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Evaluation Unknown Limfadenopaty
Evaluation Unknown Limfadenopaty
Lymphadenopathy is benign and self-limited in most patients. Etiologies include malignancy, infection, and autoim-
mune disorders, as well as medications and iatrogenic causes. The history and physical examination alone usually
identify the cause of lymphadenopathy. When the cause is unknown, lymphadenopathy should be classified as local-
ized or generalized. Patients with localized lymphadenopathy should be evaluated for etiologies typically associated
with the region involved according to lymphatic drainage patterns. Generalized lymphadenopathy, defined as two or
more involved regions, often indicates underlying systemic disease. Risk factors for malignancy include age older than
40 years, male sex, white race, supraclavicular location of the nodes, and presence of systemic symptoms such as fever,
night sweats, and unexplained weight loss. Palpable supraclavicular, popliteal, and iliac nodes are abnormal, as are
epitrochlear nodes greater than 5 mm in diameter. The workup may include blood tests, imaging, and biopsy depend-
ing on clinical presentation, location of the lymphadenopathy, and underlying risk factors. Biopsy options include
fine-needle aspiration, core needle biopsy, or open excisional biopsy. Antibiotics may be used to treat acute unilateral
cervical lymphadenitis, especially in children with systemic symptoms. Corticosteroids have limited usefulness in the
management of unexplained lymphadenopathy and should not be used without an appropriate diagnosis. (Am Fam
Physician. 2016;94(11):896-903. Copyright © 2016 American Academy of Family Physicians.)
L
CME This clinical content ymphadenopathy refers to lymph associated symptoms, and location (localized
conforms to AAFP criteria nodes that are abnormal in size vs. generalized). Table 2 lists common his-
for continuing medical
education (CME). See (e.g., greater than 1 cm) or con- torical clues and their associated diagnoses.2
CME Quiz Questions on sistency. Palpable supraclavicular, Other historical questions include asking
page 868. popliteal, and iliac nodes, and epitrochlear about time course of enlargement, tender-
Author disclosure: No rel- nodes greater than 5 mm, are considered ness to palpation, recent infections, recent
evant financial affiliations. abnormal. Hard or matted lymph nodes may immunizations, and medications.4
suggest malignancy or infection. In primary
AGE AND DURATION
care practice, the annual incidence of unex-
plained lymphadenopathy is 0.6%.1 Only About one-half of otherwise healthy chil-
1.1% of these cases are related to malignancy, dren have palpable lymph nodes at any one
but this percentage increases with advancing time.4 Most lymphadenopathy in children is
age.1 Cancers are identified in 4% of patients benign or infectious in etiology. In adults and
40 years and older who present with unex- children, lymphadenopathy lasting less than
plained lymphadenopathy vs. 0.4% of those two weeks or greater than 12 months without
younger than 40 years.1 Etiologies of lymph- change in size has a low likelihood of being
adenopathy can be remembered with the neoplastic.2,5 Exceptions include low-grade
MIAMI mnemonic: malignancies, infections, Hodgkin lymphomas and indolent non-
autoimmune disorders, miscellaneous and Hodgkin lymphoma, although both typically
unusual conditions, and iatrogenic causes have associated systemic symptoms.6
(Table 1).2,3 In most cases, the history and
EXPOSURES
physical examination alone identify the cause.
Environmental, travel-related, animal, and
History insect exposures should be ascertained.
Factors that can assist in identifying the etiol- Chronic medication use, infectious expo-
ogy of lymphadenopathy include patient age, sures, immunization status, and recent
duration of lymphadenopathy, exposures, immunizations should be reviewed as well.
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Unexplained Lymphadenopathy
SORT: KEY RECOMMENDATIONS FOR PRACTICE
Evidence
Clinical recommendation rating References
Ultrasonography should be used as the initial imaging modality for children up to 14 years C 15
presenting with a neck mass with or without fever.
