Lymphadenopathy Differential Diagnosis Steven W. Corso M.D. 12 march 2013 This is more of an organ system that multiple disease affect rather than a disease process

Lymphadenopathy Outline and Objectives Brief overview of the Lymphatic System Anatomy Physiology Clinical approach to the patient with adenopathy Localized vs generalized Develop a Differential Diagnosis Examine common/important causes of lymphadenopathy

Lymphadenopathy Lymphatic System Anatomy A component of the circulatory system composed of: small caliber vessels (lymphatic vessels) Lymph nodes We have hundreds Lymphoid tissue Spleen, thymus, bone marrow, lymphoid follicles a bunch of pts that present with lymphoma present out side of the lymph system proper with a bunch of lymph follicles elsewhere (such as the gut) = extranodal lymphomas

Lymphadenopathy Lymphatic System Physiology Network of conduits and specialized tissue with several key functions: Allows for return of fluid (lymph) to enter back into the circulatory system Liters of plasma filtered out of the capillaries daily. Most reabsorbed in blood vessels and returns via venous circulation but several liters/day left in interstitial space Accessory route for this fluid to be returned to blood Immunologically important for mobilization of WBC (lymphocytes) and filtering of antigens Most lymph enters the circulatory system through the thoracic duct

Lymphadenopathy Lymphatic System Lymphatic fluid enters the lymph node in the afferent vessel, traverses the node to exit via efferent vessel Lymph is exposed to immunologically active cells throughout the node which provide antigen processing/ presentation/recognition and proliferation of effector B and T lymphocytes

Lymphadenopathy Lymphatic System Vascular System Lymphatic System

Lymphadenopathy Lymphatic System Normal immune response leads to proliferation and expansion of cellular components of lymph nodes  lymph node enlargement Children are constantly undergoing exposure to new antigens and lymphadenopathy is the rule not the exception Lymph node swelling happens in kids all the time  just a normal, natural process of them being exposed to immune shit

Lymphadenopathy Introduction Common clinical finding and often presents a diagnostic dilemma Multiple etiologies Lymphadenopathy can be caused by a vast array of diseases and drugs Some nodal presentations suggest a specific disease process Some diseases present predominantly with adenopathy

Lymphadenopathy Diagnostic Approach History and Physical Examination Etiology is often obvious after complete H&P History Age: cervical adenopathy in a child much less worrisome than 60 yo smoker Symptoms of malignancy or infection: Fever, night sweats or weight loss Duration: Acute (days) vs chronic (weeks-months) Exposures associated with infection Cat scratch (cat scratch disease) Undercooked meat (toxoplasmosis) Tick bite (Lyme disease) Travel to endemic areas High risk behavior (IV drugs or sexual behavior) ROS for other systemic illnesses Medications

Lymphadenopathy Diagnostic Approach Medications A number of meds can cause serum sickness m/b fever, arthralgias, rash and generalized adenopathy Phenytoin associated with generalized adenopathy in absence of a serum sickness reaction Sounds like a good test question to me

Lymphadenopathy Diagnostic Approach Physical Examination Evidence of local infectious process Open wound or sore Pharyngitis/ vaginitis Focus on other signs of systemic illness Splenomegaly Cutaneous findings

Lymphadenopathy Diagnostic Approach Extent of Disease Distinguishing between localized and generalized lymphadenopathy can help to formulate a differential diagnosis A clinically useful approach is to classify lymphadenopathy as localized when it involves only one region such as the neck or axilla, and generalized when it involves more than one region Cannot see some nodes on gen exam such as intra-abdominal or intra-thoracic

Lymphadenopathy Diagnostic Approach Physical Examination Lymph nodes Location - Localized Cervical: commonly encountered due to high visibility and prevalence of infections affecting head and neck region. Inflamed nodes appearing over few days with fluctuation typically staph/strep Hard nodes in smoker is cancer till proven otherwise Epitrochlear: never palpable so if present always represents pathologic process Supraclavicular: more often associated with malignancy Axillary: drain multiple areas – cancer often found in absence of upper extremity lesions Also a common place for infectious process Inguinal: frequent finding usually due to lower extremity infection, STD or cancer Cervical lymph nodes – likely the most common you will encounter on clinical practice Most people just viral illness that causes the snots  will pop up a node in a few days If the nodes come and go (fluctuate) and have fever  think more bacterial  staph/strep KNOW THE DIFFERENCE BETWEEN NODES THAT ARE LOCALIZED OR GENERALIZED

