Lymphadenopathy

Shashi Sahai
Pediatrics in Review 2013;34;216
DOI: 10.1542/pir.34-5-216

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Article blood disorders

Lymphadenopathy
Shashi Sahai, MD*
Practice Gaps
1. Diffuse lymphadenopathy should always be evaluated by careful history and physical
Author Disclosure examination and perhaps laboratory investigation.
Dr Sahai has disclosed 2. The absence of any palpable lymph nodes in the presence of symptoms suggesting
she owns stocks/bonds infection in that drainage area should raise suspicion for immunodeficiency diseases.
in Dr. Reddy’s 3. Supraclavicular adenopathy is always abnormal and the chances of malignancy are high.
Laboratories, Ltd., and
Roche Holding, A.G.
Objectives After completing this article, readers should be able to:
This commentary does
not contain discussion 1. Define lymphadenopathy
of unapproved/ 2. Know the differential diagnosis for localized and generalized lymphadenopathy
investigative use of 3. Know the etiology and evaluation of acute and chronic cervical lymphadenopathy
a commercial product/ 4. Know the age-dependent microbiology of acute cervical lymphadenitis
device. 5. Recognize the “red flags” associated with noninfectious causes of lymphadenopathy

Introduction
Lymphadenopathy is defined as an abnormality in size and consistency of lymph nodes,
while the term lymphadenitis refers to lymphadenopathy that occurs from infectious
and other inflammatory processes. Lymph node enlargement is a common finding on phys-
ical examinations of children. In fact, the absence of any palpable lymph node in the pres-
ence of symptoms that suggest infection in a drainage area should raise suspicion for an
immunodeficiency disease. The presence of an enlarged lymph node may be a source of
anxiety in parents because of its association with malignancy. Although infections are
the most common cause of lymph node enlargement, clinicians must be aware of a broad
range of other disease processes that lead to lymph node enlargement.

Anatomy and Physiology

The lymphatic system is comprised of lymphatic vessels and lymphoid organs. The lymphatic
vessels transport interstitial fluid back to the circulating blood. Lymph is an ultrafiltrate of
blood. It is collected through the lymphatic capillaries that are present throughout the body.
The brain and heart are the only organs that are devoid of lymphatic capillaries. Lymph moves
with the help of the milking action of skeletal muscles and by peristalsis of lymphatic capil-
laries. Valves in the lymphatic vessels assure a unidirectional flow. Lymph gets into progres-
sively larger lymphatic vessels and finally into the right lymphatic and thoracic duct.
The lymphoid organs contain lymphocytes and other cells that are responsible for the
body’s immunity. The bone marrow and thymus are called primary lymphoid organs because
they are the sites for generation of B lymphocytes and T lymphocytes. Lymph nodes, spleen,
and mucosa-associated lymphoid tissue (MALT), including tonsils, the appendix, solitary lym-
phoid nodules, and Peyer patches of the ileum, are the secondary lymphoid organs. Lymph
nodes are present throughout the body and distributed along the path of the lymphatic ves-
sels. They are bean shaped and encapsulated. Lymph nodes act as filters for the lymph.
The lymph enters on the convex surface of a lymph node through the afferent lymphatics.
The efferent lymphatics and veins exit through the hilum. The hilum also provides an entry
point for nerves and arteries. Connective tissue encapsulates the lymph node and some con-
nective tissue enters the lymph node and forms trabeculae. The lymph courses through

*The Carman and Ann Adams Department of Pediatrics, Division of Hospital Medicine, Children’s Hospital of Michigan, Wayne State
University School of Medicine, Detroit, MI.

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 blood disorders lymphadenopathy

