YEDITEPE UNIVERSITY MEDICAL FACULTY APPROACH TO THE PATIENT WITH LYMPHADENOPATHY Assoc. Prof. Dr. Hülya AKAN

Objectives Approach to Adenopathy Who to investigate When to investigate How to define risk for underlying malignancy

DEFINITION Lymph node size depends on the person's age, the location of the lymph node in the body, and antecedent immunological events. In neonates, lymph nodes are barely perceptible, but a progressive increase in total lymph node mass is observed until later childhood. Lymph node atrophy begins during adolescence and continues through later life.

Lymph Nodes Anatomy Collection of lymphoid cells attached to both vascular and lymphatic systems Over 600 lymph nodes in the body Function To provide optimal sites for the concentration of free or cell-associated antigens and recirculating lymphocytes – “sensitization of the immune response” To allow contact between B-cells, T-cells and macrophages Lymphadenopathy - node greater than 1cm in size

Why do lymph nodes enlarge? Increase in the number of benign lymphocytes and macrophages in response to antigens Infiltration of inflammatory cells in infection (lymphadenitis) In situ proliferation of malignant lymphocytes or macrophages Infiltration by metastatic malignant cells Infiltration of lymph nodes by metabolite laden macrophages (lipid storage diseases)

Epidemiology 0.6% annual incidence of unexplained adenopathy in the general population 10% were referred to a subspecialist and 3.2 % required a biopsy and 1.1% had a malignancy

When to worry? Age Characteristics of the node Location of the node Clinical setting associated with lymphadenopathy

Age Children/young adults – more likely to respond to minor stimuli with lymphoid hyperplasia Lymph nodes in patients less than the age of 30 are clinically benign in 80% of cases whereas in patients over the age of 50 only 40% are benign Biopsies done in patients less than 25 yrs have a incidence of malignancy of <20% vs the over-50 age group has an incidence of malignancy of 55-80%

Characteristics of the node Nodes lasting less than 2 weeks or greater than one year with no progression of size have a low likelihood of being neoplastic – excludes low grade lymphoma Cervical nodes – up to 56% of young adults have adenopathy on clinical exam Inguinal adenopathy is common – up to 1-2 cm in size and often benign reactive nodes

Characteristics of the node Consistency – Hard/Firm vs Soft/Shotty; Fluctuant Mobile vs Fixed/Matted Tender vs Painless Clearly demarcated Size When to worry – 1.5-2cm in size Epitroclear nodes over 0.5cm; Inguinal over 1.5cm Duration and Rate of Growth

Location of the node Supraclavicular lymphadenopathy Highest risk of malignancy – estimated as 90% in patients older than 40 years vs 25% in those younger than 40 yrs Right sided node – cancer in mediastinum, lungs, esophagus Left sided node (Virchow’s) – testes, ovaries, kidneys, pancreas, stomach, gallbladder or prostate Paraumbilical node (Sister Joseph’s) Abdominal or pelvic neoplasm

Location of the node Epitroclear nodes Isolated inguinal adenopathy Unlikely to be reactive Isolated inguinal adenopathy Less likely to be associated with malignancy

Clinical Setting B symptoms – fever, night sweats, weight loss Fatigue Pruritis Evidence of other medical conditions – connective tissue disease Young patient – mononucleosis type of syndrome

History Identifiable cause for the lymphadenopathy? Localizing symptoms or signs to suggest infection/neoplasm/trauma at a particular site URTI, pharyngitis, periodontal disease, conjunctivitis, insect bites, recent immunization etc Constitutional symptoms Epidemiological clues Occupational exposures, recent travel, high-risk behaviour Medications – serum-sickness syndrome

Physical Exam Full nodal examination – nodal characteristics Organomegaly Localized – examine area drained by the nodes for evidence of infection, skin lesions or tumours

Physical Examination When lymphadenopathy is localized, the clinician should examine the region drained by the nodes for evidence of infection, skin lesions or tumors Careful palpation of the submandibular, anterior and posterior cervical, supraclavicular, axillary and inguinal nodes can be accomplished in a short time and will identify patients with generalized lymphadenopathy.

Physical Examination If lymph nodes are detected, the following five characteristics should be noted and described: 1-Size : Nodes are generally considered to be normal if they are up to 1 cm in diameter however, some authors suggest that epitrochlear nodes larger than 0.5 cm or inguinal nodes larger than 1.5 cm should be considered abnormal 2-Pain/Tenderness: When a lymph node rapidly increases in size, its capsule stretches and causes pain. The presence or absence of tenderness does not reliably differentiate benign from malignant nodes.

Physical Examination 3-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. 4- Matting : A group of nodes that feels connected and seems to move as a unit is said to be "matted." Nodes that are matted can be either benign (e.g., tuberculosis, sarcoidosis or lymphogranuloma venereum) or malignant (e.g., metastatic carcinoma or lymphomas).

