Journals AZ ≫ Mayo Clinic Proceedings ≫ 75(7) July

Transcription

Ovid: Lymphadenopathy.
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Journals A-Z ≫ Mayo Clinic Proceedings ≫ 75(7) July 2000 ≫ Lymphadenopathy.
Mayo Clinic Proceedings
Issue: Volume 75(7), July 2000, pp 723-732
Copyright: © 2000 Mayo Foundation for Medical Education and Research
Publication Type: [Subspecialty Clinics: Hematology]
ISSN: 0025-6196
Accession: 00005625-200007000-00011
[Subspecialty Clinics: Hematology]
Lymphadenopathy
Habermann, Thomas M. MD; Steensma, David P. MD
Author Information
From the Division of Hematology and Internal Medicine, Mayo Clinic, Rochester, Minn.
Address reprint requests and correspondence to Thomas M. Habermann, MD, Division of Hematology, Mayo Clinic,
200 First St SW, Rochester, MN 55905.
Abstract
Lymphadenopathy can occur in any age group, in symptomatic or asymptomatic
patients, and in a single site or at multiple sites. Lymphadenopathy is associated with
numerous disorders. An abnormal lymph node may be observed or palpated by the
patient, found by a health care worker, or discovered through radiologic evaluation.
Lymphadenopathy may be a part of a complex case presentation, or the clinical cause
may be straightforward. Patients with potentially curable malignant disorders may have
lymphadenopathy as the first sign of their disease. This review of lymphadenopathy
summarizes general considerations, discusses which patients might be considered for
biopsy, reviews which nodes are most likely to be diagnostic, outlines initial diagnostic
considerations on a region-by-region basis, and reviews a broad differential diagnosis for
adenopathy.
FNA = fine-needle aspiration; HIV = human immunodeficiency virus
Lymphadenopathy is common and affects patients of all ages. Essential diagnostic
considerations include the age of the patient, the location of the abnormal lymph
nodes, the length of time the abnormal lymph nodes have been present, any associated
signs and symptoms, the presence or absence of generalized lymphadenopathy, any
extranodal signs or symptoms, and the presence or absence of splenomegaly and/or
fever (Table 1). The critical task in approaching patients with lymphadenopathy is to
determine which nodes are likely to be associated with benign, self-limited conditions
and which nodes indicate malignancy or another serious condition requiring specific
treatment. Even in the setting of obviously malignant lymphadenopathy, it is essential
to distinguish carcinoma from lymphoma for treatment and prognostic purposes.
http://ovidsp.tx.ovid.com/spb/ovidweb.cgi
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Table 1. Essential Considerations in Lymphadenopathy: ALL AGES
GENERAL CONSIDERATIONS
Patient Age, Node Size, and Node Location
Age is the most important factor in predicting the probability of whether the
lymphadenopathy is due to a benign or malignant lesion.1 Lee et al 1 analyzed findings
from 925 patients who underwent a lymph node biopsy at Los Angeles County Hospital
between 1973 and 1977 (Table 2). This total represented 0.9% of all surgical cases at
the institution during that period. Lymphoproliferative disorders were not found to have
an age predilection, while carcinomas, predictably, were much more common in
patients older than 50 years.1 In younger patients, the differential diagnosis should
always include infectious mononucleosis. Lymph nodes biopsied during acute infectious
mononucleosis have been misdiagnosed as Hodgkin disease, as cells resembling ReedSternberg cells may sometimes be present in the pathologic specimen.2-6 However,
immunohistochemical studies differentiate infectious mononucleosis from Hodgkin
disease.
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Table 2. Lymph Node Biopsy Findings*
The size and location of an abnormal lymph node and the duration of time that the
node has been present all aid in deciding when a biopsy is necessary. It is not possible to
set a strict size limit that can distinguish between normal and abnormal lymph nodes,
because the size and distribution of normal lymphoid tissue vary with multiple factors,
including age and background antigenic exposure. In 1 series of 220 node biopsy
specimens, a lymph node size of 1.5 × 1.5 cm was the best discriminating limit for
distinguishing malignant or granulomatous lymphadenopathy from other causes of
adenopathy.7 Radiographic and autopsy series have attempted to define the upper
limits of normal size for lymph nodes in cervical, intrathoracic, and intra-abdominal
sites.8-12 In general, lymph nodes that have been present outside the inguinal region
for longer than 1 month and measure 1 × 1 cm or larger without an obvious diagnosis
should be considered for biopsy.
