What is Castleman Disease?
Castleman disease is a rare group of lymphoproliferative disorders characterized by enlarged lymph nodes with distinctive histopathological features, ranging from a localized, surgically curable form to life-threatening systemic variants driven by excessive cytokine production, particularly interleukin-6. 1
Disease Classification
Castleman disease encompasses at least four distinct disorders that share histopathological similarities but differ dramatically in etiology, presentation, and prognosis 1:
Unicentric Castleman Disease (UCD)
- Involves a single enlarged lymph node region
- Often produces minimal symptoms
- Surgical excision is typically curative
- Can present as hyaline-vascular type (most common, usually asymptomatic) or plasma cell type (more likely to cause fever, night sweats, lymphadenopathy) 2
Multicentric Castleman Disease (MCD)
MCD affects multiple lymph node regions and presents with systemic symptoms. It is further subdivided into three etiologic categories 1, 3:
1. HHV-8-associated MCD (HHV-8-MCD)
- Caused by human herpesvirus-8 infection
- Predominantly occurs in HIV-positive patients
- Associated with Kaposi sarcoma and primary effusion lymphoma
- Driven by viral IL-6 production 4
2. POEMS-associated MCD
- Occurs with polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, and skin changes
- Driven by plasma cell neoplasm producing excessive cytokines 1
3. Idiopathic MCD (iMCD)
- HHV-8-negative with no identifiable cause
- Represents more than half of MCD cases
- Further classified into three clinical subtypes 3:
iMCD Subtypes:
iMCD-TAFRO: Rapid-onset cytokine storm with thrombocytopenia, anasarca, fever, renal dysfunction/reticulin fibrosis, and organomegaly. Mimics hemophagocytic lymphohistiocytosis or sepsis with small-volume lymphadenopathy 3.
iMCD-IPL (Idiopathic Plasmacytic Lymphadenopathy): Subacute/chronic presentation with lymphadenopathy, anemia of inflammation, polyclonal hypergammaglobulinemia, and often elevated IgG4. Can mimic IgG4-related disease 3.
iMCD-NOS (Not Otherwise Specified): Does not meet TAFRO or IPL criteria. Often mimics indolent lymphoma or autoimmune conditions 3.
Pathophysiology
The disease is driven by dysregulated cytokine production, with IL-6 playing a central pathogenic role across most subtypes 1, 5. In HHV-8-MCD, viral IL-6 and human IL-6 create a cytokine storm. In iMCD, the trigger for excessive IL-6 remains unknown but results in systemic inflammation affecting multiple organ systems 3.
Clinical Presentation
Systemic symptoms include fever, night sweats, fatigue, weight loss, and generalized lymphadenopathy 2.
Laboratory abnormalities commonly show elevated inflammatory markers (CRP, IL-6, IL-10), anemia, thrombocytopenia (especially in TAFRO), polyclonal hypergammaglobulinemia, and hypoalbuminemia 3.
Organ involvement can include hepatosplenomegaly, renal dysfunction, neuropathy, skin changes, and effusions 3.
Diagnostic Challenges
Critical pitfall: Castleman-like histopathological changes can occur as reactive phenomena in autoimmune diseases, lymphomas, and infections 3. Diagnosis requires integration of histopathology with clinical and laboratory findings—not histology alone.
The disease frequently mimics autoimmune conditions, making it a diagnostic challenge for rheumatologists 6. Overlaps with Sjögren's syndrome, IgG4-related disease, and other immune-mediated conditions are well-documented 7, 3.
Histopathology
Three morphological patterns exist: hyaline-vascular (hypervascular), plasmacytic, and mixed types 8. The hyaline-vascular type shows abnormal follicles with increased interfollicular vascularity, while the plasmacytic type demonstrates sheets of mature plasma cells 2. Complete lymph node excision is essential for optimal pathological assessment 6.
Treatment Approach
For HHV-8-MCD:
Rituximab is the recommended first-line therapy in combination with antiretroviral therapy for HIV-positive patients 4. In severe cases with cytokine storm or hemophagocytic syndrome, etoposide can be added to rituximab. When Kaposi sarcoma coexists, combination with liposomal doxorubicin or etoposide is considered 4.
For iMCD:
Anti-IL-6 therapy with siltuximab (or tocilizumab if siltuximab unavailable) is the preferred first-line treatment 5, 3. In the most severe cases, adjuvant combination chemotherapy is recommended. Second-line options include rituximab, cytotoxic chemotherapy, sirolimus, and other immunomodulators tailored to disease severity 5, 3.
For UCD:
Surgical excision of the affected lymph node is curative 1.
Prognosis
UCD has excellent outcomes with surgical resection. MCD prognosis varies significantly by subtype—HHV-8-MCD outcomes have improved with rituximab and antiretroviral therapy 1, while iMCD remains challenging with variable responses to treatment. Patients with MCD remain at increased risk for lymphoma development, particularly HHV-8-associated lymphomas 4.