I. Problem/Condition.

See Figure 1.

Figure 1.

Clinical distribution.

Lymphadenopathy may be localized or generalized, but with some overlap. Either category may be benign or malignant. Malignant adenopathy may be primary or metastatic. Clinical factors indicating a benign pathology include size <1 cm, absence of matting, age <40, soft consistency, involved sites other than isolated supraclavicular or epitrochlear areas, evidence of a potential inflammatory/infectious predisposing etiology and lack of B-symptoms.

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If etiology is unclear from the history and physical, it is prudent to observe localized adenopathy for 4 weeks before initiating a diagnostic work up, provided the risk of a malignant adenopathy is low. If adenopathy is generalized then an extensive history should be sought to guide intervention, and a biopsy initiated if there is no systemic infection/inflammation or factors like causative medications.

With unexplained localized adenopathy, studies indicate that the incidence of malignancy is 0% in nodes less than 1×1 cm, about 8% with nodes larger than 1×1 cm and nearly 38% if nodes are bigger than 1.5×1.5 cm. With respect to age and unexplained localized adenopathy, incidence appears to be about 0.4% in individuals less than 40 and about 4% in those older than 40. Isolated supraclavicular nodes have high risk of being malignant with an estimated 90% in individuals older than 40 and still about 25% in those under 40 years.

Predictive rules based on some of these epidemiological findings have been used in selecting patients for lymph node biopsy. This article will guide the clinician in deciding when to work up and how to work up localized or generalized lymphadenopathy. Referral to a dedicated lymphadenopathy clinic has been shown to improve diagnostic accuracy and time to intervention.

II. Diagnostic Approach.

A. What is the differential diagnosis for this problem?

Localized lymphadenopathy:

  • Regional infections like cellulitis, cat-scratch disease, mumps

  • Sexually transmitted Infections including chancroid, LGV

  • Lyme disease, tularemia, typhus, bubonic plague

  • Malignant adenopathy from regional organs (e.g., axillary adenopathy in breast cancer)

  • Lymphoma, early stage

  • Granulomatous disorders like TB, sarcoidosis

  • Kawasaki’s disease

  • Miscellaneous conditions like silicone implants

Generalized lymphadenopathy:

  • Medications including phenytoin, carbamazepine, calcium channel blockers, hydrallazine

  • Serum sickness from PCN, cephalosporin’s, sulphonamides

  • Lymphoma, advanced

  • Acquired immunodeficiency syndrome

  • Chronic lymphocytic leukemia

  • Inflammatory disorders like SLE, Still’s disease, rheumatoid arthritis

  • Infections like Toxoplasma Gondii, secondary syphilis, hepatitis B, HTLV-1, CMV

  • Storage disorders like Gaucher’s disease

  • Others: Castleman disease, Kikuchi disease, histoplasmosis, coccidiomycosis

Generalized lymphadenopathy with splenomegaly:

  • Infectious mononucleosis

  • Chronic lymphocytic leukemia

  • Lymphoma

  • Miliary tuberculosis

  • Acquired immunodeficiency syndrome

  • Collagen vascular diseases

B. Describe a diagnostic approach/method to the patient with this problem.

A comprehensive history is important. This should include duration of illness, presence of local symptoms like pain, history of trauma/rash, fever, weight loss, medications, travel history, organ specific symptoms like cough/GI bleed, exposure to environmental toxins, occupational history, contact with animals and high risk sexual behavior.

1. Historical information important in the diagnosis of this problem.

See Figure 2.

Figure 2.

Lymph node architecture at low power (X20) showing intact follicles and normal medullary sinusoids (H⤅E).

  • General – history of B-symptoms, weight loss, fever, drenching night sweats)

  • Occupational history – hunters and trappers (Lyme disease), tularemia

  • Travel history – bubonic plague, histoplasmosis

  • Exposure history – cat scratch disease, Toxoplasma Gondii

  • Transfusions – CMV

  • High risk sexual behavior – STD’s, HIV, HSV, hepatitis B virus

  • New medications – phenytoin, PCN, sulphonamides, calcium channel blockers

2. Physical examination maneuvers likely to be useful in diagnosing causes of this problem.

See Figure 3.

