This document discusses lymphadenopathy and provides information about evaluating and diagnosing causes of lymphadenopathy. It begins by defining lymphadenopathy and describing classifications such as localized versus generalized. For patients presenting with unexplained lymphadenopathy, approximately 3/4 will have localized lymphadenopathy while 1/4 will have generalized. The document then discusses evaluating the history, performing a physical exam, potential causes of lymphadenopathy, and guidelines for biopsy of localized versus generalized lymphadenopathy. It also provides a case study of a patient, M.S., who presented with lymphadenopathy and was ultimately diagnosed with Stage IIB nodular sclerosis Hodgkin's lymphoma.

1. Lymphadenopathy
Soheir Adam , MD, MSc, MRCPath

2. 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.

3.  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
lymphadenopathy.

5. Lympahdenopathy
 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.

7. Lymphadenopathy

8. History
 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
malignancy?

9. History
 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.

10. Medications That May Cause Lymphadenopathy
Allopurinol (Zyloprim)
Atenolol (Tenormin)
Captopril (Capozide)
Carbamazepine (Tegretol)
Cephalosporins
Gold
Hydralazine (Apresoline)
Penicillin
Phenytoin (Dilantin)
Primidone (Mysoline)
Pyrimethamine (Daraprim)
Quinidine
Sulfonamides
Sulindac (Clinoril)
Adapted with permission from Pangalis GA, Vassilakopoulos TP, Boussiotis VA, Fessas P. Clinical approach to lymphadenopathy. Semin Oncol 1993; 20:570-82.

11. Physical Examination
 Size.
 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.

12. 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

13. 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
esophagus.
 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

14. Evaluation of Suggestive S & S Associated with Lymphadenopathy
Mononucleosis-type
syndromes
Fatigue, malaise, fever, atypical
lymphocytosis
Epstein-Barr virus* Splenomegaly in 50% of patients Monospot, IgM EA or VCA
Toxoplasmosis* 80 to 90% of patients are
asymptomatic
IgM toxoplasma antibody
Cytomegalovirus* Often mild symptoms; patients may
have hepatitis
IgM CMV antibody, viral
culture of urine or blood
Initial stages of HIV
infection*
"Flu-like" illness, rash HIV antibody
Cat-scratch disease Fever in one third of patients; cervical
or axillary nodes
Usually clinical criteria; biopsy
if necessary
Pharyngitis due to group A
streptococcus,
gonococcus
Fever, pharyngeal exudates, cervical
nodes
Throat culture on appropriate
medium
Tuberculosis lymphadenitis* Painless, matted cervical nodes PPD, biopsy
Secondary syphilis* Rash RPR
Hepatitis B* Fever, nausea, vomiting, icterus Liver function tests, HBsAg

15. Lymphogranuloma venereum Tender, matted inguinal nodes Serology
Chancroid Painful ulcer, painful inguinal nodes Clinical criteria, culture
Lupus erythematosus* Arthritis, rash, serositis, renal, neurologic, hematologic
disorders
Clinical criteria, antinuclear antibodies,
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
or medications
Clinical criteria, complement assays
Sarcoidosis Hilar nodes, skin lesions, dyspnea Biopsy
Kawasaki disease* Fever, conjunctivitis, rash, mucous membrane lesions Clinical criteria

16. 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.

17. 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

18. 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.

19. 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
malignancy.

20. Lymphoma

21. Risk factors for NHL
 immunosuppression or immunodeficiency
 connective tissue disease
 family history of lymphoma
 infectious agents
 ionizing radiation

22. A practical way to think of lymphoma
Category Survival of
untreated
patients
Curability To treat or
not to treat
Non-
Hodgkin
lymphoma
Indolent Years Generally
not curable
Generally
defer Rx if
asymptomatic
Aggressive Months Curable in
some
Treat
Very
aggressive
Weeks Curable in
some
Treat
Hodgkin
lymphoma
All types Variable –
months to
years
Curable in
most
Treat

23. Diagnosis requires an adequate
biopsy
 Diagnosis should be biopsy-proven
before treatment is initiated
 Need enough tissue to assess cells and
architecture
– open bx vs core needle bx vs FNA

24. Stage I Stage II Stage III Stage IV
Staging of lymphoma
A: absence of B symptoms
B: fever, night sweats, weight loss

25. 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

26. M.S. at presentation

27. M.S. at presentation

28. Case: M.S. differential diagnosis
 lymphoma
– Hodgkin
– non-Hodgkin
 lung cancer
 other neoplasms: thyroid, germ cell
 non-neoplastic causes less likely
– sarcoid, TB, ...

29. What next?
 Needle aspirate of LN: a few necrotic cells
 Needle biopsy of LN: admixture of B- and T-
lymphocytes. A few atypical cells.

30. Case: M.S. lymph node biopsy

31. Case: M.S. lymph node biopsy

32. Case: M.S. staging investigations
 CT chest / abdo / pelvis
 bone marrow
 gallium scan
 Blood work: normal

33. Staging Investigations
 bone marrow normal
 CT scan: L supraclavicular adenopathy; large
mediastinal mass; R hilum; no disease below
diaphragm
 gallium avid

34. What is her diagnosis and stage?
 nodular sclerosis HD
 stage IIB
 with bulky mediastinal mass