Approach to Lymphadenopathy PROF:AKMAL JAMAL FCPS;FRCSEd: 2013

Case 41 yo male school teacher presents to your office with right sided cervical lymphadenopathy. His past medical history is significant for hypertension and dyslipidemia. He noticed the lump in his neck last week. He has not experienced any fevers, chills or weight loss. He denies any sore throat, ear pain or dental problems. His vital signs are stable. On physical exam he has a 2cm anterior cervical lymph node which is firm, non-tender and mobile. His HEENT exam is unremarkable. No skin lesions are evident. No other lymphadenopathy is found. How should you proceed with this patient? Location and duration typical for viral etiology. Have your patient follow up for annual physical next year. Proceed to fine needle aspiration. Check a CXR and cbc. Have patient follow up in 3-4 weeks.

Learning Objectives Provide an approach to the patient with peripheral lymphadenopathy Be able to differentiate between benign and serious illness Knowledgeable of nodal distribution and anatomic drainage Present a substantial differential diagnosis Indications for nodal biopsy

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

Definition: Lymphadenopathy Lymph nodes that are abnormal in size consistency or number characterized

Definitions Pathologic Lymph Node Acute Lymphadenopathy >2cm in children is considered abnormal Acute Lymphadenopathy < 2 weeks duration Subacute Lymphadenopathy 2-6 weeks duration Chronic Lymphadenopathy > 6 weeks duration

Classification: Lymphadenopathy Generalized- if lymph nodes are enlarged in two or more noncontiguous areas Localized- if only one area is involved. characterized

Distinguishing between two is important in formulating a differential diagnosis. 3/4 of patients will present with localized lymphadenopathy 1/4 with generalized lymphadenopathy.

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)

Normally palpable lymph nodes in healthy people? The Lymphatic System Normally palpable lymph nodes in healthy people?

submandibular, axillary inguinal The Lymphatic System Normally palpable lymph nodes in healthy people. submandibular, axillary inguinal

Lymphatic System

Lymphatic System Network that filters antigens from the interstitial fluid Primary site of immune response from tissue antigens Lymphatic drainage in all organs of the body except brain, eyes, marrow and cartilage Flaccid thin walled channelsprogressive caliber 600 lymph nodes in body Slow flow, low pressure system returns interstitial fluid to the blood system Primary site of immune response from tissue antigens

Lymph nodes Capsular shell Fibroblasts and reticulin fibers Macrophages Dendritic cells T cells B cells Immune response: flow of blood and lymph can increase as much as 25X can swell up to 15X normal size Invasion by malignant cells or propagation of an inflammatory process

anatomy Each lymph node is a bean shaped organ, with an outer connective issue frame work, which dips into the structure forming numerous septa. Node has an outer convex surface and an inner concave surface- the Hilum Afferent vessels enter. Efferent vessels exit Blood vessels

HISTOLOGY CORTEX: MEDULLA: TWO ZONES: A darkly staining cortex And a lightly staining medulla CORTEX: Several rounded areas { lymphatic follicles} Paler germinal center which contain actively dividing B-lymphocytes. The para-follicular area contains T-lymphocytes MEDULLA: Lymphocytes arranged less densely in the form of cords along the reticular network Sinusoids are present for free flow of lymph

Lymph passing through these sinuses comes in intimate contact with macrophages & lymphocytes present in the node. Bacteria and other particulate matter present in the lymph are filtered by these cells

function They are centers of lymphocyte production. Both B-lymphocytes and T-lymphocytes are produced here by multiplication of pre-existing lymphocytes. Filter the products from lymph such as bacteria and other particulate matter and to prevent their entry into systemic circulation. The antibodies produced by the B-Lymphocytes are carried to the circulation… and indirectly help in mounting an immune response.

Peripheral lymphadenopathy Most cases benign, self limited illness Primary or secondary manifestation of 100 illnesses The CHALLENGE is to decide if it is representative of a serious illness… Invasion by malignant cells or propagation of a inflammatory process

Parameters to help distinguish between benign and serious illness Age Character Location

“Malignancy much more common in patients greater 50 yrs of age” Not exactly

Algorithm to evaluate Lymphadenopathy History Physical exam Confirmatory testing Indication for biopsy

History Localizing symptoms or signs to suggest a specific site Constitutional symptoms: B symptoms (fever, night sweats, >10%body wt >6months) Epidemiologic clues: occupation, travel, high risk behavior Medications

Medications That May Cause Lymphadenopathy Allopurinol Atenolol (Tenormin) Captopril (Capozide) Carbamazepine Cephalosporins Gold Hydralazine Penicillin Phenytoin Primidone Pyrimethamine Quinidine Sulfonamides Sulindac

Physical Examination

Lymph node character Size Site Consistency Pain with palpation Picture of lymph node sites

Size Greater than one centimeter generally considered abnormal Exception inguinal area, lymph nodes commonly palpated (>1.5 cm) Size does not indicate a specific disease process Obese and thin population