Figure 3.

Cervical node drainage.

Confirm localized versus generalized lymphadenopathy:

  • With localized adenopathy, the anatomic site can indicate organ/system involved. Always examine for regional malignancies.

  • Left supraclavicular adenopathy – may indicate intrathoracic or abdominal malignancy (Virchow’s node).

  • Peri-umbilical adenopathy – may be seen in abdominal malignancies (Sister Mary Joseph’s node).

  • Epitrochlear adenopathy – CLL, lymphoma, infectious mononucleosis, sarcoidosis, secondary syphilis, HIV, local trauma/infections.

  • Axillary adenopathy – cat scratch disease, breast cancer, melanoma or cellulitis of the upper extremity.

  • Inguinal adenopathy – venereal diseases, cervical/vaginal malignancy, melanoma or cellulitis of the lower extremities.

See Figure 4.

Figure 4.

Lymphadenopathy algorithm.

Confirm splenomegaly:

With generalized lymphadenopathy the presence of splenomegaly will indicate the possibility of leukemic disorders, lymphomas, miliary tuberculosis, acquired immunodeficiency syndrome, collagen vascular disorders and infectious mononucleosis syndromes.

3. Laboratory, radiographic and other tests that are likely to be useful in diagnosing the cause of this problem.

Initial work-up should include the following: complete blood count with differential, comprehensive metabolic panel, peripheral smear, and chest x-ray.

Additional tests directed by history/symptomatology may include: PPD, throat swab, HIV test, heterophile antibody test, hepatitis panel, RPR and serological tests including those for Lyme disease, Toxoplasmosis, CMV, EBV.

Lymph node pathology can be analyzed with more precision using Gene Expression Profiling (GEP). With its capacity to define global cellular function, it can characterize and differentiate tissues at the cellular level. Lymphomas have traditionally been difficult to classify using morphology or Cluster Differentiation (CD) surface markers. GEP allows diagnostic precision in situations where morphology and immunohistochemistry remain inconclusive.

The next generation of tests enabling further precision in the diagnosis of lymphoma is micro RNA expression profiling. MiRNA’s are non-coding RNA molecules measuring about 21-25 nucleotides in length which function to down-regulate gene expression. These nucleotide sequences have a greater degree of tissue specificity leading to better diagnostic precision and more accurate tissue typing.

C. Criteria for diagnosing diseases listed above.

For clinical diagnoses and confirmatory tests see Table I.

Representative diseases History/clinical signs & symptoms Diagnostic tests
Infectious Mononucleosis Triad of fever/pharyngitis/adenopathy Heterophile Ab+
Acquired immunodeficiency Syndrome High risk behavior, flu-like symptoms HIV Antibodies, HIV viral RNA
CMV Fever, malaise, arthralgia, weight loss CMV IgM Ab, CMV Antigen
Lymphoma B-symptoms, adenopathy, Splenomegaly Bx with IHC, Flow cytometry
Metastatic malignancy Organ related presentation Node Bx with IHC and H&E
CLL Adenopathy, recurrent infections P. Blood flow cytometry
Drug induced adenopathy History of recent medications changes Eosinophilia, low C3/C4
Serum Sickness Antigen/antibody therapy, arthralgias Bx-Vasculitis, low C3/C4
Cat scratch disease Exposure to kittens with trauma B Henselae serology
Secondary Syphilis History of genital ulcers, rash VDRL, RPR, FTA-ABS
Lyme disease History of hunting, Erythema migrans B Burgdorferri IgM/IgG
LGV Painless genital ulcers, Inguinal nodes Swab for PCR, RFLP
Toxoplasmosis Contact with cat feces, Cervical nodes Lymph node for T Gondii
Sarcoidosis Night sweats, erythema nodosum Granulomas in nodes
Castleman disease Chronic cough, weight loss, fever HHV-8 serology, LN Biopsy

D. Over-utilized or “wasted” diagnostic tests associated with the evaluation of this problem.

FNA should be attempted only if non-invasive tests are inconclusive.