unlined sinuses that are present along the capsule and tra- The evaluation of lymph node enlargement begins with
beculae. During the passage of lymph from cortical to med- a detailed history and physical examination that will assist
ullary sinuses, the lymph gets modified by the immune cells. in reaching a differential diagnosis. Further laboratory and
Efferent lymph is rich in newly synthesized antibodies. radiologic evaluation will be decided according to the dif-
Histologically, a lymph node consists of a cortex, para- ferential diagnosis developed through clinical evaluation.
cortex, and medulla. The most common cells in lymph
nodes are lymphocytes, macrophages, plasma cells, follic- History
ular cells, and reticular cells. Children usually present with the complaint of a lump in
the neck, axilla, or inguinal area. The lump may be an iso-
Immune Responses Mediated by Lymph Nodes lated finding. However, most often it is associated with
There are approximately 600 lymph nodes in the body. other systemic symptoms. It is important to recognize
Lymph passes through at least one lymph node in the that there are other swellings (listed in Table 1), especially
body before getting back into the blood stream. Afferent in the cervical area, that may be mistaken for a lymph
lymph contains antigens, including partly destroyed node,
microorganisms and antigens that are transported by Age is important in suggesting the likely cause of
antigen-presenting cells. This lymph also may contain mi- lymph node enlargement. Children younger than 5 years
croorganisms and cytokines from areas of inflammation old are more likely to have an infectious cause for their
and infection. Microorganisms may get phagocytosed, lymph node enlargement. Lymph node enlargement in
processed, and presented as antigens in the lymph node. neonates may represent a congenital infection such as
Lymphocytes proliferate in the lymph nodes. B cells Toxoplasma or cytomegalovirus (CMV). Although rare,
mature into plasma cells and secrete antibodies. Infection lymphadenopathy caused by histiocytosis can occur in chil-
and antigenic stimulation cause a lymph node to increase dren younger than 3 years old. (3) The likelihood of a ma-
in size. The lymph node enlarges as a result of cellular hy- lignancy such as lymphoma increases in adolescents.
perplasia, lymphocyte infiltration, and tissue edema. The Location of an enlarged lymph node is important in
swollen lymph nodes have multiple germinal centers with evaluation. Cervical lymph node enlargement is a very
active cell proliferation. The symptoms associated with common finding associated with viral upper respiratory
acute lymphadenitis reflect the pathophysiologic events infection. Supraclavicular lymphadenopathy is always
that occur in response to an infection. Malignant tumor abnormal and the chances of malignancy are high. In
cells also reach lymph nodes and then get distributed to a series(3) of excisional biopsies of supraclavicular lymph
other parts of the body. Infiltration by malignant tumor nodes, the nodes were found to be abnormal in 100% of
cells also will cause a lymph node to enlarge. specimens and were associated with lymphoma, tuber-
Understanding the anatomy of lymph node drainage culous or atypical mycobacterial infection, or sarcoidosis
is important in identifying the site of a pathologic lesion of the mediastinum. Examination of the drainage area
when a lymph node is enlarged. Figures 1 and 2 illustrate for infectious lesions is essential. The presence of two
the various drainage sites. or more noncontiguous sites of lymph node enlargement
represents a generalized lymphadenopathy. Causes of
generalized and localized adenopathy are outlined in
Normal Lymph Nodes Tables 2 and 3.
It is important to know the normal sizes of lymph nodes Time of onset and duration of lymph node enlarge-
at different sites in healthy children. A number of studies ment should be noted. An acute enlargement is more
have demonstrated enlarged and palpable lymph nodes in likely to represent an acute viral or bacterial infectious
up to one-half of healthy neonates, infants, and older chil- process. Lymphadenopathy of longer than 4 weeks’ du-
dren. (1,2) Because younger children are being exposed ration is considered to be chronic. Chronic lymphade-
constantly to newer antigens and inciting immune re- nopathy is more likely to be caused by an underlying
sponses, lymph nodes in children usually are larger than malignant process or a chronic infection.
those found in adults. Older children and adolescents In order to identify a focus of infection leading to
have smaller lymph nodes than do younger children. lymphadenopathy, the clinician should look for infectious
Lymph nodes in the axillary and cervical regions up to lesions in the drainage area. The presence of sore throat,
1 cm in diameter, those in the inguinal region up to nasal congestion, red eyes with discharge, oral ulcers,
1.5 cm in diameter, and those in the epitrochlear region dental caries, and gingival swelling should be looked
up to 0.5 cm in diameter are considered normal. for in patients who have cervical lymphadenopathy.

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blood disorders lymphadenopathy

Figure 1. Lymph nodes of the head and neck and their drainage areas. Reproduced with permission from: McClain, KL, Fletcher RH.
Causes of Peripheral Lymphadenopathy in Children. In: UpToDate, Basow DS (Ed), UpToDate, Waltham, MA 2013. Copyright 2013.
UpToDate Inc. For more information, visit www.uptodate.com.

The presence of fevers, rash, generalized pain, joint International travel to developing countries should
pain and swelling, petechiae, weight loss, failure to be inquired about because travel may raise the
thrive, night sweats, chronic cough, fatigue, red oral possibility of diseases such as tuberculosis (TB) and
mucosa, peeling of fingers, and eczema may point to leishmaniasis.
the cause of the lymphadenopathy. Symptoms of respi- Medications such as penicillin, cephalosporins,
ratory and pharyngeal compromise, such as drooling, phenytoin, and carbamazepine are known to cause
stridor, and breathing difficulty, may mandate immedi- generalized lymphadenopathy. Vaccine-preventable
ate attention. A history of recurrent infections asso- diseases such as measles, rubella, and diphtheria may
ciated with lymphadenopathy may point to a present with lymphadenopathy in an unimmunized
phagocyte function disorder such as chronic granulo- child.
matous disease.
Zoonoses that may present with lymphadenopathy Physical Examination
are listed in Table 4. It is important also to obtain The presence of fever and other vital signs or pallor
a history of exposure to other sick individuals. should be noted. Anthropometry provides important

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 blood disorders lymphadenopathy

Examination of Lymph Node

and Lymphatic Organs
The size of the enlarged lymph node
aids in determining the need for fur-
ther evaluation. Lymph nodes larger
than 2 cm are more likely to harbor
a more serious disease process. The
number of lymph nodes and the con-
sistency, fluctuance, tenderness, mo-
bility, and presence of matting
should be noted. Lymphadenitis is
characterized by swelling of lymph
nodes in conjunction with pain, skin
changes in the form of erythema
and edema, and tenderness. All other
areas of potential lymph node en-
largement should be examined. The
presence of liver and spleen enlarge-
ment should be evaluated.
It is important to examine the
drainage area in cases of localized
lymphadenopathy. A careful head,
neck, and oropharyngeal examina-
tion may reveal a primary focus of in-
Figure 2. Lymph node regions in the body. Reproduced with permission from: McClain, KL, Fletcher fection. The presence of rash and
RH. Causes of Peripheral Lymphadenopathy in Children. In: UpToDate, Basow DS (Ed), UpToDate, petechiae may help to make the diag-
Waltham, MA 2013. Copyright 2013. UpToDate Inc. For more information, visit www.uptodate.com.
nosis. Conjunctival injection without
clues in cases of chronic lymphadenopathy. Poor weight exudates may be present in patients with Kawasaki disease.
gain may be present when the lymphadenopathy is Exudative conjunctivitis is present in infection with Barto-
caused by infections such as TB or human immunode- nella, adenovirus, and Francisella tularensis (tularemia).
ficiency virus (HIV) or by lymphoma. Bone and joint tenderness should be looked for.

