1. Soheir Adam , MD, MSc, MRCPath
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:

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
Test
Associated findings
Disorder
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
Kawasaki disease*
Fever, conjunctivitis, rash, mucous membrane lesions
Clinical criteria

16. Lyme disease* Measles* Rubella* Tularemiala* Brucellosis* Plague
Less common causes of lymphadenopathy
Lyme disease*
Rash, arthritis
IgM serology
Measles*
Fever, conjunctivitis, rash, cough
Clinical criteria, serology
Rubella*
Rash
Tularemiala*
Fever, ulcer at inoculation site
Blood culture, serology
Brucellosis*
Fever, sweats, malaise
Plague
Febrile, acutely ill with cluster of tender nodes
Typhoid fever*
Fever, chills, headache, abdominal complaints
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
Hodgkin lymphoma
All types
Variable – months to years
Curable in most

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. Staging of lymphoma Stage I Stage II Stage III Stage IV
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