Empiric treatment of lymphadenopathy with antibiotics or corticosteroids is a
common practice but is not recommended.7 It is essential first to establish a diagnosis
before treatment. If observation is elected, careful measurement and recording of the
size of each abnormal node with a vernier-style caliper or ruler at each evaluation are
prudent. Measurement of lymph nodes on computed tomographic scans may be more
accurate when a loop planimeter is used.13
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Slap et al 14 retrospectively evaluated 123 lymph node biopsy specimens and
designed a size-based prediction model to assist clinicians in deciding when to proceed
with lymph node biopsy in young patients. Clinical variables such as the presence or
absence of recent ear, nose, or throat symptoms and the findings on chest x-ray films
are included in the model. This model has not been tested prospectively in a large
number of patients, and its validity remains uncertain.
Associated Signs and Symptoms
The signs and symptoms associated with lymphadenopathy are varied. Patients may
be asymptomatic. Patients may also present with "B" symptoms, which include
temperature higher than 38°C, drenching night sweats, and unexplained loss of more
than 10% of body weight.15 These are characteristic of lymphoproliferative disorders
but may also be present in infectious conditions. Some patients with Hodgkin disease
may have pain in affected lymph nodes following alcohol ingestion.16 Lymphangitic
streaking is a sign consistent with cutaneous infection. The presence or absence of
associated signs or symptoms in patients with adenopathy should not alter the general
approach, since both symptomatic and asymptomatic patients may have pathologic
lymphadenopathy.
Abnormal nodes may be tender, warm, erythematous, or fluctuant. The nodes may
be hard or rubbery, fixed or mobile. In general, qualitative characteristics such as node
consistency are not particularly helpful in distinguishing benign from malignant lesions.
Although rock-hard adenopathy is associated with metastatic cancer, Hodgkin disease,
or tuberculosis, each of these disorders also commonly presents with soft nodes. A
tender node suggests an inflammatory lesion, but malignant nodes that are rapidly
expanding or contain hemorrhage may also be tender. Sinus tract formation is
associated with infectious causes of lymphadenopathy (eg, actinomycosis and
mycobacterial species), but very large malignant nodes may also form sinus tracts.
Lymphadenopathy is associated with splenomegaly in a relatively limited number of
disorders (4.5% of cases in 1 series 7). Infectious mononucleosis, Hodgkin disease and
non-Hodgkin lymphoma, chronic lymphocytic leukemia, and acute leukemia are the
most common causes. The presence of splenomegaly is rare in metastatic cancer.17
Although lymphadenopathy in the presence of fever usually represents an infection
or lymphoma, the differential diagnosis is actually quite broad. The list of differential
diagnoses includes infectious mononucleosis (Epstein-Barr virus), cytomegalovirus
infection, toxoplasmosis, syphilis, subacute bacterial endocarditis, histoplasmosis,
sarcoidosis, salmonellosis, tuberculosis, acquired immunodeficiency syndrome, Hodgkin
disease, non-Hodgkin lymphoma, angioimmunoblastic lymphadenopathy, mixed essential
cryoglobulinemia, systemic mastocytosis, chronic lymphocytic leukemia, agnogenic
myeloid metaplasia, Waldenström macroglobulinemia, multiple myeloma, systemic
lupus erythematosus, rheumatoid arthritis, Kawasaki disease, Whipple disease, serum
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sickness, and Kaposi sarcoma.
Location
When considering a lymph node biopsy in a patient with more than 1 abnormal
lymph node, the key issue is which of the nodes should be biopsied. In general, the
largest node is most likely to yield a diagnosis. The least helpful lymph nodes to biopsy
are in the inguinal region. Occasionally, however, the most accessible or most abnormal
node is in the inguinal area, and it is reasonable to attempt to biopsy these. One
retrospective series of inguinal biopsies demonstrated a diagnostic rate of 53%, probably
because of careful patient selection by surgeons.18
If multiple nodal sites are involved, the preferable initial biopsy site is the largest
peripheral node outside the inguinal area. If no peripheral nodes are available, then
mediastinal nodes (if present) are often more easily accessible than abdominal or
retroperitoneal nodes. If several peripheral nodes are similar in size (eg, in a patient
with generalized lymphadenopathy), the most common nodes to biopsy, in descending
order, are the supraclavicular, cervical, axillary, epitrochlear, and inguinal nodes.
