Lymphadenopathy resident survival guide

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Javaria Anwer M.D.[2]
Synonyms and keywords: lymphadenopathy management guide, lymph node pathology management guide

Lymphadenopathy resident survival guide microchapters
Overview
Causes
Management
Do's
Don'ts

Overview

Lymphadenopathy (LAD) is used to describe abnormal size, consistency, and the number of lymph nodes. Under normal conditions, lymph nodes may not be palpated. The lymph nodes maybe central or peripheral located deep in the subcutaneous tissue. Common causes of lymphadenopathy include infectious and non-infectious. A thorough physical exam is important to establish a differential diagnosis. The common causes of lymphadenopathy can be remembered using pneumonic CHICAGO (Cancer, Hypersensitivity, Infection, Connective tissue disorders, Atypical lymphoproliferative disorders, Granulomatous, and Others). Excisional biopsy is the gold standard for tissue diagnosis. Infections can be treated with antibiotics while cancers require surgical resection, staging and chemotherapy or radiotherapy.

Causes

Life Threatening Causes

Life-threatening causes include conditions that may result in death or permanent disability within 24 hours if left untreated.

• Infectious mediastinal lymphadenopathy

Common Causes

The American Academy of Family Physicians (AAFP) and many research articles utilize a pneumonic CHICAGO to include all causes of lymphadenopathy based on etiology. The causes may also be remembered based on the location of lymph nodes.

• Cancers:
  • Hematologic: Hodgkin's lymphoma, non-Hodgkins lymphoma, leukemia (acute/ chronic), multiple myeloma, mastocytosis, waldenstrom macroglobulinemia.
  • Metastasis: Breast cancer, gastric cancer, liver cancer, renal cancer, lung cancer, and prostate cancer.
• Hypersensitivity :
  • Serum sickness, immunization reactions, graft-vs-host disease, silicone allergy, and drug allergy (such as sulfonamides, allopurinol, carbamazepine, etc).
• Infections:
  • Fungal, Protozoan, Rickettsial (Typhus), Helminthes.
  • Bacterial: Tiberculosis, syphilis (primary and secondary), chancroid, staphylococcus or streptococcal skin infections.
  • Viral: IM, CMV, HIV,lymphadenitis post vaccination, adenovirus, herpes zoster, and hepatitis (infectious), and melioidosis.
  • Chlamydial (lymphogranuloma venereum), protozoan (toxoplasmosis), mycotic (histoplasmosis, coccidioidomycosis, helminthic (filariasis, and rickettsial (typhus).
• Connective tissue disorders:
  • SLE, rheumatoid arthritis, dermatomyositis, sjogren's syndrome, mixed connective tissue disease.
• Atypical lymphoproliferative disorders :
  • Granulomatosis with polyangiitis, Castleman's disease, Wegener's granulomatosis, angioimmunoblastic T-cell lymphoma, lymphomatoid granulomatosis, and angiocentric immunoproliferative disorder.
• Granulomatous:
  • Cryptococcosis, histoplasmosis, berylliosis, cat scratch disease, silicosis, mycobacterial infection.
• Others:
  • Rosai Dorfman disease, Kikuchi disease, pseudotumor of L.N, transformation of germinal centers, and vascular transformation of sinuses.
• For more detailed information in the causes of lymphadenopathy, click here.

Management

Diagnostic algorithm and management

Abbreviations: UVUltraviolet rays; UTIUrinary tract infection; HEENT: Head, Eyes, Ears. Nose, and Throat exam; IM: Infectious Mononucleosis; L.N: Lymph node;CBC: Complete blood count; ESR: Erythrocyte sedimentation rate; CMP: Comprehensive metabolic panel; LFTs:Liver function tests; URTI: Upper respiratory tract infection; CMV: Cytomegalovirus; IgM: Immuniglobulin M; IgG:Immunoglobuin G; ANA:Antinuclear antibodies; CXR:Chest X-ray; CT: CT scan; VDRL: Venereal disease research laboratory; RPR:Reactive plasma reagen

The algorithm illustrates the approach to management of lymphadenopathy. Borrowed from:

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History ❑Patient age (specific demographic characteristics (age) of certain malignancies) ❑ Duration of lymphadenopathy (<2 weeks or >1 year without an increase in size has low malignant potential) ❑ Past medical history of underlying disease, suggestive of immunodeficiency, or recurrent infections ❑ Sexual history suggestive of infection transmission ❑ Family history of certain malignant disorders (breast cancer, or melanoma) ❑ Exposure to communicable infectious diseases/ travel to high-risk areas ❑ Environmental exposure such as UV (skin cancer risk)/ animals/ occupational exposure ❑ Social history such as tobacco use, alcohol use (head and neck cancers risk) ❑ Associated symptoms such as pain, fever, weight loss, anorexia, cough, or recurrent UTIs

Physical exam Appearance of the patient Cachexia or surgical scar marks demonstrating previous malignancy treatment ❑ Vital signs ❑ Temperature: High-grade / low-grade fever may demonstrate infection. ❑ Heart rate: Tachycardia with regular pulse may demonstrate infection. ❑ Respiratory rate: Tachypnea may demonstrate respiratory system involvement (infection\ metastasis). ❑ Blood pressure: Chronic hypertension or hypotension (may indicate sepsis as a complication). ❑ Oxygen saturation: may be low if the respiratory system is affected. ❑ HEENT ❑ Cardiovascular examination ❑ Respiratory examination ❑ Gastrointestinal system exam includes oral examination, abdominal examination, and digital rectal exam. ❑ Splenomegaly) may demonstrate IM, hodgkin's/ non-Hodgkin's lymphoma, and sarcoidosis ❑ Extremities exam ❑ Skin exam: Evaluate for the lesions that indicate malignancy such as melanoma/ potential inoculation sites for germ such as traumatic lesions.

Palpable lymph node ❑ Location: (Localized vs generalized) ❑ For nodes involving several groups of nodes; suspect malignancy. ❑ An enlarged node in a lymphatic rich region; suspect local disease. ❑ Associated red streaking, suspect lymphangitis. ❑ Left supraclavicular L.N (Virchow's nodes); suspect gastric carcinoma ❑ Right supraclavicular L.N, suspect intra-thoracic carcinoma ❑ Dimensions The aforementioned dimensions are abnormal for a palpable lymph node but do not lead to the suspicion of a neoplasm. ❑ supraclavicular, iliac, epitrochlear, and popliteal lymph nodes >0.5cm ❑ Inguinal nodes > 1.5 cm ❑ Other area lymph nodes >1 cm ❑ Tenderness or pain: ❑ Suspect infection. ❑ A neoplastic node may also demonstrate pain due to hemorrhage associated with central necrosis or a brisk growing tumor. ❑ Consistency ❑ Hard on palpation; suspect chronic inflammation ❑ consistent- acute inflammation ❑ Stony-hard and painless nodes-metastatic cancer/ granuloma ❑ Firm and rubbery nodes- lymphoma ❑ Matted L.N suspect mycobacterium / sarcoidosis/ lymphoma / metastatic carcinoma) ❑ Mobility ❑ Freely movable; suspect infections and collagen vascular disease ❑ Fixed L.N to surrounding tissue; suspect malignancy

Labs ❑ CBC with differential ❑ ESR ❑ CMP ❑ Peripheral smaer ❑ LFTs Labs may be required at a later stage pf diagnosis

Diagnostic of self-limiting or benign disease Pharyngitis, URTI, conjunctivitis, cat-scratch disease, etc

Suggests infection/ serious infection

Unexplained

Suggests malignancy

May require specific tests ❑ Throat swab ❑ Sputum exam

Perform specific tests ❑ IM: Heterophile Antibody and monospot test ❑ Syphilis: VDRL, RPR ❑ HIV: HIV antibody test ❑ CMV: Anti CMV IgM ❑ Autoimmune disorders: ANA, Rheumatoid factor, etc ❑ Tuberculosis: PPD ❑ Cat scratch disease: IgM, IgG