Table 1. Differential Diagnosis of Lymph Node Enlargement

Lesion Description Location
Cystic hygroma A compressible painless soft mass that Supraclavicular and posterior to the
(lymphangioma) transilluminates; may increase in size sternocleidomastoid on the left side, but
during upper respiratory infections may extend to other areas such as the
floor of the mouth and axilla
Branchial cleft cyst Recurrent swelling that may be infected; Lateral neck with sinus along anterior
may have a sinus or pit border of the lower 2/3 of the
sternocleidomastoid
Thyroglossal duct cyst May present with infection and moves Midline at the level of the thyrohyoid
with tongue protrusion and swallowing membrane; communicates with the base
of the tongue. Occasionally may be felt
lateral to the midline
Cervical rib Hard, bony feel Supraclavicular
Thyroid nodule Painless firm to hard Midline in thyroid area
Sternocleidomastoid Soft mass in the sternocleidomastoid, Inferior portion of sternocleidomastoid
fibroma torticollis with chin pointing to the
opposite side of hematoma
Epidermoid cyst Superficial, smooth Suprasternal

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blood disorders lymphadenopathy

Table 2. Differential Diagnosis of Systemic Generalized Lymphadenopathy

Infant Child Adolescent
COMMON CAUSES
Syphilis Viral infection Viral infection
Toxoplasmosis EBV EBV
CMV CMV CMV
HIV HIV HIV
Toxoplasmosis Toxoplasmosis
Syphilis
RARE CAUSES
Chagas disease (congenital) Serum sickness Serum sickness
Congenital leukemia SLE, JRA SLE, JRA
Congenital tuberculosis Leukemia/lymphoma Leukemia/lymphoma/Hodgkin disease
Reticuloendotheliosis Tuberculosis Lymphoproliferative disease
Lymphoproliferative disease Measles Tuberculosis
Metabolic storage disease Sarcoidosis Histoplasmosis
Histiocytic disorders Fungal infection Sarcoidosis
Plague Fungal infection
Langerhans cell histiocytosis Plague
Chronic granulomatous disease Drug reaction
Sinus histiocytosis Castleman disease
Drug reaction
This table was published in Practical Strategies in Pediatric Diagnosis and Therapy. 2nd edition, by Kliegman RM, Greenbaum LA, Lye PS, p 863. Copyright
Elsevier, 2004.
Author’s note: Hemophagocytic lymphohistiocytosis may also be a cause of generalized lymphadenopathy.
CMV¼cytomegalovirus; EBV¼Epstein-Barr virus; HIV¼human immunodeficiency virus; JRA¼juvenile rheumatoid arthritis (Still disease); SLE¼systemic
lupus erythematosus.

Investigations also may be indicative of bone marrow involvement with

After a careful history and physical examination, it is pos- malignancy. Lymphopenia may be indicative of HIV infec-
sible to narrow the differential diagnosis of lymphadenop- tion or congenital immunodeficiency disorders. The eryth-
athy. Laboratory evaluation may aid in narrowing the rocyte sedimentation level (ESR) and C-reactive protein
diagnosis of both chronic and generalized lymphadenopa- level may be used as tools to look for inflammation and
thy. In the presence of an acute localized lymphadenopa- infection and also might help in assessing the patient’s re-
thy, when a focus of infection has not been identified and sponse to treatment. Lactate dehydrogenase and uric acid
the lymph nodes raise suspicion of a bacterial infection, levels provide a screen for rapid cell turnover associated
a trial of antibiotics may be given before embarking on with malignancy. High liver enzyme levels may indicate in-
an extensive evaluation. The antibiotics chosen should pro- volvement of the liver due to a systemic infection or an in-
vide coverage for both Staphylococcus aureus and group A filtrative process.
Streptococcus. When Bartonella is suspected, it is reasonable Serology may be obtained for evidence of infection
to add azithromycin. Laboratory and imaging studies may with EBV, HIV, CMV, and parvovirus. Bartonella serol-
be necessary if a lymph node does not regress after treat- ogy and polymerase chain reaction studies may be needed
ment or after resolution of the associated acute symptoms. when there is more generalized involvement. The purified
protein derivative (PPD) test is a useful screen for myco-
bacterial infection. Interferon-gamma release assays also
Laboratory Evaluation
may be used in place of the tuberculin skin test with
COMPLETE BLOOD CELL COUNT WITH DIFFERENTIAL.
PPD. Specific atypical mycobacterial antigen may be used
Results may show a neutrophilic leukocytosis, which can
when atypical mycobacterial lymphadenitis is suspected.
indicate an acute bacterial infection. A predominantly
lymphocytic leukocytosis may be associated with Eb- Radiologic Evaluation
stein-Barr virus (EBV) infection. Leukocytosis with blasts Chest radiograph (CXR) is an essential test in the evalua-
on peripheral smear is indicative of leukemia. Leukopenia tion of chronic localized and generalized lymphadenopathy
with depression of the hemoglobin level and platelet count and may reveal the presence of mediastinal widening due

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 blood disorders lymphadenopathy