Occasionally, multiple biopsies may be required from different sites at the time of
initial evaluation or as a case evolves over time. Biopsy of nodes in the region of the
parotid gland may injure the facial nerve or its branches, and biopsy of nodes in the
posterior triangle of the neck is the most common cause of iatrogenic injury to the
spinal accessory nerve.19,20
Biopsy Methods and Sample Processing
Lymph nodes may be biopsied by excisional methods (via direct surgical extirpation,
mediastinoscopy, open surgery, or laparoscopy) or by needle aspiration (core or fine
needle). Gupta et al 21 performed concomitant fine-needle aspirations (FNAs) and
excisional biopsies of lymph nodes on 100 patients in Delhi, India. In their series, the
accuracy rate of FNAs was 77% in reactive hyperplasia; 77% in tuberculous lymphadenitis
(the most common diagnosis); 75% in non-Hodgkin lymphoma; and 85% in metastatic
carcinoma. Although FNA is simple, safe, and inexpensive, lymph node disorders such as
reactive hyperplasia, Hodgkin disease, and non-Hodgkin lymphoma may be extremely
difficult to distinguish from one another with FNA alone. On the other hand, FNA is very
helpful in the evaluation of pancreatic and peripancreatic disorders, in the
differentiation of adenocarcinomas from other disorders, and in the diagnosis of head
and neck carcinoma, thyroid lesions, malignant melanoma, and relapsed
lymphoproliferative disorders or carcinomas. In patients without an established
diagnosis and with accessible peripheral adenopathy, however, excisional biopsy is
preferred over FNA to ensure adequate sampling.
In 1996, Pinkus 22 wrote, "One would have considerable reservation regarding the
routine use of needle biopsy to establish a primary diagnosis of malignant lymphoma
because of the broad spectrum of lymphoid proliferations, the limitations of this
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technique, and the current level of diagnostic precision required to determine
treatment options." For the initial diagnosis of suspected lymphoma, the procedure of
choice is surgical biopsy if the clinical condition of the patient allows. If the condition of
the patient is such that surgical biopsy is contraindicated, or if the site of disease is
difficult to access, a needle biopsy may be the procedure of choice. A core needle
biopsy is preferred to FNA.23,24
The overall diagnostic yield of lymph node biopsies is good, but careful processing
of specimens according to local institutional protocol is important. In a review 18 of 290
excisional lymph node biopsy specimens processed according to strict guidelines at
Creighton University between 1970 and 1974, a "positive yield" was obtained in 63% of
cases. "Positive yield" was defined as a pathologic result that confirmed, changed, or
excluded the clinical diagnosis.18 Prior to the introduction of handling guidelines, the
rate of positive yield at Creighton was less than 50%. Sinclair et al 25 at Massachusetts
General Hospital also reported a 63% specific diagnosis rate from node biopsy, excluding
patients with known malignancies, systemic diseases, or abnormal chest x-ray films.
Careful selection of patients is essential. In 1 large series,26 63% of all lymph node
biopsy specimens were classified as "reactive, nonspecific." These 2 older series,
compiling data on cases evaluated before the advent of modern hematopathologic
technologies, provide interesting insights.
The pathologic interpretation of "atypical hyperplasia" was once common to denote
biopsy specimens in which the pathologist was concerned about neoplasia but was not
able to diagnose lymphoma definitively.27-29 In 1979, Schroer and Franssila 30 followed
up on 70 patients who had pathologic interpretations of atypical hyperplasia at Barnes
Hospital between 1961 and 1972. Thirty-seven percent were later diagnosed as having
malignant lymphoproliferative disorders. On blinded reexamination of the initial 70
specimens by 2 pathologists, 19 nodes contained clearly benign lesions, 10 were clearly
malignant, 37 could still be denoted only as atypical hyperplasia, and 4 had
angioimmunoblastic lymphadenopathy. Suspicious but non-diagnostic lymph node
specimens may be diagnosed as atypical hyperplasia with a recommendation for
consideration for repeat biopsy at a later time.