Pain….. Indication of rapid increase in size: stretch of capsular shell NOT useful in determining benign vs malignant state Inflammation, suppuration, hemorrhage

Consistency Stone hard: typical of cancer usually metastatic Firm rubbery: can suggest lymphoma Soft: infection or inflammation Shotty “buckshot under skin” Suppurated nodes: fluctuant Matted

Location, location, location

Post cervical: scalp, neck skin of arms thorax cervical and axillary nodes (lymphoma, head/neck ca)

Facial Papule with Adenopathy

Suppurative Lymphadenitis with Overlying cellulitis

Mycobacterial Lymphadenitis

Mycobacterial Lymphadenitis

Famous nodes Virchows Left supraclavicular (abdominal or thoracic ca) Sister Joseph Para-umbilical (gastric adenoca) Delphian node Prelaryngeal (thyroid or laryngeal ca) Node of Cloquet (Rosenmuller node) Deep inguinal near femoral canal Surgeon William J Mayo’s Scrub nurse predict the findings when scrubbing abdomen preoperatively

Creating a Differential CHICAGO

Causes It results from a vast array of disease processes whose broad categories are easily recalled using the mnemonic “MIAMI” representing Malignancies, Infections, Autoimmune disorders, Miscellaneous and unusual conditions, and Iatrogenic causes.

Chicago Cancer Heme malignancies: Hodgkins, NHL, acute and chronic leukemias, waldenstroms, multiple myeloma (plastmocytomas) Metastatic: solid tumor breast, lung, renal, cell ovarian

cHicago Hypersensitivity syndromes Serum sickness Serum sickness like illness Drugs Silicone Vaccination Graft vs Host Serum sickness TYPE III immune complex mediated antibody antigen and complement cascade (horse serum to treat diptheria) humoral response to foreign protein

Specific Medications Cephalosporins Atenolol Captopril Dilantin Sulfonamides Carbamazepine Primodine Gold Allupurinol Believed to be caused by a different mechanism which is NOT classical serum sickness…delayed reaction to above

Chicago Infections Viral Bacterial Protozoan Mycotic Rickettsial (typhus) Helminthic (filariasis)

VIRAL EBV…mono spot test CMV….cmv titers, immunsuppresed, transplant recipient, recent blood transfusion HIV…IV drug use, high risk sexual behavior Hepatitis….IV drug use Herpes Zoster….superficial cutaneous nodules

Bacterial Staph/strep: cutaneous source, lymphadenitis Cat scratch: bartonella hensalae, two weeks after inoculation Mycobacterium: TB and non-tb, host characteristics (HIV, foreign born, low socioeconomic status, homeless) Cat scratch (bite, scratch or flea bite): two weeks after inoculation Half of tb (Mexico, Philippines, Vietnam, India, china)

Lt cat scratch Rt lympahdenitis with suppuration

Spirochete Syphilis: Treponema pallidum Primary localized inguinal lymph nodes and secondary, non-treponemal, treponemal Lyme disease

Protozoan Toxoplasmosis: ELISA assay, intracellular protozoan toxoplasmosis gondii….bilateral, symmetrical, non-tender cervical adenopathy …consider undercooked meat, reactivation in immuncompromised host Felines protozoan completes reproductive cycle: oocytes in feces, ingested by humans other animals : predominately undercooked meat, invade gi epithelium and lie dormant in neural and muscular tissue, 10% adults are seropositive

chicago Connective Tissue Disease Rheumatoid Arthritis SLE Dermatomyositis Mixed connective tissue disease Sjogren Arthralgias, skin manifestations

chicago Atypical lymphoproliferative disorders Castleman’s disease Wegeners Angioimmuonplastic lymphadenopathy with dysproteinemia Lymphoprolifertative disorder (associatin with HIV and HHV-8) localized no systemic symptoms and systemic fevers night sweats Multicentric form

chicaGo Granulomatous Histoplasmosis Mycobacterial infections Cryptococcus Silicosis: coal, foundry, ceramics, glass Berylliosis: metal, alloys Cat Scratch

OTHER…….chicago RARE Kikuchi Rosia Dorfman Kawasaki Transformation of germinal centers Young woman painless lymphadenopathy unilateral in cervical region resolves in 3 months unknown etiology: histiocytic necrotiziing lympadenitis RD: greatly exaggerated lymph node reaction children bl cervical lymph node

Non-Infectious Lymphadenopathy

Kawasaki Disease Lymphomucocutaneous Disease Five Characteristics of Disease (4/5 for diagnosis) Fever >5 days Cervical lymphadenopathy (usually unilateral) Erythema and edema of palms and soles with desquamation of skin Nonpurulent Bilateral Conjunctivitis Strawberry Tongue Treatment IVIG and Aspirin