Table 3. Sites of Local Lymphadenopathy and Associated Diseases

Cervical
Oropharyngeal infection (viral, group A streptococcal, staphylococcal)
Scalp infection
Mycobacterial lymphadenitis (tuberculosis and nontuberculous mycobacteria)
Viral infection (EBV, CMV, HHV-6)
Cat scratch disease
Toxoplasmosis
Kawasaki disease
Thyroid disease
Kikuchi disease
Sinus histiocytosis
Autoimmune lymphoproliferative disease
Anterior auricular
Conjunctivitis
Other eye infection
Oculoglandular tularemia
Cat scratch disease
Facial cellulitis
Otitis media
Viral infection (especially rubella, parvovirus)
Supraclavicular
Malignancy or infection in the mediastinum (right)
Metastatic malignancy from the abdomen (left)
Lymphoma
Tuberculosis
Epitrochlear
Hand infection, arm infection*
Cat scratch disease
Lymphoma[†]
Sarcoid
Syphilis
Inguinal
Urinary tract infection
Venereal disease (especially syphilis or lymphogranuloma venereum)
Other perineal infections
Lower extremity suppurative infection
Plague
Hilar (not palpable, found on chest radiograph or CT)
Tuberculosis[†]
Histoplasmosis[†]
Blastomycosis[†]
Coccidioidomycosis[†]
Leukemia/lymphoma[†]
Hodgkin disease[†]
Metastatic malignancy*
Sarcoidosis[†]
Castleman disease
Axillary
Cat scratch disease
Arm or chest wall infection
Malignancy of chest wall
Leukemia/lymphoma
Brucellosis
Abdominal
Malignancies
Mesenteric adenitis (measles, tuberculosis, Yersinia, group A Streptococcus)
This table was published in Practical strategies in pediatric diagnosis and therapy, 2nd ed, by Kliegman RM, Greenbaum LA, Lye PS, p 864, Copyright Elsevier, 2004.
CMV¼cytomegalovirus; CT¼computed tomography; EBV¼Epstein-Barr virus; HHV-6¼human herpesvirus 6.
*Unilateral. †Bilateral.

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blood disorders lymphadenopathy

to lymphadenopathy from lymphoma and sarcoid. Up to taking the risk of sedation, it is important to recognize the
two-thirds of patients who have Hodgkin lymphoma limited therapeutic and diagnostic benefits of this proce-
may show mediastinal widening on a CXR. Mediastinal dure, which has a high false-negative rate and is associated
lymph node enlargement compressing the intrathoracic with inadequate architectural detail. There is also the po-
airway may present with wheezing. It is important to ob- tential for a sinus tract formation, especially when the ad-
tain a CXR of a child who is wheezing for the first time enopathy is due to a mycobacterial infection.
before treating with corticosteroids. CXR also may show
hilar lymph node enlargement and calcification in TB Excisional Biopsy
and histoplasmosis. An excisional biopsy will confirm the presence of malignancy
or disclose the granulomatous lesions of TB or sarcoid. It
Radiographs of the Neck is important to consider an early excisional biopsy when
In patients in whom airway compromise is evident, radio- there is a high suspicion for malignancy. The features that
graphs of the neck may indicate the extent of involvement make a malignancy highly likely are a supraclavicular loca-
and can evaluate the retropharyngeal space. A lateral neck tion, hard consistency, absence of head and neck infection,
radiograph should be obtained in inspiration, with the rubbery consistency, fevers lasting longer than 1 week,
mouth closed and neck extended. Retropharyngeal space in- night sweats, weight loss, mediastinal widening on chest
volvement may appear as thickening of the retropharyngeal radiograph, an abnormal blood picture suggestive of
soft tissues, with smooth, curved anterior displacement of leukemia or lymphoma, and hepatosplenomegaly.
the cervical airway and loss of the normal step-off of the pos- It is important for the excisional biopsy to be per-
terior hypopharyngeal wall and posterior wall of the trachea. formed at a medical center where there is multidisciplin-
ary support available for the diagnosis and treatment of
Ultrasonography children with cancers. Adequate staining, preparation
Ultrasonography (US) is a noninvasive and nonirradiat- of smears, and cultures for viruses and fungi should be
ing imaging procedure that may be helpful in looking performed as required. When malignancy is suspected,
for a hypoechoic, suppurative center of a lymph node. specimens for immunohistochemical, cytogenetic, and
US is more specific but less sensitive than contrast com- molecular genetic tests should be obtained. The largest
puted tomography (CT) for diagnosis of an abscess. (4) accessible node should be biopsied.
Color Doppler imaging may show the increased blood The size, location, consistency, and associated clinical
flow pattern of inflamed nodes. An experienced radiolo- features must be considered in a decision to perform a
gist may be able to comment on certain specific patterns; lymph node biopsy. (5) See Table 5 for features that
for example, in Kawasaki disease, the lymph nodes may may prompt a lymph node biopsy. Fifty percent of these
show a “cluster of grapes” pattern. When there is suspi- nodes usually turn out to be enlarged due to reactive hy-
cion of a congenital lesion in the neck mimicking lymph perplasia. Approximately 30% are associated with a granu-
nodes, ultrasonography can be a helpful technique. lomatous process such as cat scratch disease, atypical
mycobacterial infection, TB, or a fungal infection. Malig-
Computed Tomography nancy is discovered in up to 13% of the patients, and
When more anatomic detail is required, CT may be nec- Hodgkin disease constitutes 67% of the malignancies. It
essary and might be advisable before undertaking a surgi- is important to monitor enlarged nodes. A pathologic pro-
cal procedure. Contrast-enhanced CT is a highly sensitive cess may be found on a repeat biopsy even in the presence
modality for detecting an infection in a deep neck space of an initial normal biopsy. In approximately one-half of all
but it is not very specific for identifying frank pus because patients with chronic lymphadenopathy, a definitive diag-
the imaging findings of a phlegmon are similar to that of nosis may not be established despite extensive evaluation.
frank pus. CT of the neck can also be a useful test for con-
firming a retropharyngeal abscess. Treatment
The treatment of lymphadenopathy depends on the eti-
Fine Needle Aspiration ology. Therapy with glucocorticoids should be avoided
Although fine needle aspiration might appear to be a good until a definitive diagnosis is made. Glucocorticoids will
option for decompressing a suppurative lymph node and mask and delay the diagnosis of leukemia and lympho-
for obtaining a tissue specimen for histopathology, the mas. Patients also may become ineligible for certain treat-
technique has its limitations. Children will always require ment protocols for leukemia and lymphoma if they have
sedation or general anesthesia for such a procedure. Before received glucocorticoids.