Risk factors for malignancy Family history, age, exposure, etc

Perform specific tests

Excisional biopsy

Positive

Negative

Negative

Positive

❑ Treat ❑ To read about the treatment of strept throat, click here ❑ Fluctuant L.N: Incision and drainage (avoid if tuberculosis is suspected) ❑ For an untreatable or disease with residual symptoms counsel the patient ❑ Follow up for advancing or persistent LAD

Treat ❑ IM treatment ❑ Syphilis treatment ❑ HIV treatment ❑ CMV treatment ❑ Treatment of autoimmune disorders ❑ Tuberculosis treatment ❑ cat scratch disease treatment

Staging

Treat Surgical resection/ chemotherapy/ radiotherapy

Low risk

High risk

Specific tests/ biopsy

Localized

Generalized

Review history and clues suggesting malignancy

Review history and clues suggesting malignancy Anti-VCA IgM and IgG for EBV, HIV antibody,PPD, HbsAg anti-CMV IgM, anti-toxoplasma IgM/ IgG, and ANA

Positive

Treat

Negative

❑ Specific tests such as CXR, ultrasound, CT, lab workup, biopsy. ❑ The US findings that help differentiate benign LAD from malignant include: ❑ Benign: An isoechoic oviod shaped lesion with variable borders. High long axis/short axis ratio(L/S) of >2. A hilum is present with blood flow. Pulsatility index id <1.5. ❑ Malignant: A hypoechoic round lesion with sharp borders. Low L/S ratio of <2. Hilum is absent with peripheral blood flow distribution.

Observe 3-4 weeks

Undiagnostic

Diagnostic

Progress/persists

Regress

No follow-up

Biopsy

Treatment

Positive

Negative

Staging

Follow-up

Biopsy

Treatment

Negative

Positive

Staging

Treatment

Differential diagnosis and management

• For detailed information on the neck lymphadenopathy and its diagnostic findings please click here.

Localised lymphadenopathy

• The table describes possible infectious and oncologic differential diagnoses based upon the location of lymphadenopathy. Please click on the disease name in the management section for a detailed review of the medical therapy utilized in the management of the specific entity. Please click on the disease name in other columns for a detailed review of the disease in general.

Region	Lymphadenopathy	Infections	Malignancies	Management (click on disease name to read about the treatment)
Head and neck	Preauricular and posterior cervical	Mycobacterial infection Scalp infections Kikuchi disease	4. Lymphoma 5. Squamous cell carcinoma (head and neck) 6. Skin cancer	Leprosy, mycobacterium bovis infection, TB Fungal infections-topical antifungals Kikuchi disease Lymphoma: Non-Hodgkin lymphoma, Hodgkin's lymphoma Squamous cell carcinoma Skin cancer
	Submandibular and anterior cervical	URTI Infectious mononucleosis (IM or mononucleosis) CMV odontogenic infection Rubella Toxoplasmosis Mycobacterial infection	7. Lymphoma 8. Squamous cell carcinoma (head and neck) 9. Leukemias: AML, ALL, CLL, CML	URTI Mononucleosis Odontogenic infection Rubella Toxoplasmosis Leprosy, mycobacterium bovis infection, TB Lymphoma: Non-Hodgkin lymphoma, Hodgkin's lymphoma Squamous cell carcinoma Leukemias: AML, ALL, CLL, CML
	Supraclavicular	Mycobacterial infection Mycosis	3. Breast cancer 4. Lung cancer 5. Esophageal cancer 6. mediastinal cancer 7. Stomach cancer (Virchow's node) 8. Laryngeal cancer 9. Thyroid cancer (papillary, medullary,follicular, and anaplastic)	Leprosy, mycobacterium bovis infection, TB Mycosis Breast cancer Lung cancer Esophageal cancer Mediastinal cancer Stomach cancer Laryngeal cancer Thyroid cancer: papillary thyroid cancer, medullary thyroid cancer, follicular thyroid cancer and anaplastic thyroid cancer
Axillary	Infraclavicular		Non-Hodgkin's lymphoma	Non-Hodgkin lymphoma
	Axillary	Secondary syphilis Sarcoidosis Cat-scratch disease Tularemia Leprosy Leishmaniasis Brucellosis Sporotrichosis Skin infection/ skin trauma Breast infections/[[breast abscess]	11. Breast adenocarcinoma 12. Lymphoma 13. Leukemias: AML, ALL, CLL, CML 14. Kaposi sarcoma 15. Skin cancer	Secondary syphilis Sarcoidosis Cat scratch disease Tularemia Leprosy Leishmaniasis Brucellosis Sporotrichosis Skin infection/ skin trauma: erysipelas and cellulitis. Trauma may require minor surgery and antibiotics. Breast abscess, may require surgery Breast adenocarcinoma Lymphoma: Non-Hodgkin lymphoma, Hodgkin's lymphoma Leukemias: AML, ALL, CLL, CML Kaposi's sarcoma Skin cancer
	Epitrochlear	Skin infections (erysipelas/ impetigo of arm and/ or hand)	2. Lymphoma 3. Skin cancer	Erysipelas (in addition to antibiotics, bed rest, leg elevation, and administration of anticoagulants among patients at risk of venous thromboembolism) and cellulitis Lymphoma: Non-Hodgkin lymphoma, Hodgkin's lymphoma Skin cancer
Superficial inguinal	Horizontal and vertical	STDs (chlamydia, HIV, herpes simplex, hepatitis B, and hepatitis C) Skin infections (such as erysipelas, impetigo, and cellulitis) Benign reactive lymphadenopathy	4. Lymphoma 5. Squamous cell carcinoma (vulva, vagina, penis, and anus) 6. Skin cancer 7. Kaposi sarcoma	Chlamydia, HIV, herpes simplex, hepatitis B, and hepatitis C Erysipelas, Impetigo, cellulitis Benign reactive lymphadenpathy Lymphoma: Non-Hodgkin lymphoma, Hodgkin's lymphoma Vulvar cancer, vaginal cancer, penile cancer, and anal cancer Skin cancer Kaposi's sarcoma

