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Am Fam Physician. 2001;63(1):138-140

Lymphadenopathy is a common condition affecting all ages; however, its lengthy differential diagnosis can be quite challenging. Habermann and Steensma discuss essential diagnostic considerations that can help in the evaluation of a patient with lymphadenopathy.

Cancers
Hematologic malignancies: Hodgkin's disease, non-Hodgkin's lymphoma, acute and chronic leukemia, Waldenström macroglobulinemia, multiple myeloma (uncommon), systemic mastocytosis
Metastatic “solid” tumors: breast, lung, renal cell, prostate, other
Hypersensitivity syndromes
Serum sickness
Drug sensitivity: diphenylhydantoin, carbamazepine, primidone, gold, allopurinol, indomethacin, sulfonamides, others
Silicone reaction
Vaccination related
Graft-vs-host disease
Infections
Viral: infectious mononucleosis (Epstein-Barr virus), cytomegalovirus, infectious hepatitis, postvaccinial lymphadenitis, adenovirus, herpes zoster, HIV/AIDS, human T-lymphotropic virus 1
Bacterial: cutaneous infections (staphylococcus, streptococcus), cat-scratch fever, chancroid, melioidosis, tuberculosis, atypical mycobacteria, primary and secondary syphilis
Chlamydial: lymphogranuloma venereum
Protozoan: toxoplasmosis
Mycotic: histoplasmosis, coccidioidomycosis
Rickettsial: scrub typhus
Helminthic: filariasis
Connective tissue diseases
Rheumatoid arthritis, systemic lupus erythematosus, dermatomyositis, mixed connective tissue disease, Sjögren's syndrome
Atypical lymphoproliferative disorders
Angiofollicular (giant) lymph node hyperplasia (Castleman disease), angioimmunoblastic lymphadenopathy with dysproteinemia, angiocentric immunoproliferative disorders, lymphomatoid granulomatosis, Wegener's granulomatosis
Granulomatous disorders
Tuberculosis, histoplasmosis, mycobacterial infections, cryptococcus, silicosis, berylliosis, cat-scratch fever
Other unusual causes of lymphadenopathy
Inflammatory pseudotumor of lymph nodes, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease), vascular transformation of sinuses, progressive transformation of germinal centers

The authors provide an acronym, “CHICAGO” (cancers, hypersensitivity syndromes, infections, connective tissue disease, atypical lymphoproliferative disorders, granulomatous lesions, other unusual causes of lymphadenopathy) that includes common causes of lymphadenopathy (see Table 1). The essential considerations in lymphadenopathy follow another acronym, “ALL AGES” (age, location, length of time present, associated signs and symptoms, generalized lymphadenopathy, extranodal associations, splenomegaly and fever). The critical task is to decide which nodes are associated with benign disease rather than malignancy, thus determining treatment. The authors state that age is the most important factor predicting benign or malignant disease, and they cite a study of 925 patients in which carcinoma was found to be more common in patients older than 50 years. Lymphoproliferative disorders, however, were not found to have an age predilection.

Although some patients are asymptomatic, others have a temperature higher than 38°C (100.4°F), drenching night sweats and unexplained weight loss. The physician should be aware that symptomatic and asymptomatic patients may have pathologic lymphadenopathy, and that qualitative characteristics like node consistency may not be helpful in distinguishing benign versus malignant lesions. For example, metastatic disease, Hodgkin's disease and tuberculosis can be associated with rock-hard nodes, but they can also present with soft nodes. Two helpful tips the authors present are that lymphangitic streaking is often consistent with cutaneous infection, and that splenomegaly is rare in metastatic cancer. Splenomegaly is more commonly associated with infectious mononucleosis, Hodgkin's disease, non-Hodgkin's lymphoma, chronic lymphocytic leukemia and acute leukemia. Adenopathy in the presence of fever points toward a broad differential, mainly consisting of infection or lymphoma.

The size, length of time present and location can help determine when a biopsy is needed. If lymphoma is suspected, a surgical biopsy is preferred over needle aspiration to ensure adequate sampling. The least helpful biopsies are in the inguinal region, unless the most abnormal or accessible node is located there. The authors recommend that lymph nodes that have been present outside the inguinal region for longer than one month and measure 1 cm or larger in diameter without an obvious diagnosis should be considered for biopsy. When multiple sites are involved, the initial biopsy site should be in the largest peripheral node outside of the inguinal region. When nodes are the same size, the following order should be used: supraclavicular, cervical, axillary, epitrochlear, inguinal. Table 2 lists the various regions of lymphadenopathy and associated etiologies.

Cervical
Infections: pharyngitis, dental abscess, otitis media and otitis externa, infectious mononucleosis, toxoplasmosis, cytomegalovirus, hepatitis, adenovirus, rubella
Malignancies: Hodgkin's disease, non-Hodgkin's lymphoma, squamous cell carcinoma of the head and neck
Kikuchi disease
Supraclavicular and prelaryngeal
Virchow node: abdominal and thoracic neoplasm
Delphian node: thyroid and laryngeal disease
Infections: mycobacterial (e.g., scrofula), fungal
Axillary
Infections: staphylococcal and streptococcal arm infections, cat-scratch fever, tularemia, sporotrichosis
Malignancies: breast carcinoma, Hodgkin's disease, non-Hodgkin's lymphoma, melanoma
Epitrochlear
Lymphoproliferative disorders
Connective tissue diseases and sarcoidosis
Dermatologic diseases
“Historical” associations: syphilis, leprosy, leishmaniasis, rubella
Inguinal
Benign reactive (especially in shoeless walkers)
Malignancies: Hodgkin's disease, non-Hodgkin's lymphoma, melanoma, squamous cell carcinoma of the penis and vulva, anal cancer
Infections: cellulitis, venereal disease
Hilar
Unilateral
Infections: bacterial pneumonia, mycobacterial diseases, fungal infections, tularemia, psittacosis, pertussis
Other granulomatous diseases
Malignancies: bronchogenic carcinoma, metastatic breast cancer and gastrointestinal cancers, non-Hodgkin lymphoma, Hodgkin disease
Bilateral
Granulomatous diseases: sarcoidosis, berylliosis, etc.
Bilateral infections
Malignancies: non-Hodgkin's lymphoma, Hodgkin's disease, metastatic carcinoma
Calcified: tuberculosis, histoplasmosis, silicosis
Mediastinal
Exclude other causes of mediastinal widening
Differential diagnosis is similar to that for hilar lymphadenopathy
Abdominal
Malignancies: metastatic adenocarcinoma (including gastric), non-Hodgkin lymphoma, transitional cell carcinoma of the urinary collecting system, chronic lymphocytic leukemia, hairy cell leukemia, Hodgkin disease (rarely mesenteric)
Tuberculosis
Generalized
Hematologic malignancies: non-Hodgkin's lymphoma, Hodgkin's disease, chronic lymphocytic leukemia, acute lymphocytic leukemia
Infections: infectious mononucleosis, cytomegalovirus, human immunodeficiency virus, tuberculosis, toxoplasmosis, histoplasmosis, coccidioidomycosis, brucellosis
Rheumatoid arthritis, systemic lupus erythematous
Sarcoidosis
Angioimmunoblastic lymphadenopathy

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