Lymphadenopathy

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 lymphadenopathy.

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.

Lymphadenopathy

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?

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.

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.

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.

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 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

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

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

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 malignancy.

Lymphoma

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 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

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

Stage I Stage II Stage III Stage IV

Staging of lymphoma

A: absence of B symptomsB: 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

lymphoma– Hodgkin– non-Hodgkin

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 diaphragm

gallium avid

What is her diagnosis and stage?

nodular sclerosis HD stage IIB with bulky mediastinal mass