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Soheir Adam , MD, MSc, MRCPath

The Lymphatic System

The body has approximately 600 lymph nodes, but

only those in the submandibular, axillary or inguinal
regions may normally be palpable in healthy
people.1 Lymphadenopathy refers to nodes that are
abnormal in either size, consistency or number.
There are various classifications of
lymphadenopathy, but a simple and clinically useful
system is to classify lymphadenopathy as
"generalized" if lymph nodes are enlarged in two or
more noncontiguous areas or "localized" if only one
area is involved.
Distinguishing between localized and
generalized lymphadenopathy is important in
formulating a differential diagnosis.
In primary care patients with unexplained
lymphadenopathy, approximately 3/4 of
patients will present with localized
lymphadenopathy and 1/4 with generalized

Findings from a Dutch study revealed a 0.6%

annual incidence of unexplained lymphadenopathy
in the general population.

Of 2,556 patients in the study who presented with

unexplained lymphadenopathy to their family
physicians, 256 (10 %) were referred to a
subspecialist and 82 (3.2 %) required a biopsy, but
only 29 (1.1 %) had a malignancy.

First, are there localizing symptoms or signs to

suggest infection or neoplasm in a specific site?
Second, are there constitutional symptoms such as
fever, weight loss, fatigue or night sweats to suggest
disorders such as tuberculosis, lymphoma, collagen
vascular diseases, unrecognized infection or

Third, are there epidemiologic clues such as

occupational exposures, recent travel or high-risk
behaviors that suggest specific disorders?
Fourth, is the patient taking a medication that may
cause lymphadenopathy? Some medications are
known to specifically cause lymphadenopathy (e.g.,
phenytoin ), while others, such as cephalosporins,
penicillins or sulfonamides, are more likely to cause
a serum sickness-like syndrome with fever,
arthralgias and rash in addition to lymphadenopathy.
Medications That May Cause Lymphadenopathy

Allopurinol (Zyloprim) Penicillin

Atenolol (Tenormin) Phenytoin (Dilantin)
Captopril (Capozide) Primidone (Mysoline)
Carbamazepine (Tegretol) Pyrimethamine (Daraprim)
Cephalosporins Quinidine
Gold Sulfonamides
Hydralazine (Apresoline) Sulindac (Clinoril)

Adapted with permission from Pangalis GA, Vassilakopoulos TP, Boussiotis VA, Fessas P. Clinical approach to lymphadenopathy. Semin Oncol 1993; 20:570-82.
Physical Examination

Pain/Tenderness :The presence or absence of tenderness
does not reliably differentiate benign from malignant nodes.
Consistency: Stony-hard nodes are typically a sign of cancer,
usually metastatic. Very firm, rubbery nodes suggest
lymphoma. Softer nodes are the result of infections or
inflammatory conditions. Suppurant nodes may be fluctuant.
The term "shotty" refers to small nodes that feel like buckshot
under the skin, as found in the cervical nodes of children with
viral illnesses.
Physical Examination

Matting : can be either benign (e.g.,

tuberculosis, sarcoidosis) or malignant (e.g.,
metastatic carcinoma or lymphomas
Location : infectious mononucleosis causes
cervical adenopathy and a number of
sexually transmitted diseases are associated
with inguinal adenopathy
Physical Examination

Supraclavicular lymphadenopathy has the highest risk of

malignancy, estimated as 90 percent in patients older than 40
years and 25 percent in those younger than age.
Lymphadenopathy of the right supraclavicular node is
associated with cancer in the mediastinum, lungs or
The left supraclavicular (Virchow's) node receives lymphatic
flow from the thorax and abdomen, and may signal pathology in
the testes, ovaries, kidneys, pancreas, prostate, stomach or
gallbladder. Although rarely present
Evaluation of Suggestive S & S Associated with Lymphadenopathy

Mononucleosis-type Fatigue, malaise, fever, atypical

syndromes lymphocytosis
Epstein-Barr virus* Splenomegaly in 50% of patients Monospot, IgM EA or VCA
Toxoplasmosis* 80 to 90% of patients are IgM toxoplasma antibody
Cytomegalovirus* Often mild symptoms; patients may IgM CMV antibody, viral
have hepatitis culture of urine or blood
Initial stages of HIV "Flu-like" illness, rash HIV antibody
Cat-scratch disease Fever in one third of patients; cervical Usually clinical criteria; biopsy
or axillary nodes if necessary
Pharyngitis due to group A Fever, pharyngeal exudates, cervical Throat culture on appropriate
streptococcus, nodes medium
Tuberculosis lymphadenitis* Painless, matted cervical nodes PPD, biopsy
Secondary syphilis* Rash RPR
Hepatitis B* Fever, nausea, vomiting, icterus Liver function tests, HBsAg
Lymphogranuloma venereum Tender, matted inguinal nodes Serology