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 blood disorders lymphadenopathy

Table 4. Zoonoses that Present as Lymphadenopathy

Disease Animal/Bird Inoculation
Cat scratch disease Kittens Through skin
Toxoplasmosis Cat Ingestion of material contaminated
with cat feces
Tularemia Multiple animals especially Tick bite or skin and mucosal exposure to
rodents and insects infected animal tissue
Brucellosis Sheep, cattle, goat, pigs Contact with animal fluid or consumption
of unpasteurized milk products
Cutaneous anthrax Rodents in southwestern Bite of an infected flea
United States
Histoplasmosis Birds and bats Inhalation exposure in heavily contaminated
areas such as coops, caves, abandoned
buildings
Trypanosomiasis Antelope, goats vectored by Bite by tsetse fly
tsetse fly in Africa

acute or subacute. Table 6 lists the bacteria that can cause

Disorders Associated With Lymphadenopathy
lymphadenitis.
The following is a brief description of the common dis-
orders that present with lymphadenopathy. ACUTE PRESENTATION OF LYMPHADENITIS. Patients
who have acute lymphadenitis often experience fever, ear
Reactive Lymph Nodes pain, and sore throat. Other associated findings are pharyn-
This cause of lymph node enlargement occurs as a result gitis, tonsillitis, impetigo, and cellulitis in the drainage area.
of reactive hyperplasia secondary to an infection in the The infected cervical lymph node is enlarged, tender, and
drainage area. The reactivity occurs commonly in re- warm and may become fluctuant with abscess formation. It
sponse to pharyngitis and upper respiratory infection. is important to recognize that retropharyngeal nodes serve
A skin infection such as impetigo or cellulitis also can as a drainage path for the nasopharynx and tonsils; hence,
cause reactive lymphadenopathy. The viruses that are as- lymphadenitis occurs commonly in these nodes in 1- to 5-
sociated commonly with a viral upper respiratory infec- year-olds. These nodes have the potential to compromise
tion are rhinovirus, parainfluenza virus, influenza virus, the airway when significantly enlarged. Suppuration and
respiratory syncytial virus, coronavirus, adenovirus, and perforation of retropharyngeal nodes may lead to retro-
reovirus. Other viral infections that may lead to general- pharyngeal abscess formation.
ized lymphadenopathy are CMV and EBV. Viruses that
cause lymphadenopathy less frequently are mumps, mea-
sles, rubella, varicella, coxsackie, and herpes simplex vi- When to Consider
Table 5.

ruses as well as human herpesvirus 6 (roseola). Possible Lymph Node Biopsy

Both the anterior and posterior groups of lymph no-
des in the cervical region are involved with pharyngitis SIZE
and tonsillitis. Preauricular lymph nodes are enlarged Greater than 2 cm
Increasing over 2 weeks
with adenoviral keratoconjunctivitis. Hepatosplenome- No decrease in size of node after 4 weeks
galy may be associated with EBV and CMV. Rashes spe- LOCATION
cific for viruses such as rubella and CMV may occur in Supraclavicular lymph node
association with the lymphadenopathy. Virus-associated CONSISTENCY
lymphadenopathy resolves spontaneously with resolution of Hard
Matted
the viral illness. Antiviral therapy is indicated in rare patients Rubbery
afflicted with immunosuppression or severe hepatitis. ASSOCIATED FEATURES
Abnormal chest radiograph suggestive of lymphoma
Fever
Bacterial Lymphadenitis Weight loss
Bacterial lymphadenitis usually results from an infectious Hepatosplenomegaly
process in the cervical area. The presentation may be