Lymphadenopathy Diagnostic Approach Physical Examination Lymph nodes Location – Generalized Predominant feature of a number of systemic illnesses. Some common or especially important diseases include: HIV: nontender nodes primarily involving the axillary cervical and occipital nodes seen with initial infection Mycobacterial infection: can present with adenopathy alone – neck (scrofula); usually nontender and noted to enlarge over weeks-months Infectious mononucleosis: typically symmetric cervical (posterior) nodes associated with fever and pharyngitis Systemic lupus erythematosus: seen in 50% of patients; typically non tender discrete cervical, axillary and inguinal nodes Anyone with chronic illness, and their lymph nodes change out of proportion to the disease state  worry about cancer KNOW THE DIFFERENCE BETWEEN NODES THAT ARE LOCALIZED OR GENERALIZED

Lymphadenopathy Diagnostic Approach Physical Examination Lymph nodes Location Size (Does matter) < 1 cm rarely malignant In one series, no patient with a lymph node smaller than 1 cm2 had cancer, compared with 8 and 38 percent of those with nodes 1 to 2.25 and greater than 2.25 cm2 “Shotty” used to describe multiple small nodes but has no particular diagnostic significance Consistency Hard  post inflammatory fibrosis/sclerosis or solid tumors Ex. Pancreatic and met breast cancer  hard and usually fixed nodes Firm/rubbery  hematologic malignancy Soft  inflammatory or infectious Fixation: freely mobile or matted/fixed to surrounding tissue/nodes Ex. Seen with met or neglected breast cancer Tenderness: typical for inflammatory processes Malignant nodes are rarely tender No one cares about - In one series, no patient with a lymph node smaller than 1 cm2 had cancer, compared with 8 and 38 percent of those with nodes 1 to 2.25 and greater than 2.25 cm2 Just know to follow up on the pt and make sure it isn’t enlarging rapidly Shotty nodes – no particular path process, usually pea sized

Lymphadenopathy Diagnostic Approach Diagnostic Tests Labs Confirm suspected diagnosis (Rapid Strep) Unknown diagnosis CBC Consider PPD, HIV, RPR, ANA Imaging studies Can define size and distribution more precisely CT, U/S, or MRI all useful at providing clues to Dx but usually cannot replace biopsy CXR Some kid walks in with cervical lymph nodes and a sore throat  strep test CBC will help with heme malignancy Can order specific markers if suspected certain things There is no necessarily one best imaging study for lymph nodes US good for axillary nodes Supraclavicular nodes  may need CT of chest and abdomen  do not jump to a pet scan

Lymphadenopathy Diagnostic Approach To Biopsy or Not To Biopsy: That is the Question! Many review articles examining the approach to evaluation and diagnosis of lymphadenopathy Goal is to identify those patients most likely to benefit from Bx (cancer, granulomatous diseases) Hematology clinic - Greece study of causes of peripheral lymphadenopathy in 475 consecutive patients over the age of 14 followed for a median of 69 months 58% had nonspecific Specific findings included toxoplasmosis, lymphoma, metastatic carcinoma, tuberculosis and infectious mononucleosis This study tells you that more than half of these people with lymphadenopathy is just nothing  don’t know what brought it on and there is no specific diagnosis, but they will be fine - Consider this bc your goal is to Bx pts who would benefit from it the most Vassilakopoulos TP, et al Medicine (Baltimore). 2000;79(5):338

Lymphadenopathy Diagnostic Approach When to perform biopsies of enlarged peripheral lymph nodes in young patients. Slap GB et al; JAMA. 1984;252(10):1321.  123 patients (9-25 yo) who underwent biopsies of enlarged peripheral lymph nodes 72 (58%) patients had biopsy results that did not lead to treatment, and 51 (42%) had results that did lead to treatment A predictive model was developed that assigned 95% of the cases to the correct biopsy group based on: lymph node size; history of recent ear, nose, and throat symptoms chest roentgenogram. When tested prospectively on new patients, the model correctly classified 32 (97%) of 33 patients Parallel with the Greece study  over half the people, nothing was found that required intervention Of the 42% that did require tx, tried to develop a model that you could predict something Larger lymph nodes  more likely cancer or a process that needs to be identified Recent ear, nose and throat issues  less likely to be met, more like to be infectious process Give all pts CXR