Chancroid Painful ulcer, painful inguinal nodes Clinical criteria, culture

Lupus erythematosus* Arthritis, rash, serositis, renal, neurologic, hematologic Clinical criteria, antinuclear antibodies,
disorders complement levels

Rheumatoid arthritis* Arthritis Clinical criteria, rheumatoid factor

Lymphoma* Fever, night sweats, weight loss in 20 to 30% of patients Biopsy

Leukemia* Blood dyscrasias, bruising Blood smear, bone marrow

Serum sickness* Fever, malaise, arthralgia, urticaria; exposure to antisera Clinical criteria, complement assays
or medications

Sarcoidosis Hilar nodes, skin lesions, dyspnea Biopsy

Kawasaki disease* Fever, conjunctivitis, rash, mucous membrane lesions Clinical criteria
Less common causes of lymphadenopathy

Lyme disease* Rash, arthritis IgM serology

Measles* Fever, conjunctivitis, rash, cough Clinical criteria, serology

Rubella* Rash Clinical criteria, serology

Tularemiala* Fever, ulcer at inoculation site Blood culture, serology

Brucellosis* Fever, sweats, malaise Blood culture, serology

Plague Febrile, acutely ill with cluster of tender nodes Blood culture, serology

Typhoid fever* Fever, chills, headache, abdominal complaints Blood culture, serology

Still's disease* Fever, rash, arthritis Clinical criteria, antinuclear antibody,

rheumatoid factor

Dermatomyositis* Proximal weakness, skin changes Muscle enzymes, EMG, muscle biopsy

Amyloidosis* Fatigue, weight loss Biopsy

*--Causes of generalized lymphadenopathy.

EA=early antibody; VCA=viral capsid antigen; CMV=cytomegalovirus; HIV=human immunodeficiency virus; PPD=purified protein derivative; RPR=rapid plasma reagin; HBsAg=hepatitis B
surface antigen; EMG=electromyelography.
Unexplained Lymphadenopathy

Generalized Lymphadenopathy
almost always indicates a systemic disease is
present, proceed with specific testing as indicated.
If a diagnosis cannot be made, the clinician should
obtain a biopsy of the node.
The diagnostic yield of the biopsy can be maximized
by obtaining an excisional biopsy of the largest and
most abnormal node
The physician should not select inguinal and axillary
nodes for biopsy, since they frequently show only
reactive hyperplasia
Unexplained Lymphadenopathy

Localized Lymphadenopathy

The decision about when to biopsy is more difficult.

Patients with a benign clinical history, an unremarkable
physical examination and no constitutional symptoms
should be reexamined in three to four weeks to see if the
lymph nodes have regressed or disappeared.
Patients with unexplained localized lymphadenopathy who
have constitutional symptoms or signs, risk factors for
malignancy or lymphadenopathy that persists for three to
four weeks should undergo a biopsy.
Unexplained Lymphadenopathy

Localized Lymphadenopathy
Biopsy should be avoided in patients with
probable viral illness because lymph node
pathology in these patients may
sometimes simulate lymphoma and lead
to a false-positive diagnosis of
Risk factors for NHL

immunosuppression or immunodeficiency
connective tissue disease
family history of lymphoma
infectious agents
ionizing radiation
A practical way to think of lymphoma

Category Survival of Curability To treat or

untreated not to treat

Non- Indolent Years Generally Generally

Hodgkin not curable defer Rx if
lymphoma asymptomatic
Aggressive Months Curable in Treat

Very Weeks Curable in Treat

aggressive some

Hodgkin All types Variable Curable in Treat

lymphoma months to most
Diagnosis requires an adequate

Diagnosis should be biopsy-proven

before treatment is initiated
Need enough tissue to assess cells and
open bx vs core needle bx vs FNA
Staging of lymphoma
Stage I Stage II Stage III Stage IV

A: absence of B symptoms
B: fever, night sweats, weight loss
Case: M.S.

25 year old woman

persistent dry cough
fever, NS, weight loss x 3 months
left cervical lymphadenopathy (2 cm)
left supraclavicular node (2 cm)
no splenomegaly
M.S. at presentation
M.S. at presentation
Case: M.S. differential diagnosis

lung cancer
other neoplasms: thyroid, germ cell
non-neoplastic causes less likely
sarcoid, TB, ...
What next?

Needle aspirate of LN: a few necrotic cells

Needle biopsy of LN: admixture of B- and T-
lymphocytes. A few atypical cells.
Case: M.S. lymph node biopsy
Case: M.S. lymph node biopsy
Case: M.S. staging investigations

CT chest / abdo / pelvis

bone marrow
gallium scan
Blood work: normal
Staging Investigations

bone marrow normal

CT scan: L supraclavicular adenopathy; large
mediastinal mass; R hilum; no disease below
gallium avid
What is her diagnosis and stage?

nodular sclerosis HD
stage IIB
with bulky mediastinal mass