With newer immunohistochemical, cytogenetic, and molecular genetic
technologies, nondiagnostic biopsy findings may be seen less often.31 However, data
confirming this impression have not been published. Consultation with a pathologist
prior to biopsy may improve the diagnostic evaluation, and appropriate ancillary test
results can then be reviewed. Formal laboratory triage systems are important.
Immunohistochemical staining of frozen tissue and flow cytometric immunophenotyping
are both effective in diagnosing lymphoma.32 The advantage of immunohistochemical
frozen-section analysis is that the nodal morphology is intact, and the tissue can be
stored for future evaluation and studies with frozen tissue. In addition,
immunohistochemical analysis of paraffin-embedded tissue has improved considerably in
recent years.
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DIFFERENTIAL DIAGNOSIS
The differential diagnosis of lymphadenopathy of unknown origin is similar to that
of fever of unknown origin or an elevated erythrocyte sedimentation rate, in that most
cases are due to an infection, a malignancy, or an immune disorder.33 There are 3
broad models to categorize lymphadenopathy. The extensive differential diagnosis may
be grouped incorporating an acronym, CHICAGO (cancers, hypersensitivity syndromes,
Infections, connective tissue diseases, atypical lymphoproliferative disorders,
granulomatous lesions, and other unusual causes of lymphadenopathy) (Table 3). More
specifically, the letters of the alphabet serve as a method to catalog the lengthy list of
causes of lymphadenopathy (Table 4). The region of the lymph node involvement can be
valuable information in narrowing this lengthy differential diagnosis (Table 5).
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Table 3. Causes of Lymphadenopathy: CHICAGO*
Table 4. Differential Diagnosis of Lymphadenopathy*
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Table 5. Regional Differential Diagnosis of Lymphadenopathy*
Cervical Lymphadenopathy
The differential diagnosis of cervical lymphadenopathy primarily consists of
infections and malignancies. Common infectious etiologies include bacterial pharyngitis,
dental abscesses, otitis media and otitis externa, infectious mononucleosis, gonococcal
pharyngitis, cytomegalovirus, toxoplasmosis, hepatitis, and adenovirus. The most
common malignancies presenting in the cervical region include non-Hodgkin lymphoma,
Hodgkin disease, and squamous cell carcinoma of the head and neck. Isolated posterior
cervical and occipital adenopathy is associated with rubella, toxoplasmosis, and Kikuchi
disease (histiocytic necrotizing lymphadenitis). Kikuchi disease is a syndrome of
unknown etiology that was first described in 1972 in Japan.95 The classic patient is a
young woman who presents with painless lymphadenopathy that is unilateral in the
posterior cervical region and resolves in 3 months.
Supraclavicular Lymphadenopathy
The Virchow node, a pathological anterior left supraclavicular lymph node also
known as the signal node or Troisier ganglion, heralds the presence of an abdominal or
thoracic neoplasm.138 Common causes include breast carcinoma, non-Hodgkin
lymphoma, Hodgkin disease, gastrointestinal neoplasms, and bronchogenic carcinoma.
Chronic fungal and mycobacterial infections (eg, scrofula) can also cause supraclavicular
adenopathy. The Delphian node is a midline prelaryngeal lymph node that has
traditionally been believed to be an oracle of thyroid disease or laryngeal malignancy,
but objective data are lacking and patients with lymphoma may have lymphadenopathy
in this region.139
Axillary Lymphadenopathy
Axillary adenopathy, like cervical adenopathy, is usually secondary to infection or
malignancy. Hodgkin disease, non-Hodgkin lymphoma, carcinoma of the breast, and
melanoma are common. Characteristic infectious causes of axillary lymph nodes include
staphylococcal and streptococcal bacterial infections of the arm, cat-scratch fever,
tularemia, and sporotrichosis.