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Table 6. Lymphadenitis-Causing Bacteria Atypical mycobacterial

lymphadenitis. In the United
Bacteria Clinical features States, 70% to 95% of mycobacterial
lymphadenitis is due to atypical my-
ACUTE
Streptococcus pyogenes Associate tonsillopharyngitis cobacteria. Nontuberculous atypi-
Group B Streptococcus Infants, unilateral facial or cal mycobacteria are acquired from
submandibular swelling environmental source; they exist as
Anaerobic such as Bacteroides species, May have associated dental and saprophytes in water and soil. Sub-
Peptococcus species, Propionibacterium gingival disease mandibular lymphadenopathy is the
acnes, and Fusobacterium nucleatum
Francisella tularensis most common presentation. Fifty
Pasteurella multocida May occur after animal bites or percent of patients who have nontu-
scratch berculous lymphadenitis develop an
Yersinia pestis Flea bites on head and neck in abscess. Sinus tract formation may
western United States occur in 10% of these patients. Iden-
Haemophilus influenzae type B
Rare gram-negative bacilli, pneumococcus, tification of the bacteria along with
Group C streptococci, Yersinia a drug susceptibility profile is helpful
enterocolitica, Staphylococcus in management. Atypical mycobacte-
epidermidis, alpha hemolytic ria respond poorly to antibiotics and
streptococci these infections require surgical exci-
SUBACUTE
Atypical mycobacterium species such as Rapid onset nodal enlargement, sion. If surgery cannot be performed,
avium-intracellulare (common), overlying skin becomes a 3- to 6-month course of antibiotics
scrofulaceum, kansasii (common), erythematous, thin and is recommended. Clarithromycin or
fortuitum, haemophilum parchment like erythromycin combined with rifabutin
Mycobacterium tuberculosis High risk groups like immigrant or ethambutol may be effective.
populations, travel or residence in
endemic areas Tuberculous lymphadenitis. The
Bartonella henselae History of contact with kittens, large presence of 2 of the following 3 cri-
single lymph node enlargement, teria has 92% sensitivity in identifying
systemic involvement tuberculous lymphadenitis. The cri-
teria are (1) a positive PPD skin test
Up to 80% of acute unilateral cervical lymphadenitis in result, (2) an abnormal chest radiograph, and (3) contact
children younger than age 5 years are due to infections with a person who has infectious TB. The PPD may be pos-
with Staphylococcus aureus and Streptococcus pyogenes. An- itive in atypical mycobacterial infection. Tuberculous
tibiotic therapy is directed at antibiotics that will cover lymphadenitis requires treatment with multiple antituber-
S pyogenes and methicillin-resistant S aureus. Children culous antibiotics for 18 months. Surgical treatment is re-
older than age 5 years who have dental or periodontal dis- quired rarely.
ease will require coverage also for anaerobic bacteria. Pa- Cat scratch disease. This infection results from entry of
tients who have high fever, poor oral intake, pain, and the Bartonella henselae through a scratch in the skin. Exposure
potential for airway compromise from retropharyngeal in- to a kitten and the resultant skin papule may have been for-
volvement may require hospitalization. Identification of bac- gotten by the time lymphadenopathy develops 5 days to 2
teria may be done through a culture from a primary site such months later. Most lymphadenopathy occurs in the axillary
as the pharynx or skin. Antibiotics are administered for 10 group (50%), followed by the cervical group. Constitutional
days or for 5 additional days after resolution of symptoms, symptoms such as low-grade fever, malaise, and anorexia
whichever is longer. Improvement may be noted in 2 to 3 may be associated. This infection can be confirmed by serol-
days, although complete resolution may require a few weeks. ogy. The condition resolves spontaneously in 1 to 3 months.
Lymphadenitis may be complicated by an abscess forma- Although the benefit of antibiotic therapy is questionable in
tion in up to 25% of patients and surgical intervention with localized disease, azithromycin is known to cause a rapid res-
incision and drainage may be necessary. olution of lymph node swelling. Systemic involvement can
lead to hepatitis, encephalitis, endocarditis, and osteomyeli-
SUBACUTE AND CHRONIC PRESENTATIONS. The more tis. Antibiotics used for systemic infection with Bartonella
common causes of subacute and chronic lymphadenopa- are rifampin, ciprofloxacin, gentamicin, trimethoprim, sulfa-
thy in children are as follows: methoxazole, clarithromycin, and azithromycin.

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 blood disorders lymphadenopathy

