What is Castleman disease?

Castleman Disease Overview

Castleman disease is a rare lymphoproliferative disorder characterized by non-cancerous lymph node hyperplasia, classified into unicentric (UCD) and multicentric (MCD) forms, with UCD being localized and typically curable by surgical resection, while MCD is systemic and requires medical management. 1, 2

Classification and Subtypes

Castleman disease divides into two primary forms based on lymph node involvement 1, 3:

• Unicentric Castleman Disease (UCD): Involves a single lymph node region, presents as localized disease with benign symptoms including painless, slow lymph node enlargement that is generally asymptomatic 4, 3

• Multicentric Castleman Disease (MCD): Involves multiple lymph node regions with constitutional symptoms and organ dysfunction due to cytokine storm (particularly IL-6), further subdivided into 1, 5:

  • HHV-8-associated MCD (occurs in immunocompromised individuals, particularly HIV-positive patients) 1, 2
  • Idiopathic MCD (iMCD), which includes TAFRO syndrome variant 5
  • POEMS-associated MCD 6

Clinical Presentation

Unicentric Disease

• Benign, painless lymph node enlargement at a single site 4
• Generally asymptomatic with excellent prognosis 4, 3
• May cause symptoms from compression of neighboring vital structures in unresectable cases 3

Multicentric Disease

• Multiple regions of enlarged lymph nodes 2, 5
• Constitutional symptoms including fever 7, 5
• Organ dysfunction and systemic inflammatory manifestations 2, 5
• TAFRO syndrome variant presents with thrombocytopenia, anasarca, fevers, reticulin myelofibrosis, organomegaly, and normal or slightly elevated immunoglobulin levels 5
• Non-TAFRO iMCD typically shows thrombocytosis, less severe fluid accumulation, and hypergammaglobulinemia 5

Diagnostic Evaluation

Laboratory workup should include 1:

• Complete blood count with differential
• Inflammatory markers
• HHV-8 testing
• HIV testing (recommended by American Society of Transplantation) 1

Treatment Approach

Unicentric Castleman Disease

Complete surgical resection is the preferred first-line therapy and is often curative 3:

• All 48 UCD patients in one series underwent curative surgical resection with excellent prognosis 4
• Asymptomatic unresectable UCD may be observed 3
• Symptomatic unresectable UCD from compression may be rendered amenable to resection by medical therapy (rituximab, steroids), radiotherapy, or embolization 3
• Siltuximab (anti-IL-6 monoclonal antibody) should be considered for unresectable UCD patients with inflammatory syndrome 3

HHV-8-Associated Multicentric Castleman Disease

Rituximab monotherapy is first-line treatment, with etoposide added for severe cases 1:

• Rituximab monotherapy recommended as first-line by American College of Oncology 1
• Cytotoxic chemotherapy added for patients with concomitant Kaposi sarcoma 1
• Antiretroviral therapy must always be administered in HIV-positive patients 1
• Rituximab treatment reduces non-Hodgkin lymphoma incidence, though risk remains elevated 1

Idiopathic Multicentric Castleman Disease

Treatment options for severe inflammation or inadequate IL-6 blockade response include 1:

• Triple therapy with corticosteroids, rituximab, and cyclophosphamide 1
• Siltuximab (anti-IL-6 therapy) as targeted approach 2, 3
• Interferon-based therapies and anakinra for pediatric cases 1

POEMS-Associated Castleman Disease

Radiation therapy is definitive first-line treatment for localized disease; systemic chemotherapy followed by autologous stem cell transplantation for disseminated disease 6:

• Radiation achieves 97% 4-year overall survival for solitary/limited sclerotic bone lesions 6
• Melphalan-dexamethasone achieves 81% hematologic response and 100% neuropathy improvement 6
• Lenalidomide-dexamethasone preferred in patients with neuropathy due to lower neurotoxicity 6
• Autologous stem cell transplantation should be offered after induction chemotherapy, achieving 100% clinical improvement in eligible patients 6
• Avoid bortezomib-based regimens first-line due to induced neuropathy risk 6

Follow-up and Monitoring

Clinical follow-up every 3-6 months is recommended, monitoring for 1:

• Disease relapse
• Development of non-Hodgkin lymphoma
• Reactivation or progression of concomitant Kaposi sarcoma

For POEMS-associated disease, serum VEGF levels should be monitored as disease activity marker 6

Prognosis

• UCD: Excellent prognosis with complete surgical removal 4, 3
• MCD: Associated with considerable morbidity and mortality 2
• TAFRO syndrome: May have worse prognosis than non-TAFRO iMCD 5
• POEMS-CD: 68% 5-year survival with modern therapies, particularly interferon-based treatment; neurologic improvement significantly lags behind hematologic response with maximum response expected after 2-3 years 1, 6

Associated Conditions

Castleman disease can be associated with 8, 6:

• Immune complex-mediated membranoproliferative glomerulonephritis (MPGN) 8
• POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes) 1, 6
• Increased risk of malignancies including non-Hodgkin lymphoma 1

Critical Management Pitfalls

• Do not use radiation alone for disseminated POEMS-CD; systemic therapy is mandatory 6
• Do not discontinue treatment prematurely in POEMS-CD if immediate neurologic improvement is not apparent; continue therapy as neurologic response lags 2-3 years behind hematologic response 6
• Splenectomy may be considered for severe refractory anemia and thrombocytopenia 1
• Treatment should be continued indefinitely if tolerated in MCD 1