Epitrochlear Lymphadenopathy
Selby et al 140 performed a prospective study of epitrochlear adenopathy in 324
patients. None of the 140 healthy controls in the study had any epitrochlear nodes
palpable. A total of 184 consecutive patients with conditions associated with
adenopathy in other regions were examined; of these, 49 patients (27%) had palpable
epitrochlear adenopathy. The 2 most common diagnoses in the patients with
epitrochlear adenopathy were lymphoma/chronic lymphocytic leukemia (22 patients)
and infectious mononucleosis (12 patients). Other diagnoses included sarcoidosis, human
immunodeficiency virus (HIV) infection, dermatologic diseases, and some connective
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tissue disorders. Historically, epitrochlear adenopathy has been associated with
secondary syphilis, lepromatous leprosy, leishmaniasis, and rubella.
Inguinal Lymphadenopathy
Most adults have some degree of inguinal lymph node enlargement. Benign reactive
inguinal lymphadenopathy is more common in patients who walk shoeless outdoors.141
Common malignant causes include non-Hodgkin lymphoma, Hodgkin disease, malignant
melanoma, squamous cell carcinoma of the penis, and squamous cell carcinoma of the
vulva. Benign causes include cellulitis and venereal disease (syphilis, chancroid, genital
herpes, and lymphogranuloma venereum). The node of Cloquet (also known as the
Rosenmüller node) is a deep inguinal lymph node located near the femoral canal; when
pathologically enlarged, it may be mistaken for an inguinal hernia.142
Popliteal Lymphadenopathy
Little data exist on popliteal adenopathy in humans, although rat popliteal nodes
are a common immunologic research model. One author does not routinely check for
popliteal nodes, stating, "the physical examination must not be stretched beyond its
limits."143
Hilar and Mediastinal Lymphadenopathy
The most common causes of hilar prominence on chest x-ray films are vascular
engorgement and adenopathy. On chest x-ray evaluation alone, it may be difficult to
distinguish vascular enlargement from nodal enlargement. The differential diagnosis of
hilar lymphadenopathy is extensive.144,145 Fraser et al 145 have articulated an
extensive differential diagnosis, evaluation approaches, and radiologic findings.
Unilateral hilar adenopathy may be related to pneumonitis or neoplasia. Any bacterial
pneumonia can cause unilateral hilar adenopathy; granulomatous disease, tuberculosis,
atypical mycobacterial infections, histoplasmosis, coccidioidomycosis, tularemia,
psittacosis, and pertussis are also considerations. Common neoplastic etiologies of
unilateral hilar disease include bronchogenic carcinoma, metastatic carcinoma of the
breast and gastrointestinal tract, non-Hodgkin lymphoma, and Hodgkin disease. Bilateral
hilar adenopathy is commonly caused by sarcoidosis, non-Hodgkin lymphoma, Hodgkin
disease, metastatic carcinoma, chronic granulomatous infections, or berylliosis.
Calcified hilar adenopathy may be secondary to tuberculosis, histoplasmosis, or silicosis
(classically egg-shaped nodes).
The approach to evaluating hilar adenopathy includes a detailed history and
physical examination, evaluation of old chest x-ray films, judicious use of serologic
studies (fungal, serum angiotensin-converting enzyme, etc), cultures when appropriate,
and lymph node biopsy. Mediastinoscopy is the preferred initial approach; other
potential approaches include limited anterior thoracotomy or needle biopsy.
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It may be difficult to distinguish mediastinal lymph-adenopathy from the many
other causes of mediastinal widening.145 Diffuse mediastinal widening may be related
to acute mediastinitis, hemorrhage, lipomatosis, or fibrosing mediastinitis. Acute
mediastinitis is usually bacterial and related to entities such as esophageal rupture
(secondary to Boerhaave syndrome, foreign body ingestion, invasive esophageal
carcinoma, penetrating or blunt chest trauma, or therapeutic esophageal dilatation),
empyema, lung abscess, bacterial pericarditis, retropharyngeal abscess, or an infected
bronchogenic cyst. Anterior mediastinal masses may represent a thymoma, a teratoma
or other germ cell tumor, an intrathoracic goiter, Hodgkin or non-Hodgkin lymphoma, a
parathyroid mass, choriocarcinoma, or benign tumors such as lipomas, fibromas,
hemangiomas, and lymphangiomas. Middle mediastinal masses may be secondary to nonHodgkin and Hodgkin lymphoma, carcinoma of the trachea, metastatic carcinoma,
granulomatous mediastinitis, bronchogenic cyst, pleuropericardial cyst, diaphragmatic
hernia through the foramen of Morgagni, Castleman disease, or vascular dilatation.