Computed tomography should be used as the initial imaging modality for children older than C 15
14 years and adults presenting with solitary or multiple neck masses.
In children with acute unilateral anterior cervical lymphadenitis and systemic symptoms, empiric C 17
antibiotics that target Staphylococcus aureus and group A streptococci may be given.
Corticosteroids should be avoided until a definitive diagnosis of lymphadenopathy is made because C 4
they could potentially mask or delay histologic diagnosis of leukemia or lymphoma.
Fine-needle aspiration may be used to differentiate malignant from reactive lymphadenopathy. C 19-22
A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-oriented
evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, go to http://www.aafp.org/afpsort.
Table 3 lists medications commonly associ- drainage patterns, as well as common etiol-
ated with lymphadenopathy.2 Tobacco and ogies of lymphadenopathy in these regions.2
alcohol use and ultraviolet radiation expo- A skin examination should be performed to
sure increase concerns for neoplasm. An rule out other lesions that would point to
occupational history that includes mining, malignancy and to evaluate for erythema-
masonry, and metal work may elicit work- tous lines along nodal tracts or any trauma
related etiologies of lymphadenopathy, such that could lead to an infectious source of
as silicon or beryllium exposure. Asking the lymphadenopathy. Finally, abdomi-
about sexual history to assess exposure to nal examination focused on splenomegaly,
genital sores or participation in oral inter- although rarely associated with lymph-
course is important, especially for ingui- adenopathy, may be useful for detecting
nal and cervical lymphadenopathy. Finally,
family history may identify familial causes
of lymphadenopathy, such as Li-Fraumeni
Table 1. MIAMI Mnemonic for Differential Diagnosis
syndrome or lipid storage diseases.2 of Lymphadenopathy
ASSOCIATED SYMPTOMS
Malignancies
A thorough review of systems aids in iden- Kaposi sarcoma, leukemias, lymphomas, metastases, skin neoplasms
tifying any red flag symptoms. Arthralgias, Infections
muscle weakness, and rash suggest an auto- Bacterial: brucellosis, cat-scratch disease (Bartonella), chancroid, cutaneous
immune etiology. Constitutional symptoms infections (staphylococcal or streptococcal), lymphogranuloma venereum,
of fever, chills, fatigue, and malaise indicate primary and secondary syphilis, tuberculosis, tularemia, typhoid fever
an infectious etiology. In addition to fever, Granulomatous: berylliosis, coccidioidomycosis, cryptococcosis,
drenching night sweats and unexplained histoplasmosis, silicosis
weight loss of greater than 10% of body Viral: adenovirus, cytomegalovirus, hepatitis, herpes zoster, human immuno
weight may suggest Hodgkin lymphoma or deficiency virus, infectious mononucleosis (Epstein-Barr virus), rubella
non-Hodgkin lymphoma.2,3,6 Other: fungal, helminthic, Lyme disease, rickettsial, scrub typhus,
toxoplasmosis
Physical Examination Autoimmune disorders
Dermatomyositis, rheumatoid arthritis, Sjögren syndrome, Still disease,
Overall state of health and height and systemic lupus erythematosus
weight measurements may help identify Miscellaneous/unusual conditions
signs of chronic disease, especially in chil- Angiofollicular lymph node hyperplasia (Castleman disease), histiocytosis,
dren.7 A complete lymphatic examination Kawasaki disease, Kikuchi lymphadenitis, Kimura disease, sarcoidosis
should be performed to rule out generalized Iatrogenic causes
lymphadenopathy, followed by a focused Medications, serum sickness
lymphatic examination with consideration
of lymphatic drainage patterns. Figures 1 Information from references 2 and 3.