Lymphadenopathy Diagnostic Approach Lymph Node Biopsy Open biopsy Generally the best diagnostic test because histologic examination of intact tissue provides information about both the presence of abnormal cells (carcinoma, microorganisms) and abnormal node architecture False negative results occur when the wrong node is taken, which is not uncommon Outpatient procedure under local anesthesia Most abnormal node selected if multiple nodes are involved If no single node predominates, the choice in descending order of preference is supraclavicular, neck, axilla, and groin nonspecific result are greatest with axillary and inguinal nodes complications of lymph node biopsy, infection and damage to the neurovascular structures is higher in the groin and axilla Open biopsy is generally the best approach

Lymphadenopathy Diagnostic Approach Lymph Node Biopsy Fine needle aspiration Cytology no histology False negatives common Core needle Biopsy Increasingly utilized when node not easily accessible Improved ancillary studies Easy to do a FNA in the pcp office, but you get very limited info from a few cells and there is a high degree of false neg - Better results with core needle biopsy

Lymphadenopathy Differential Diagnosis Infection Bacterial Pyogenic bacteria, cat-scratch disease, syphilis, tularemia Mycobacterial Tuberculosis, leprosy Fungal Histoplasmosis, coccidiodomycosis Chlamydial Lymphogranuloma venereum Parasitic Toxoplasmosis, trypanosomiasis, filariasis Viral EBV, CMV, rubella, hepatitis, HIV Didn’t stress this

Lymphadenopathy Differential Diagnosis Infection Benign disorders of the immune system Rheumatoid arthritis SLE Serum sickness/ drug reactions Langerhans’ cell histiocytosis Kawasaki syndrome Kimura’s disease Most fall into autoimmune disorders Langerhans’ cell histiocytosis Not really a malignancy, but not completely a benign process. This is rare I would not memorize this, just know there are many benign disorders presenting with lymphadenopathy

Lymphadenopathy Differential Diagnosis Infection Benign disorders of the immune system Malignant disorders of the immune system Lymphoma – Hodgkin’s and Non-Hodgkin’s Leukemia – chronic and acute Plasma cell dyscrasias – myeloma, Waldenstrom’s macroglobulinemia

Lymphadenopathy Differential Diagnosis Infection Benign disorders of the immune system Malignant disorders of the immune system Metastatic cancer (lung, breast, melanoma) Storage diseases (Gaucher’s and Niemann-Pick Disease) Endocrinopathies (hyperthyroidism, adrenal insufficiency, thyroiditis) Miscellaneous: (sarcoidosis, amyloidosis)

Lymphadenopathy Differential Diagnosis Most common causes in USA Unexplained Infection Drainage area of infection: pharyngitis with cervical adenopathy Disseminated: mononucleosis Immune disorders: rheumatoid arthritis Neoplasms Hematologic Solid tumors Unexplained > infection > immune disorders > neoplasms in the US

Lymphadenopathy Diff Dx – Cervical Adenopathy Scenario 1 10 y.o. with sore throat and fever x 2 days during cold and flu season PE: Temp- 102.5 ill but non toxic appearing, right tender anterior cervical LN Oropharynx with erythema and exudate on tonsils Extremely common presentation Prob strep throat

Lymphadenopathy Diff Dx – Cervical Adenopathy Scenario 1 Cervical Lymphadenitis Acute bilateral disease Rhinovirus, EBV, CMV, HSV, Adenovirus, Enterovirus, Mycoplasma pneumoniae, Group A streptococcus, Influenza Conservative management recommended due to most likely etiology (viral) Follow up with further eval if adenopathy persist or progresses Acute unilateral disease Staphylococcus aureus, Group A streptococcus, Anaerobic bacteria Further eval depends on severity of symptoms and presenting features Exudative pharyngitis with + rapid strep test manage with oral Abx Ill/toxic child with fluctuant node may require FNA with oral/IV Abx

Lymphadenopathy Diff Dx – Cervical Adenopathy Scenario 2 20 yo college student presents with fever, malaise, and posterior adenopathy PE: Temp-101 ill but non toxic appearing multiple non tender bilateral cervical nodes <1cm and occipital adenopathy, tender RUQ and mild splenomegaly EBV

Lymphadenopathy Diff Dx – Cervical Adenopathy Scenario 2 Acute Bilateral Cervical Adenopathy Dx: Infectious mononucleosis presenting with classic triad of fever, tonsillar pharyngitis and cervical adenopathy Pathogenesis: Epstein-Barr Virus = widely disseminated herpes virus (90% of adults EBV+), spread by intimate contact Dx Evaluation: CBC with lymphocytosis with atypical lymphocytes on peripheral smear, CMP with elevated AST/ALT, Monospot positive Treatment: Supportive Not everyone who gets EBV will present with mono symptoms, may just have viral symptoms for a few days