Posterior mediastinal masses are usually due to neurogenic tumors, neuroenteric cysts,
gastroenteric cysts, thoracic duct cysts, esophageal neoplasms and diverticula,
diaphragmatic hernia through the foramen of Bochdalek, disease of the thoracic spine,
or extramedullary hematopoiesis.
The initial approach to the mediastinal mass is similar to that of the hilar mass,
including detailed history and physical examination, review of old chest x-ray films, and
judicious laboratory testing, followed by other evaluations that may include a computed
tomographic scan with subsequent biopsy.
Abdominal Lymphadenopathy
Lymphadenopathy limited to the abdomen (mesenteric and/or retroperitoneal) is
often malignant. Causes include non-Hodgkin lymphoma, metastatic adenocarcinoma,
gastric adenocarcinoma, Hodgkin disease (characteristically retroperitoneal node
involvement and rarely mesenteric involvement), transitional cell carcinoma of the
bladder, chronic lymphocytic leukemia, hairy cell leukemia, and tuberculosis. A classic
sign of gastric adenocarcinoma is the Sister (Mary) Joseph nodule in the umbilical area,
which may represent a direct metastatic deposit or an enlarged anterior abdominal
lymph node.146-148 Umbilical metastases may also be seen in other
malignancies.149,150 This physical sign is named after surgeon William J. Mayo's scrub
nurse, who was able to predict the findings at laparotomy if she felt a periumbilical
mass while scrubbing the patient's abdomen.151 It has been suggested that the "Mary" in
"Sister Mary Joseph" is incorrect,147,152 but there is clear historical evidence to the
contrary.153,154
Generalized Lymphadenopathy
Common malignant causes of generalized lymphadenopathy include the hematologic
malignancies, especially non-Hodgkin lymphoma, Hodgkin disease, chronic lymphocytic
leukemia, and acute lymphocytic leukemia. Benign causes include infectious
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mononucleosis, cytomegalovirus, toxoplasmosis, tuberculosis, histoplasmosis,
coccidioidomycosis, brucellosis, sarcoidosis, rheumatoid arthritis, systemic lupus
erythematosus, HIV infection, and angioimmunoblastic lymphadenopathy.
SPECIAL CLINICAL AND LABORATORY ASSOCIATIONS
Historical and laboratory associations may aid in establishing the diagnosis in
difficult cases associated with lymph-adenopathy (Table 6). The differential diagnosis of
lymph-adenopathy with malabsorption includes gluten-sensitive enteropathy, Crohn
disease, amyloidosis, and Whipple disease. Rheumatoid arthritis, systemic lupus
erythematosus, Wegener granulomatosis, or Whipple disease may cause
lymphadenopathy associated with arthralgias or arthritis. Renal disease and
lymphadenopathy are seen together with systemic lupus erythematosus, mixed
connective tissue disease, amyloidosis, Whipple disease, and Hodgkin disease with
paraneoplastic minimal change disease. Hypogammaglobulinemia and lymphadenopathy
may be associated with chronic lymphocytic leukemia, amyloidosis, common variable
immunodeficiency, and Whipple disease.133 Monoclonal proteins in the serum or urine
may be associated with non-Hodgkin lymphoma, chronic lymphocytic leukemia, multiple
myeloma, or amyloidosis.
Table 6. Historical and Laboratory Associations With Lymphadenopathy
CONCLUSION
Lymphadenopathy is an important physical finding with an extensive differential
diagnosis that often presents interesting challenges to the clinician. Skill in palpating
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peripheral lymph nodes improves with time. Clinicians should be encouraged to
consistently measure the peripheral nodes that are discovered on physical examination
with calipers. Node biopsies, when appropriate, should be performed in a manner most
likely to yield a useful result. Knowledge of the broad differential diagnosis of
lymphadenopathy, the relationships of other signs and symptoms, and key laboratory
associations all aid in a thoughtful and expeditious diagnosis.
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