through 3 demonstrate typical lymphatic
Fever, night sweats, weight loss, or Leukemia, lymphoma, solid tumor CBC, nodal biopsy or bone marrow biopsy; imaging
node located in supraclavicular, metastasis with ultrasonography or computed tomography
popliteal, or iliac region, may be considered but should not delay referral for
bruising, splenomegaly biopsy
Fever, chills, malaise, sore throat, Bacterial or viral pharyngitis, Limited illnesses may not require any additional
nausea, vomiting, diarrhea; no hepatitis, influenza, testing; depending on clinical assessment, consider
other red flag symptoms mononucleosis, tuberculosis CBC, monospot test, liver function tests, cultures,
(if exposed), rubella and disease-specific serologies as needed
High-risk sexual behavior Chancroid, HIV infection, HIV-1/HIV-2 immunoassay, rapid plasma reagin,
lymphogranuloma venereum, culture of lesions, nucleic acid amplification for
syphilis chlamydia, migration inhibitory factor test
Recent travel, insect bites Diagnoses based on endemic Serology and testing as indicated by suspected
region exposure
Arthralgias, rash, joint stiffness, Rheumatoid arthritis, Sjögren Antinuclear antibody, anti-doubled-stranded DNA,
fever, chills, muscle weakness syndrome, dermatomyositis, erythrocyte sedimentation rate, CBC, rheumatoid
systemic lupus erythematosus factor, creatine kinase, electromyography, or
muscle biopsy as indicated
CBC = complete blood count; CDC = Centers for Disease Control and Prevention; HIV = human immunodeficiency virus.
Information from reference 2.
898 American Family Physician www.aafp.org/afp Volume 94, Number 11 ◆ December 1, 2016
Unexplained Lymphadenopathy
Preauricular nodes:
Drain scalp, skin
Differential diagnosis:
Scalp infections, Submandibular nodes:
mycobacterial infection Drain oral cavity
Malignancies: Differential diagnosis:
Skin neoplasm, lymphomas, Mononucleosis, upper
head and neck squamous respiratory infection,
cell carcinomas mycobacterial infection,
toxoplasma, cytomegalovirus,
dental disease, rubella
Posterior cervical nodes: Malignancies:
Drain scalp, neck, upper Squamous cell carcinoma
thoracic skin of the head and neck,
Differential diagnosis: lymphomas, leukemias
Same as preauricular nodes
Figure 1. Lymph nodes of the head and neck and the regions that they drain.
Reprinted with permission from Bazemore AW, Smucker DR. Lymphadenopathy and malignancy. Am Fam Physician. 2002;66(11):2106.
Epitrochlear nodes:
Drain ulnar forearm, hand
Differential diagnosis:
Skin infections, lymphomas,
and skin malignancies
900 American Family Physician www.aafp.org/afp Volume 94, Number 11 ◆ December 1, 2016
Unexplained Lymphadenopathy
Evaluation of Lymphadenopathy
History (includes infectious contacts, medications, travel, environmental
exposures, occupational exposure, sexual history, family history)
Treat appropriately
Negative Resolves
Figure 4. Algorithm for evaluating lymphadenopathy. (ANA = antinuclear antibody; CBC = complete blood count;
HBsAg = hepatitis B surface antigen; HIV = human immunodeficienty virus; PPD = purified protein derivative; RPR = rapid
plasma reagin.)
Adapted with permission from Bazemore AW, Smucker DR. Lymphadenopathy and malignancy. Am Fam Physician. 2002;66(11):2109.
Radiologic evaluation with computed a reactive lymph node is likely, core needle
tomography, magnetic resonance imaging, biopsy can be avoided, and FNA used alone.
