the lymph nodes continue
to increase in size or lymph nodes
at other sites start enlarging or appearing, the following tests are
recommended.
Ultrasound
Specific characteristics obtained via ultrasound can provide clues about the etiology of
the lymphadenopathy, but discrimination between such causes
as bacterial, cat scratch disease,
or TB is not possible based on ultrasound finding alone.24 Ultrasound can be helpful in
differentiating non-suppurative
adenopathy from suppurative
lymphadenitis and possibly helpful in distinguishing Kawasaki’s
disease from bacterial lymphadenitis. Ultrasound of cervical
nodes in Kawasaki’s disease patients showed a pattern of a “cluster of grapes.” This feature is similar to that of nodes enlarged
secondary to EBV, but not of bac-
terial lymphadenitis. 25 In addition, ultrasound of lymph nodes
may provide information regarding selection of nodes to be biopsied. Certainly, an experienced radiologist familiar with the
characteristic f indings of enlarged nodes would be required
for an ultrasound to be useful at
all. If the clinician is unsure if a
mass is even a lymph node or not,
especially in the head and neck
region where congenital cysts may
be present, a computed tomography (CT) scan may provide additional anatomic infor mation
(Figure 3).
Needle Aspiration
When a large, fluctuant node
is present, needle aspiration of its
contents can be a valuable diagnostic aid in determining the etiology of the lymphdenopathy. Aspirated material should be
studied for aerobic, anaerobic
and mycobacterial organisms by
appropriate stains and cultures.
Figure 3. Computed tomography scan of the neck shows cervical lymphadenopathy. Subsequently, he was found to have abscess in the left carotid
space.
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31
Nield, Kamat
In chronic unilateral lymph node
enlargement, workup for fungal
infection could also be undertaken. In many instances, fineneedle aspiration may not be
helpful and the possibility of
forming a sinus tract as a complication (if mycobacteria is the
cause) must be considered before
undertaking this procedure. 13
Serour and colleagues reported
on the usefulness of needle aspiration as a viable alternative to
open surgical drainage of suppurative cer vical lymphadenitis. 26
Although fine needle aspiration
has several advantages such as low
morbidity, it is limited by the lack
of adequate fluid that may be obtained from the procedure for
analysis and culture.13
Biopsy
The definitive test for ruling
out the most feared diagnosis,
cancer, is a biopsy of the enlarged
lymph node. Table 3 lists the features that should prompt referral
for lymph node biopsy. The presence of only one feature may or
may not require immediate attention, but a combination of features makes the situation more
critical. A persistent node, despite
a trial of antibiotics, or lymphadenopathy associated with
worrisome systemic signs and
symptoms will need a biopsy
sooner than later. In particular,
the presence of supraclavicular
adenopathy, fever, arthrlagias,
and weight loss should spark the
clinician to refer the patient for a
biopsy for definitive diagnosis.6,11
A “r ubber y” consistency to a
lymph node may indicate
Hodgkin’s lymphoma, 27 but in
general, the consistency is typically not helpful. Unfortunately,
there is no single clinical feature
that can predict the histologic di-
32
agnosis of a biopsied lymph node,
but the features listed in Table 3
are more likely to be present when
a more serious condition is triggering the lymphadenopathy. Knight
and colleagues recommend that if
an enlarged node has increased in
size after 2 weeks of monitoring or
the node has not decreased in size
by 4 to 6 weeks or returned to normal size by 8 to 12 weeks, then a
biopsy is recommended if the diagnostic evaluation thus far has
been unrevealing.6 Slap and colleagues described 3 clinical findings to differentiate patients whose
nodal biopsy results lead to a treatable diagnosis from patients whose
biopsy results did not.12 The 3 clinical findings included lymph node
size greater than 2.0 cm; absence
of ear, nose, and throat symptoms;
and presence of an abnormal
chest radiograph.
If referral for a biopsy is undertaken, the good news is that
the over whelming majority of
nodes will have a pathologic diagnosis of reactive hyperplasia.6,11
However, it should be remembered that a single biopsy may not
give the definitive answer and
long-term monitoring and further evaluation of the patient may
be necessary. Lake and Oski reported that 7 of their patients
eventually were found to have a
pathologic process despite initial
non-diagnostic biopsy.11 In 2 instances, it took as long as 2 years
after an initial negative biopsy to
determine the definitive diagnosis. Biopsy of additional nodes
or bone marrow aspiration may
be required to determine the
etiology of the lymphadenopathy. Children with persistently
enlarged nodes and negative
Table 3
FEATURES PROMPTING A POSSIBLE BIOPSY*
• Node size greater than 2.0 cm
• Node increasing in size over 2 weeks
• No decrease in node size after 4–6 weeks
• Node not returned to baseline size after 8–12 weeks
• No decrease in size despite one or two antibiotic trials
• Absent ears, nose, and throat symptoms
• Abnormal chest radiograph
• Presence of a supraclavicular node
• “Rubbery” consistency to the node
• Presence of systemic signs and symptoms
Fever
Weight loss
Arthralgia
Hepatosplenomegaly
*A feature may or may not indicate the biopsy of lymph node, a combination may.
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L ymphadenopathy in Children
workup should still be observed
closely, possibly over years, with
repeated physical examinations
to determine if the node is regressing or if any new worrisome
signs or symptoms are emerging. Parents can be reassured by
informing them that studies show
that the exact etiology of lymphadenopathy may not be ascertained in over 40% to 50% of all
cases, despite extensive investigations including biopsy.6,11,28 Hopefully this approach will ease
parental fears even though one is
unable to give them a specific diagnosis or predict when the lymphadenopathy will go away.
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