Lymphadenopathy Diff Dx – Cervical Adenopathy Scerario 3 Otherwise healthy, 7 yo girl with 2 week history of a swelling behind her left ear. She had no systemic illness and noted no improvement with a course of amoxicillin–clavulanate PE: revealed a red, tender, retroauricular fluctuant lymph node measuring 2 by 2 cm behind her left earlobe. No other lymph nodes were enlarged. Follow up with pts to make sure this actually resolves

Lymphadenopathy Diff Dx – Cervical Adenopathy Further History obtained about recent exposure and she reported having regular contact with cats and remembered being scratched by one two weeks earlier, shortly before the mass appeared. Diagnosis =

Lymphadenopathy Diff Dx – Cervical Adenopathy Scenario 3 Cat Scratch Disease Cat scratch disease (CSD) is an infectious disease characterized by self-limited regional lymphadenopathy Epidemiology/Pathogenesis Bartonella henselae is the etiologic agent responsible for CSD. Cats serve as the natural reservoir and transmitted via a cat scratch or bite (flea bite also reported). Organism typically causes a local infection that manifest as regional lymphadenopathy More commonly seen in children

Lymphadenopathy Diff Dx – Cervical Adenopathy Scenario 3 Cat Scratch Disease Clinical Manifestations Typically begins with a cutaneous lesion at the site of inoculation; develops 3-10 days after the bite/scratch and evolves through vesicular, erythematous and papular phases

Lymphadenopathy Diff Dx – Cervical Adenopathy Scenario 3 Cat Scratch Disease Clinical Manifestations Lymphadenopathy: Regional adenopathy is the hallmark of CSD. Enlarged tender nodes proximal to the site of inoculation appear at about 2 weeks. Very commonly (85%) present with solitary node involved Know that cat scratch disease gives REGIONAL lymphadenopathy, not generalized

Lymphadenopathy Diff Dx – Cervical Adenopathy Scenario 3 Cat Scratch Disease Clinical Manifestations Visceral organ involvement: liver-spleen Constitutional: FUO, weight loss Ocular: neuroretinitis, Parinaud’s oculoglandular syndrome Neurologic: encephalopathy Musculoskeletal: Myalgias/arthralgias These are far less common

Lymphadenopathy Diff Dx – Cervical Adenopathy Scenario 3 Cat Scratch Disease Diagnosis Typical Hx and PE Serology for B. henselae Poor sens/spec IFA IgG titer > 1:256 strongly suggest active or recent infection PCR or positive Warthin-Starry stain Treatment Most patients will have gradual resolution without intervention Recommended to treat with azithromycin x 5 days Serology not that sensitive or specific IFA (immunofluorescence) better PCR most diagnostic

Lymphadenopathy Diff Dx – Cervical Adenopathy Scenario 4 24 yo female shooting a movie in NC presents to the ED with fever x 1 week and cervical adenopathy. No prior medical problems. Only other complaint is fatigue. She reports uncle died of NHL and he presented with fever and adenopathy PE: Healthy appearing, Temp 100.9 normal exam except for some firm, nonfixed right cervical nodes

Lymphadenopathy Diff Dx – Cervical Adenopathy Diagnostic Evaluation Labs – normal except for WBC-3500 and atypical lymphocytes, ESR-70, LDH -250 Serology for EBV HIV and CSD are negative Imaging studies – normal CT scan of C/A/P; neck with enlarged right cervical nodes ESR and LDH is up, WBC is down  concerning CBC

Lymphadenopathy Diff Dx – Cervical Adenopathy Scenario 4 Biopsy performed FNA non diagnostic Excisional biopsy reveals a histiocytic cellular polyclonal infiltrate with preservation of nodal architecture Consistent with an unusual disease

Lymphadenopathy Diff Dx – Cervical Adenopathy Scenario 4 Diagnosis: Kikuchi’s disease Rare, benign condition of unknown cause usually characterized by cervical lymphadenopathy and fever Most commonly seen in young women Diagnosis made by lymph node biopsy and excluding other causes Self limited illness in majority of patients No effective treatment May the odds be ever in your favor!

Lymphadenopathy Dr. J Armitage Approach Does the patient have a know illness that causes lymphadenopathy? Treat and monitor for resolution Is there an obvious infection to explain the lymphadenopathy? Are the nodes very large and/or firm and thus suggestive of malignancy? Perform a biopsy Is the patient very concerned about a malignancy and unable to be reassured that cancer is unlikely? If none of the preceding are true, perform a CBC and if normal then monitor with follow up in 2-6 weeks. Biopsy if progression noted or no regression