or ultrasonography may help to characterize Combined, they allow cytologic and histo-
lymphadenopathy. The American College pathologic assessment of lymph nodes. How-
of Radiology recommends ultrasonography ever, the use of both techniques may not be
as the initial imaging choice for cervical needed because the diagnostic accuracy of
lymphadenopathy in children up to 14 years FNA in adult populations has been reported
of age and computed tomography for per- to approach 90%, with a sensitivity and
sons older than 14 years.15 Based on the loca- specificity of 85% to 95% and 98% to 100%,
tion of the abnormal nodes, the sensitivity of respectively.19,20 False-positive diagnoses are
these modalities for diagnosing metastatic rare with FNA. False-negative results occur
lymph nodes varies; therefore, history and secondary to early or partial involvement of
clinical examination must guide selection.16 lymph nodes, inexperience with lymph node
If the diagnosis is still uncertain, biopsy is cytology, unrecognized lymphomas with
recommended. heterogeneity, and sampling errors.20 There
In children with acute unilateral anterior are concerns about the reliability of FNA in
cervical lymphadenitis and systemic symp- the diagnosis of diseases such as lymphoma
toms, antibiotics may be prescribed. Empiric because it is unable to assess lymph node
antibiotics should target Staphylococcus architecture. Regardless, FNA may be a use-
aureus and group A streptococci. Options ful triage tool for differentiating benign reac-
include oral cephalosporins, amoxicillin/ tive lymphadenopathy from malignancy.21
clavulanate (Augmentin), orclindamycin.17 Open excisional biopsy remains a diag-
Corticosteroids should be avoided until a nostic option for patients who do not wish
definitive diagnosis is made because treat- to undergo additional procedures. When
ment could potentially mask or delay histo- selecting nodes for any method, the largest,
logic diagnosis of leukemia or lymphoma.5 most suspicious, and most accessible node
should be sampled. Inguinal nodes typically
Biopsy display the lowest yield, and supraclavicular
Fine-needle aspiration (FNA) and core nodes have the highest.22,23
needle biopsy can aid in the diagnostic
This review updates previous articles on this topic by
evaluation of lymph nodes when etiology is Bazemore and Smucker 2 and Ferrer. 24
unknown or malignant risk factors are pres-
Data Sources: A PubMed search was completed
ent (Table 44,6,10). FNA cytology is a quick, in Clinical Queries. Key terms: lymphadenopathy,
accurate, minimally invasive, and safe tech- peripheral, generalized, evaluation, treatment, imag-
nique to evaluate patients and aid in tri- ing, management. The search included meta-analyses,
age of unexplained lymphadenopathy.18 If randomized controlled trials, clinical trials, and reviews.
Also searched were Essential Evidence Plus, the Agency
for Healthcare Research and Quality evidence reports,
Clinical Evidence, Google Scholar, and the Cochrane
Table 4. Risk Factors for Malignancy database. Reference lists of retrieved articles were also
searched. Search dates: September 2015 and July 2016.
Age older than 40 years The opinions and assertions contained herein are the
Duration of lymphadenopathy greater than four to six weeks private views of the authors and are not to be construed
as official or as reflecting the views of the U.S. Air Force
Generalized lymphadenopathy (two or more regions involved) Medical Department or the U.S. Air Force at large.
Male sex
Node not returned to baseline after eight to 12 weeks
The Authors
Supraclavicular location
Systemic signs: fever, night sweats, weight loss, hepatosplenomegaly HEIDI L. GADDEY, MD, is the program director at the
White race Ehrling Bergquist Family Medicine Residency Program,
Offutt Air Force Base, Neb.
Information from references 4, 6, and 10. ANGELA M. RIEGEL, DO, is faculty at the Ehrling Bergquist
Family Medicine Residency Program.
902 American Family Physician www.aafp.org/afp Volume 94, Number 11 ◆ December 1, 2016
Unexplained Lymphadenopathy
Address correspondence to Heidi L. Gaddey, MD, Ehrling 13. Mauch PM, Kalish LA, Kadin M, Coleman CN, Osteen R,
Bergquist Clinic, 2501 Capehart Road, Offutt Air Force Hellman S. Patterns of presentation of Hodgkin disease.
Base, NE 68113. (e-mail: heidi.gaddey@us.af.mil). Implications for etiology and pathogenesis. Cancer.
Reprints are not available from the authors. 1993;71(6):2062-2071.
14. Skinner DG, Leadbetter WF, Kelley SB. The surgical
management of squamous cell carcinoma of the penis.
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