Infectious Mononucleosis HISTOPLASMA CAPSULATUM, BLASTOMYCES

This infection is caused by EBV, and the patient typically DERMATITIDIS, AND COCCIDIOIDES IMMITIS. These
develops fever, malaise, sore throat, anorexia, and lymph- fungal agents are soil saprophytes. They are endemic to
adenopathy. Other organisms that cause mononucleosis-like specific geographic regions in the United States. Patients
illness are CMV, Toxoplasma gondii, adenovirus, HIV, have pulmonary disease and secondary nodal involve-
hepatitis viruses, and rubella. EBV is transmitted by sex- ment. Diagnosis is by serology. Most infections are
ual contact and contact with saliva, as occurs with sharing self-limited, but severe symptoms may require treatment.
of utensils and with kissing. The incubation period is 30
HUMAN IMMUNODEFICIENCY VIRUS. HIV is a retrovi-
to 50 days. More than 95% of the world population is in-
rus transmitted by sexual contact, parenteral exposure to
fected eventually. Most children younger than 4 years old
blood, or vertical perinatal transmission. Presentation
have asymptomatic infection. Older children and adoles-
may be in the form of fever, malaise, failure to thrive,
cents have physical findings of generalized lymphadenopa-
nontender lymphadenopathy, hepatosplenomegaly, and
thy (90%), splenomegaly (50%), and hepatomegaly (10%).
chronic diarrhea. Diagnosis is made by serology.
Patients develop marked exudative tonsillitis and petechiae
over the hard palate. There may be edema of the eyelids
Other Causes of Lymphadenopathy
and rash.
Kawasaki Disease
Some patients may present with leukocytosis, throm-
Nontender lymphadenopathy of the anterior cervical area
bocytopenia, and hemolytic anemia. The definitive diag-
is an early manifestation of Kawasaki disease, an acute fe-
nosis is made by serology. These patients may require a
brile vasculitic disorder that affects the medium-sized
bone marrow aspiration for cytology to eliminate the pos-
vessels. Other manifestations are rash, swelling of hands
sibility of a malignancy. The widely used spot test is falsely
and feet, red oral mucosa, and nonexudative conjuncti-
negative in patients younger than 4 years of age. The de-
vitis. Coronary artery disease is a severe component of
tection of immune globulin M antibody to viral capsid
Kawasaki disease in up to 25% of untreated children.
antigen is the most specific serologic test for diagnosis.
There is no specific treatment for infectious mononu- Leukemia
cleosis, although corticosteroids may be used for airway Approximately 50% of children who have leukemia will
compromise, thrombocytopenia with bleeding, hemo- have lymphadenopathy at presentation. Lymph nodes
lytic anemia, seizures, and meningitis, but corticosteroids usually are large and grow rapidly. Other clinical manifes-
should be used with caution because of the danger of im- tations are pallor, fever, petechiae, generalized pains,
munosuppression in a patient infected with oncogenic vi- bruising, and hepatosplenomegaly. An associated finding
rus. Corticosteroids also may mask signs of leukemia and is pancytopenia. The white count may be high or normal.
lymphoma temporarily. Contact sports are to be avoided
for 2 to 3 weeks until the splenic enlargement resolves. Lymphoma
Hodgkin disease presents as cervical or supraclavicular
Other Infectious Agents lymphadenopathy in the majority of patients. The lymph-
NOCARDIA. Infection with Nocardia occurs when skin adenopathy usually develops over weeks and months.
gets inoculated by contact with soil and decaying vegeta- The nodes are nontender, discrete, firm, mobile, large,
ble matter. The content of the pustule may be cultured and rubbery. Approximately 30% of the children may
for diagnosis. The infection is treated with sulfonamides. have systemic symptoms such as fever, anorexia, weight
ACTINOMYCES. Actinomyces invades locally from the loss, or pruritis. Non-Hodgkin lymphoma presents over
oral flora and can cause brawny induration and secondary a shorter duration, and patients may lack systemic symp-
lymph node enlargement when there is cervicofacial in- toms. Hodgkin lymphoma is unusual in children younger
volvement. Diagnosis requires biopsy and histopathologic than age 4 years, commonly occurring in older children
examination that shows sulfur granules. The infection is and adolescents. Non-Hodgkin lymphoma is more com-
treated with a 3- to 12-month course of penicillin. mon in children younger than age 10 years.

TOXOPLASMA. The intracellular protozoan Toxoplasma Other Malignancies

gondii is acquired via the oral route from consumption of Neuroblastoma arising in the high thoracic and cervical
meat or milk containing cysts and oocysts. Affected lymph sympathetic ganglia may manifest as supraclavicular lymph-
nodes are discrete and tender. Patients who have severe adenopathy and Horner syndrome. Cervical lymphadenop-
symptoms need treatment with pyrimethamine. athy also may be a manifestation of secondary involvement

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blood disorders lymphadenopathy

by rhabdomyosarcoma, thyroid carcinoma, and nasopha- Kikuchi Disease

ryngeal carcinoma. Kikuchi disease is known also as histiocytic necrotizing
lymphadenitis. The histologic changes that occur sug-
Autoimmune and Collagen Vascular Disorder gest a T-cell immune response to an infectious agent.
Serum sickness may present as lymphadenopathy with fe- The condition presents with fever and localized cervical
ver, arthritis, malaise, pruritis, and urticarial rash. Serum lymphadenopathy in an older child. Associated findings
sickness may occur in response to a viral illness and med- are transient rash, weight loss, night sweats, nausea, and
ications such as phenytoin, penicillins, cephalosporins, and diarrhea. The lymph nodes are firm, smooth, discrete,
carbamazepine. Other autoimmune disorders that lead to tender, and mobile. There may be leukopenia and an el-
lymphadenopathy are juvenile idiopathic arthritis, systemic evated ESR. Lymph node biopsy is diagnostic. There is
lupus erythematosus, dermatomyositis, and sarcoidosis. usually spontaneous resolution of this disease.

Autoimmune Lymphoproliferative Syndrome Rosai-Dorfman Disease

Rosai-Dorfman disease is known also as sinus histiocytosis
Autoimmune lymphoproliferative syndrome is a genetic dis-
with massive lymphadenopathy. The cervical lymph nodes
order of lymphocyte apoptosis leading to lymphadenopathy,
are large, discrete, soft, and mobile. Laboratory evaluation
pancytopenia, and splenomegaly. Having the condition in-
shows neutrophilic leukocytosis, elevation of the ESR, and
creases the risk of developing B-cell lymphoma. Diagnosis is
hypergammaglobulinemia. A biopsy of the involved node
made according to revised diagnostic criteria from a 2009
shows hyperplasia, histiocytosis, and plasmacytosis. Pro-
National Institute of Health international workshop. Treat-
gressive disease may require chemotherapy.
ment involves the use of immunosuppressive agents.