Generalized lymphadenopathy

• The table describes possible differential diagnoses of generalized lymphadenopathy based upon the cause. Please click on the disease name in the management section for a detailed review of the medical therapy utilized in the management of the specific entity. Please click on the disease name in other columns for a detailed review of the disease in general.

Autoimmune	Drug reactions	Infections	Malignancies	Storage disorders	Management (click on disease name to read about the treatment)
SLE Sjögren’s syndrome Rheumatoid arthritis	4. Drugs such as sulfonamides, allopurinol, carbamazepine, etc.	5. Infectious mononucelosis 6. Sarcoidosis 7. Syphilis 8. HIV 9. Typhoid 10. Plague 11. Miliary tuberculosis	12. Lymphoma 13. Leukemias: AML, ALL, CLL, CML	14. Gaucher's disease 15. Niemann-Pick disease	Mononucleosis Sarcoidosis Syphilis HIV Typhoid Plague Miliary tuberculosis Lymphoma: Non-Hodgkin lymphoma, Hodgkin's lymphoma Leukemias: AML, ALL, CLL, CML Gaucher's disease Niemann-Pick disease

Staging

• TNM stands for Tumor, Nodes, and Metastasis. The TNM staging system is widely utilized in staging tumors, especially solid tumors. For a detailed review of the TNM staging system please click here.
• For a detailed review of the staging systems utilized in cancer management please click here.
• Ann Arbor staging is utilized to stage lymphomas. Pleaseclick here for a detailed review on the staging system.

Do's

• Patients with immunodeficiency should have a wide differential diagnosis considering non-Hodgkin's lymphoma and Kaposi sarcoma.
• Remember that lymphadenopathy involving supraclavicular L.N poses the highest risk of malignancy (90% among patients >40 years of age) and 25% among < 40 years old.
• Needle aspiration biopsy or excisional biopsy is the gold standard for the tissue diagnosis and evaluation for lymphadenopathy.
• When lymphadenopathy is present, it is important to examine the whole area of lymphatic drainage of the particular organ. For example, examining the region beneath the umbilicus in case of inguinal lymphadenopathy.

Don'ts

• Physical examination should never be missed as a finding may change the course of differential diagnosis. Missing the physical exam may lead to unnecessary investigations and delays.

References

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