Invasive testing of inguinal nodes should if possible be avoided due to their low diagnostic yield.

ANA and ACE levels are non-specific and are best avoided in place of more diagnostic tests.

III. Management while the Diagnostic Process is Proceeding.

A. Management of Clinical Problem Lymphadenopathy.

Management should be based on results of the initial diagnostic workup and may include treatment of systemic or local infectious or inflammatory conditions. Empiric treatments however should be avoided as far as possible.

Superior vena cava syndrome from mediastinal lymphadenopathy is a medical emergency. However, studies do not support empirical emergent therapy since outcomes are superior following a biopsy and definitive treatment.

Systemic steroids, in spite of potential confounding of diagnostic work up, should be used for acute cord compression or an SLE flare.

B. Common Pitfalls and Side-Effects of Management of this Clinical Problem.

Empiric use of antibiotics for localized adenopathy of unclear etiology has not been shown to change outcomes.

Avoid use of corticosteroids since they may confound a subsequent biopsy interpretation due to their lympholytic effect.

Selection of node for diagnostic study is important. If possible, avoid inguinal or axillary nodes due to high incidence of reactive changes.

Surgical approach to a selected enlarged node may involve a FNA, core biopsy or excisional biopsy. Sample the largest node possible.

Always consider an excisional biopsy if lymphoma is suspected. This allows diagnostically important architecture to be preserved.

FNA allows only cellular morphology to be studied with sample often being inadequate for flow cytometry and architecture is absent.

Core biopsy provides more sample allowing immunohistochemistry and flow cytometry, but often architecture is lost from crush artifacts.

VII. What's the evidence?

Slap, GB, Brooks, SJ, Schwartz, JS. “When to perform biopsies of enlarged peripheral lymph nodes in young patients”. JAMA. vol. 252. 1984. pp. 1321-1326.

Libman, H. “Generalized Lymphadenopathy”. Gen Intern Med. vol. 2. 1987. pp. 48-58.

Pangalis, GA, Vassilakopoulos, TP. “Clinical approach to lymphadenopathy in 1103 patients”. Acta Cytologica. vol. 42. 1998. pp. 899-906.

Nasuti, JF, Mehrotra, R, Gupta, PK. “Diagnostic value of fine-needle aspiration in supraclavicular lymphadenopathy: A study of 106 patients and review of literature”. Diagn Cytopathol. vol. 25. 2001 Dec. pp. 351-355.

Chau, I, Kelleher, MT, Cunningham, D, Norman, AR. “Rapid access multi-disciplinary lymph node diagnostic clinic: Analysis of 550 patients”. Br J Cancer. vol. 88. 2003 Feb 10. pp. 354-61.

Richner, S, Laifer, G. “Peripheral Lymphadenopathy in immuno-competent adults”. Swiss Med Wkly. vol. 140. 2010 Feb 20. pp. 98-104.

Jeong, WJ, Park, MW, Park, SJ, Ahn, SH. “Initial work-up for cervical adenopathy: Back to basics”. Eur Arch otorhinolaryngol. vol. 269. 2012 Oct. pp. 2255-63.

Monaco, SE, Khalbuss, WE, Pantanowitz, L. “Benign non-infectious causes of lymphadenopathy: A review of cytomorphology and differential diagnosis”. Diagn Cytopathol. vol. 40. 2012 Oct. pp. 925-38.

Orsborne, C, Byers, R. “Impact of gene expression profiling in lymphoma diagnosis and prognosis”. Histopathology.. vol. 58. 2011 Jan. pp. 106-27.

Iqbal, J. “Global microRNA expression profiling uncovers molecular markers for classification and prognosis in aggressive B-cell lymphoma”. Blood. vol. 125. 2015 Feb 12. pp. 1137-45.