Hemophagocytic Lymphohistiocytosis Summary

Hemophagocytic lymphohistiocytosis is a potentially fatal
hyperinflammatory disease that occurs more commonly in • Lymphadenopathy in children results from a benign
children younger than 4 years old. The condition presents infectious process in the majority of patients;
with fever, irritability, maculopapular or petechial rash, however, a wide spectrum of infectious and
noninfectious conditions can cause both inflammatory
hepatosplenomegaly, lymphadenopathy, respiratory dis- and noninflammatory lymph node enlargement.
tress, and aseptic meningitis. The diagnosis can be made • It is important to recognize the signs of a malignant
in the presence of set criteria that include laboratory find- process in order to initiate an early evaluation.
ings such as hypertriglyceridemia, hyperferritinemia, cyto- • In the absence of any symptoms and signs directly
penia, low natural killer cell activity, hemophagocytosis in suggestive of a neoplastic process, close monitoring is
essential to look for resolution of an enlarged node. If
bone marrow or lymph nodes, and elevated soluble CD-25 the node does not regress over a period of 4 weeks, it
antibody levels. The condition may be associated with ge- is important to get a biopsy to exclude malignancy.
netic mutation of perforin or the munc13-4 gene. The
treatment and prognosis depend on the underlying cause.
References
Periodic Fever, Aphthous Stomatitis, 1. Herzog LW. Prevalence of lymphadenopathy of the head and neck
in infants and children. Clin Pediatr (Phila). 1983;22(7):485–487
Pharyngitis, and Cervical Adenitis Syndrome 2. Bamji M, Stone RK, Kaul A, Usmani G, Schachter FF, Wasserman
This condition is an autoinflammatory disease of unknown E. Palpable lymph nodes in healthy newborns and infants. Pediatrics.
etiology that cycles every 2 to 9 weeks and undergoes spon- 1986;78(4):573–575
taneous resolution. One manifestation is tender cervical 3. Knight PJ, Mulne AF, Vassy LE. When is lymph node biopsy
lymphadenopathy. The condition usually presents in chil- indicated in children with enlarged peripheral nodes? Pediatrics.
1982;69(4):391–396
dren who are younger than 5 years old and resolves by
4. Twist CJ, Link MP. Assessment of lymphadenopathy in children.
10 years of age. There is no specific diagnostic test. The Pediatr Clin North Am. 2002;49(5):1009–1025
children experience normal health and growth between ep- 5. Gosche JR, Vick L. Acute, subacute, and chronic cervical
isodes. Corticosteroids and nonsteroidal anti-inflammatory lymphadenitis in children. Semin Pediatr Surg. 2006;15(2):99–106
drugs are used to alleviate severe symptoms. A single dose
of corticosteroid is an effective agent for symptom allevia-
Suggested Reading
1. Friedman ER, John SD. Imaging of pediatric neck masses.
tion when given at the onset of an episode. Tonsillectomy Radiol Clin North Am. 2011;49(4):617–632, v
is considered a controversial therapy to treat this disease that 2. Nield LS, Kamat D. Lymphadenopathy in children: when and
may resolve spontaneously. how to evaluate. Clin Pediatr (Phila). 2004;43(1):25–33

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 blood disorders lymphadenopathy

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1. A 15-year-old boy is brought into your office for evaluation of “swollen neck glands.” The patient’s mother is quite
concerned because her brother was diagnosed as having Hodgkin disease. You take a thorough history from the
patient. Of the following components of the history, which is most suggestive of a malignant rather than an
infectious cause of lymphadenopathy?
A. Aphthous stomatitis.
B. Chronic cough.
C. Lymph node enlargement for less than 4 weeks.
D. Patient younger than age 4 years.
E. Weight loss.
2. You proceed to perform a careful physical examination of the boy. You palpate each region of the body for lymph nodes.
An enlarged lymph node in which of the following locations would be most concerning for malignancy?
A. Anterior cervical.
B. Inguinal.
C. Posterior cervical.
D. Submandibular.
E. Supraclavicular.
3. A 4-year-old girl presents with a 10-day history of unilateral anterior cervical lymph node enlargement. She has
a temperature of 39.5oC. The node is approximately 2 cm in diameter, warm, and fluctuant. The only pertinent finding
on physical examination is mild pharyngeal erythema. You suspect acute bacterial lymphadenitis. Of the following,
which are the most likely infectious agents to cause lymphadenitis in a 5-year-old?
A. Bartonella and Staphylococcus.
B. Epstein-Barr virus and Staphylococcus.
C. Mycobacterium tuberculosis and Staphylococcus.
D. Staphylococcus and Streptococcus.
E. Toxoplasma and Nocardia.
4. An 8-year-old boy presents to your clinic with progressive enlargement of a right axillary node, now tender, and daily
fevers (up to 38.6oC). You discover that the boy has been playing frequently with his family’s new kitten. You suspect
the child may have a specific bacterial infection and he is uncomfortable enough to treat. Of the following, which is
the preferred antibiotic?
A. Amoxicillin.
B. Azithromycin.
C. Cephalexin.
D. Doxycycline.
E. Penicillin.
5. A 16-year-old girl presents with 2 weeks of fatigue, fever, and sore throat. On examination, you identify enlarged
posterior and anterior cervical nodes, and a palpable spleen tip. She has mild thrombocytopenia (platelet count of 120 3
103/mL [120 3 109/L]). Of the following, which would be the most specific test to confirm the suspected diagnosis?
A. Bartonella henselae antibody titers.
B. Epstein-Barr virus antibody titers.
C. HIV antibody titers.
D. Throat culture for group A Streptococcus.
E. White blood cell count with differential.

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 Lymphadenopathy
Shashi Sahai
Pediatrics in Review 2013;34;216
DOI: 10.1542/pir.34-5-216

Updated Information & including high resolution figures, can be found at:
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http://pedsinreview.aappublications.org/content/34/5/216#BIBL
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