What labs should be ordered for a patient suspected to have Castleman disease?

Laboratory Evaluation for Suspected Castleman Disease

For any patient with suspected Castleman disease, order interleukin-6 (IL-6) levels, C-reactive protein (CRP), complete blood count with differential, comprehensive metabolic panel, erythrocyte sedimentation rate (ESR), serum protein electrophoresis with quantitative immunoglobulins (IgG, IgA, IgM, IgE), albumin, and HHV-8 viral load testing. 1, 2, 3, 4

Essential Laboratory Tests

Inflammatory and Cytokine Markers

• Interleukin-6 (IL-6) is the single most important biomarker, as IL-6 overproduction drives most symptoms and laboratory abnormalities in multicentric Castleman disease (MCD), with elevated levels found in 57 of 63 patients (90%) in systematic reviews 2, 4
• C-reactive protein (CRP) should be measured as it is elevated in the majority of cases (65/79 patients, 82%) and reflects the inflammatory state 4
• Erythrocyte sedimentation rate (ESR) provides additional inflammatory assessment 5, 4
• Interleukin-10 can be measured when available, as it is often elevated in MCD 1

Hematologic Parameters

• Complete blood count with differential to detect anemia (present in 79/91 patients, 87%), thrombocytopenia (especially in iMCD-TAFRO subtype), and other cytopenias 3, 4
• Peripheral blood smear review for morphologic abnormalities 1
• Hemoglobin levels specifically, as anemia of inflammation is a hallmark feature 3, 5
• Platelet count is critical, as severe thrombocytopenia defines the iMCD-TAFRO subtype 3

Protein and Immunologic Studies

• Serum protein electrophoresis to identify polyclonal hypergammaglobulinemia, present in 63/82 patients (77%) 4
• Quantitative immunoglobulins (IgG, IgA, IgM) with particular attention to IgG levels, as elevated IgG (especially IgG4) characterizes the iMCD-IPL subtype 3
• Serum IgE levels should be measured 4
• Albumin to detect hypoalbuminemia, found in 57/63 patients (90%) 5, 4

Metabolic and Organ Function

• Comprehensive metabolic panel including liver function tests, renal function (creatinine), and electrolytes to assess organ involvement 1, 3
• Lactate dehydrogenase (LDH) as a marker of disease activity 1

Viral and Infectious Workup

• HHV-8 serum viral load is mandatory to distinguish HHV-8-positive MCD from idiopathic MCD (iMCD), as this fundamentally changes management 1, 3, 6
• HIV testing if HIV status is unknown, as HHV-8-positive MCD is associated with HIV infection 1, 3

Additional Specialized Markers

• Soluble interleukin-2 receptor (sIL-2R) is elevated in 20/21 patients (95%) when measured and can help monitor disease activity 4
• VEGF levels are elevated in 16/20 patients (80%) and may provide additional diagnostic information 4
• Vitamin B12 levels should be checked as part of the comprehensive workup 1

Critical Diagnostic Considerations

Distinguishing Subtypes

The laboratory pattern helps classify iMCD into three subtypes 3:

• iMCD-TAFRO: Severe thrombocytopenia, anasarca, fever, renal dysfunction, and organomegaly with relatively small lymph nodes
• iMCD-IPL: Marked polyclonal hypergammaglobulinemia (often with elevated IgG4), anemia, and prominent lymphadenopathy
• iMCD-NOS: Features not meeting TAFRO or IPL criteria

Monitoring Treatment Response

After initiating therapy, significant improvements should be seen in hemoglobin, platelet count, CRP, ESR, IL-6, albumin, and IgG levels 5

Common Pitfalls to Avoid

• Do not rely on a single elevated cytokine level for diagnosis; Castleman disease requires correlation of clinical features, laboratory abnormalities, and characteristic lymph node histopathology 3
• Do not miss HHV-8 testing, as HHV-8-positive MCD has different treatment implications and prognosis compared to iMCD 3, 6
• Do not confuse reactive lymph node changes from autoimmune diseases, lymphoma, or infections with true Castleman disease; histologic findings must be combined with the complete clinical and laboratory picture 3
• Do not overlook the 22% risk of concurrent malignancy in iMCD patients, which is significantly higher than age-matched controls 4
• Do not forget that IL-6 levels correlate with disease activity and can be used to monitor treatment response, particularly with anti-IL-6 therapies like siltuximab 2, 3