Soheir Adam , MD, MSc, MRCPath 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 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

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

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.

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 Hodgkin lymphoma All types Variable – months to years Curable in most

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

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 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