Physical Examination 5- Location : The anatomic location of localized adenopathy will sometimes be helpful in narrowing the differential diagnosis. For example, cat-scratch disease typically causes occipital adenopathy, infectious mononucleosis causes cervical adenopathy and a number of sexually transmitted diseases are associated with inguinal adenopathy

Physical Examination In patients with generalized lymphadenopathy, the physical examination should focus on searching for signs of systemic illness. The most helpful findings are rash, mucous membrane lesions, hepatomegaly, splenomegaly or arthritis Splenomegaly and lymphadenopathy occur concurrently in many conditions, including mononucleosis-type syndromes, lymphocytic leukemia, lymphoma and sarcoidosis.

Approach to Lymphadenopathy In most cases, a careful history and physical examination will identify a readily diagnosable cause of the lymphadenopathy, such as upper respiratory tract infection, pharyngitis, periodontal disease, conjunctivitis, lymphadenitis, tinea, insect bites, recent immunization, cat-scratch disease or dermatitis, and no further assessment is necessary

Approach to Lymphadenopathy Localized – one area involved Generalized – two or more non-contiguous areas

Generalized Lymphadenopathy Malignancy – lymphoma, leukemia, Kaposi’s sarcoma, metastases Autoimmune – SLE, RA, Sjogren’s syndrome, Still’s disease, Dermatomyositis Infectious – Brucellosis, Cat-scratch disease, CMV, HIV, EBV, Rubella, Tuberculosis, Tularemia, Typhoid Fever, Syphilis, viral hepatitis, Pharyngitis Other – Kawasaki’s disease, sarcoidosis, amyloidosis, lipid storage diseases, hyperthyroidism, necrotizing lymphadenitis, histiocytosis X, Castlemen’s disease

Drugs Allopurinol Atenolol Captopril Carbamazepine Gold Hydralazine Penicillins Phenytoin Primidone Pyrimethamine Quinidine Trimethoprim/Sulfamethozole Suldinac

Management Identify underlying cause and treat as appropriate – confirmatory tests Generalized adenopathy – usually has identifiable cause Localized adenopathy 3-4 week observation period for resolution if not high clinical suspicion for malignancy Biopsy if risk for malignancy - excisional

Fine Needle Aspirate Convenient, less invasive, quicker turn-around time Most patients with a benign diagnosis on FNA biopsy do not undergo a surgical biopsy

Confirmatory tests CBC count, including a careful evaluation of the peripheral blood smear. An erythrocyte sedimentation rate is nonspecific but may be helpful. Evaluation of hepatic and renal function and a urine analysis are useful to identify underlying systemic disorders Additional studies, such as lactate dehydrogenase (LDH), uric acid, calcium, and phosphate, may be indicated if malignancy is suspected.

Skin testing for tuberculosis is usually indicated Titers for specific microorganisms may be indicated, particularly if generalized adenopathy is present. These may include Epstein-Barr virus, CMV, Toxoplasma species, and HIV.

Chest radiography is usually the primary screening imaging study Supraclavicular adenopathy, with its high associated rate of serious underlying disease, may be an indication for other studies, including CT scanning of the chest, abdomen, or both. Nuclear medicine scanning is helpful in the evaluation of lymphomas Ultrasonography may be helpful in evaluating the changes in the lymph nodes and in evaluating the extent of lymph node involvement in patients with lymphadenopathy.

Conclusions Lymphadenopathy – initial presenting symptom Reactive vs Malignant Probability History Physical Exam Biopsy if not resolved in 3-4 weeks for low risk patients Biopsy all high risk patients – excisional biopsy

Epidemiologic Clues to the Diagnosis of Lymphadenopathy General Cat Undercooked meat Tick bite Tuberculosis Recent blood transfusion or transplant High-risk sexual behavior Intravenous drug use Cat-scratch disease, toxoplasmosis Toxoplasmosis Lyme disease, tularemia Tuberculous adenitis Cytomegalovirus, HIV HIV, syphilis, herpes simplex virus, cytomegalovirus, hepatitis B infection HIV, endocarditis, hepatitis B infection

Epidemiologic Clues to the Diagnosis of Lymphadenopathy Occupational Hunters, trappers Fishermen, fishmongers, slaughterhouse workers Tularemia Erysipeloid

Epidemiologic Clues to the Diagnosis of Lymphadenopathy Travel-related Arizona, southern California, New Mexico, western Texas Southwestern United States Southeastern or central United States Southeast Asia, India, northern Australia Central or west Africa Central or South America East Africa, Mediterranean, China, Latin America Mexico, Peru, Chile, India, Pakistan, Egypt, Indonesia Coccidioidomycosis Bubonic plague Histoplasmosis Scrub typhus African trypanosomiasis (sleeping sickness) American trypanosomiasis (Chagas' disease) Kala-azar (leishmaniasis) Typhoid fever