What is Castleman disease?

What is Castleman Disease?

Castleman disease is a rare lymphoproliferative disorder characterized by non-cancerous lymph node enlargement with specific histopathological features, classified into unicentric (UCD) and multicentric (MCD) forms, with MCD further divided into HHV-8-associated and idiopathic subtypes. 1, 2

Classification and Epidemiology

Castleman disease encompasses two primary forms with distinct clinical behaviors 3, 4:

• Unicentric Castleman Disease (UCD): Involves a single lymph node region or localized area, representing approximately 75% of all cases 4
• Multicentric Castleman Disease (MCD): Affects multiple lymph node stations throughout the body, accounting for approximately 25% of cases 4

MCD is further subdivided into 1, 2:

• HHV-8-associated MCD: Caused by human herpesvirus-8 infection
• Idiopathic MCD (iMCD): HHV-8-negative cases with unknown etiology

The annual incidence in the United States ranges from 6,500 to 7,700 cases 4.

Pathophysiology

The disease involves hyperproliferation of specific B cells that produce the cytokine interleukin-6 (IL-6), which drives the inflammatory manifestations 5. This IL-6-mediated inflammation explains many of the systemic symptoms and laboratory abnormalities seen in MCD 2.

Clinical Presentation

Unicentric Castleman Disease

• Presents as benign, painless, slow lymph node enlargement that is generally asymptomatic 5
• Typically discovered incidentally or as a well-circumscribed mass on imaging 6
• May be mistaken for malignancy on initial imaging due to intense homogenous enhancement 6

Multicentric Castleman Disease

• Exhibits a progressive clinical course with systemic symptoms 5
• Presents with multiple enlarged lymph nodes, fever, and constitutional symptoms 7, 2
• Associated with laboratory abnormalities including anemia, elevated inflammatory markers, and hypergammaglobulinemia 1, 2
• Can be associated with KSHV-associated inflammatory cytokine syndrome (KICS) 7

Associated Conditions

Castleman disease can occur as a secondary manifestation in several conditions 8:

• Immune complex-mediated membranoproliferative glomerulonephritis (MPGN)
• Chronic infections (hepatitis B and C, fungal, parasitic)
• Autoimmune disorders (SLE, Sjögren syndrome, rheumatoid arthritis)
• Hematologic malignancies (chronic lymphocytic leukemia, lymphoma)
• Plasma cell dyscrasias or monoclonal gammopathy of undetermined significance (MGUS)

Diagnostic Approach

The American College of Oncology recommends 1:

• Classification based on lymph node involvement pattern (unicentric vs. multicentric)
• Laboratory evaluation including complete blood count with differential, inflammatory markers, and HHV-8 testing
• HIV testing for all patients, as recommended by the American Society of Transplantation 1

Diagnostic criteria for iMCD require 2, 4:

• Characteristic histopathologic findings on lymph node biopsy
• Enlargement of multiple lymph node regions (for MCD)
• Presence of multiple clinical and laboratory abnormalities
• Exclusion of infectious, malignant, and autoimmune disorders that can mimic iMCD

Prognosis

Unicentric Disease

UCD exhibits benign symptoms with excellent prognosis following complete surgical resection 5. All 48 UCD patients in one retrospective series had curative outcomes after surgical removal 5.

Multicentric Disease

MCD has a more aggressive course with potential for malignancy 5. The 5-year survival with modern therapies, particularly interferon-based treatment, is approximately 68% 1. Rituximab treatment reduces the incidence of non-Hodgkin lymphoma, though the risk remains elevated 1.

Common Pitfalls

• Misdiagnosis: The disease is often undiagnosed or misdiagnosed due to its rarity and overlap with other lymphoproliferative disorders 5
• Imaging interpretation: UCD can mimic malignancy on imaging studies due to intense enhancement patterns 6
• Incomplete evaluation: Failure to test for HHV-8 and HIV can lead to inappropriate treatment selection 1
• Overlooking secondary causes: In cases presenting with MPGN, Castleman disease should be considered as a potential underlying etiology 8