Systemic Manifestations of Kawasaki Disease

Kikuchi-Fujimoto disease Also known as necrotizing lymphadenitis Benign condition Affects young Japanese girls Associated Signs and Symptoms Fever Nausea Weight loss Night Sweats Arthralgias Hepatosplenomegaly Thought to have viral or autoimmune etiology The majority spontaneously regress within 6 months, however some patients have recurrences

Rosai-Dorfman Massive, painless, bilateral cervical adenopathy Benign condition Generalized proliferation of sinusoidal histiocytes First decade of life with 2M:1F Associated signs and symptoms Fever Neutrophilic leukocytosis Polyclonal hypergammaglobulinemia Most patients will get a biopsy given the large adenopathy Characteristic biopsy showing sinus expansion with histiocytes and phagocytosed lymphocytes (Foucar 1990) Treatment is supportive and most patients have spontaneous regression

Rosai-Dorfman Lymphadenopathy

Langerhans Cell Histiocytosis Eosinophilic Granuloma Solitary bone, skin, lung, or stomach lesions Hands-Schuller-Christian Disease Diabetes Insipidus, Exophthalmos, Lytic bone lesions Letterer-Siwe disease Life threatening multisystem disorder 50% 5 year survival 1/3 of patients will have background LAD Histopathology shows normal lymph node architecture but increase sinusoidal Langerhans’ cells, macrophages, and eosinophils Treatment with topical steroids, oral steroids, and even chemoradiation therapy

Investigations Unexplained lymphadenopathy without signs or symptoms of serious disease or malignancy can be observed for one month, after which specific imaging or biopsy should be performed fine-needle aspiration, excisional biopsy remains the initial diagnostic procedure of choice. Modern cross-sectional imaging modalities such as ultrasound (US), computed tomography (CT) and magnetic resonance (MR) imaging allow reliable detection of cervical lymph nodes. However, the differentiation between benign and malignant lymph nodes remains challenging Alternative imaging modalities such as single photon emission computed tomography (SPECT) and positron emission tomography (PET) can help to differentiate between benign and malignant lymph nodes

Wait 3-4 weeks and reexamine No indication for empiric antibiotics or steroids Glucorticoids can be harmful and delay diagnosis can obscure diagnosis due to lympholytic affect

Unexplained Generalized lymphadenopathy Always requires an evaluation Start with CXR and CBC Review Medications PPD, RPR, Hepatitis screen, ANA, HIV No yield on above test: Biopsy most abnormal node

Role of Ultrasound No radiation exposure Good for following the progress of an abscess Differentiate Reactive vs Malignant nodes Reactive <1 cm Oval (S/L ratio <0.5cm) Normal hilar vascularity Low resistive index with high blood flow Malignant >1 cm Round (S/L ratio >0.5cm) No echogenic hilus Cogaulative necrosis present High resistive index with low blood flow Extracapsular spread Sensitivity 95% and Specificity 83% for differentiating reactive vs metastatic lymph nodes

The Role of FNA Minimally invasive Low morbidity Not as reliable in children as in adults so you can only trust FNA if it is positive (Twist 2000) Chau et al. 2003 Evaluated FNA of 289/550 patients referred with LAD Sensitivity 49% and Specificity of 97% False negative rate of 45% 83% of false negatives were lymphomas

The Role of Excisional Biopsy Still the gold standard for diagnosis Consider if FNA is inconclusive or if FNA is negative but your suspicion for malignancy is high You must excise the largest and firmest node that is palpable and must remove the node with the capsule intact (Twist 2000)

BIOPSY Can be done by bedside, open surgery, mediastinocopy or by needle aspiration* FNA not recommended cannot distinguish between lymphomas (nodal architecture needs to be intact) FNA reserved for established diagnosis and to demonstrate recurrence

Diagnostic Yield Ideally axillary and inguinal nodes are avoided as often demonstrate reactive hyperplasia Preferred supraclavicular, cervical, axillary, epitrochlear, inguinal Complications include vascular and nerve injury

Unexplained Lymphadenopathy Localized Lymphadenopathy When to biopsy ?

Unexplained Lymphadenopathy Localized Lymphadenopathy Patients with benign clinical history, an unremarkable physical examination no constitutional symptoms should be reexamined in three to four weeks to see if the lymph nodes have regressed or disappeared.

Unexplained Lymphadenopathy Localized Lymphadenopathy 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.

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

Case 41 yo male school teacher presents to your office with right sided cervical lymphadenopathy. His past medical history is significant for hypertension and dyslipidemia. His medications include hctz and simvastatin. He has no known drug allergies. He believes he noticed the lump in his neck last week. He has not experienced any fevers, chills or weight loss. He denies a sore throat, ear pain or dental problems. His vital signs are stable. On physical exam he has a 2cm anterior cervical lymph node which is firm, non-tender and mobile. His HEENT exam is unremarkable. No skin lesions are evident. No other lymphadenopathy is found. How should you proceed with this patient? Location and duration typical for viral etiology. Have your patient follow up for annual physical next year. Proceed to fine needle aspiration Check a CXR and cbc Have patient follow up in 3-4 weeks.