Castleman Disease

Content of This Page

1- Introduction

2- Pathophysiology

3- Classification of Castleman Disease

4- Epidemiology and Risk Factors

5- Clinical Features

6- Investigations

7- Treatment

8- Prognosis & Follow-up

9- Castleman Disease in HIV and HHV-8 Infection

Introduction

Castleman Disease (CD) is a rare, non-clonal lymphoproliferative disorder characterized by abnormal growth of lymphoid tissue. First described by Dr. Benjamin Castleman in the 1950s, it represents a heterogeneous group of conditions that share similar histopathological features but differ widely in clinical presentation, pathogenesis, and prognosis. It is classified into:

Unicentric Castleman Disease (UCD): Affects a single lymph node region, often asymptomatic, and usually curable with surgery.
Multicentric Castleman Disease (MCD): Involves multiple lymph nodes with systemic symptoms; may be linked to HHV-8 or occur idiopathically.

Pathophysiology

1. Unicentric Castleman Disease (UCD):

The exact cause is unclear, but it is thought to result from a localized, reactive lymph node hyperplasia.
Abnormal follicular dendritic cell (FDC) proliferation and increased vascularity are common histologic findings.
Interleukin-6 (IL-6) may be locally elevated but is usually not systemically increased.

2. Multicentric Castleman Disease (MCD):

MCD is driven by chronic systemic inflammation, often mediated by elevated IL-6 levels, leading to widespread lymphoid hyperplasia and systemic symptoms.

a. HHV-8-associated MCD:

Common in HIV-positive individuals.
HHV-8 infects B cells and promotes excessive IL-6 and viral IL-6 (vIL-6) production.
This leads to systemic inflammation, angiogenesis, and immune dysregulation.

b. Idiopathic MCD (iMCD):

Occurs without HHV-8 or HIV infection.
Cause remains uncertain, but IL-6 is a key driver.
Likely involves autoimmune, autoinflammatory, or neoplastic mechanisms.
Some cases show involvement of plasmablasts or clonal expansions of immune cells.

Key Mediators:

Interleukin-6 (IL-6): Central to both MCD and, to a lesser extent, UCD.
Vascular Endothelial Growth Factor (VEGF): Contributes to angiogenesis and lymph node enlargement.
B-cell and plasma cell activation: Drives lymph node hyperplasia and systemic symptoms.

Classification of Castleman Disease

1. Clinical Classification:

A. Unicentric Castleman Disease (UCD):

Involves a single lymph node region.
Often asymptomatic or causes local symptoms due to mass effect.
Usually has a benign course and is curable with surgical excision.

B. Multicentric Castleman Disease (MCD):

Involves multiple lymph node regions.
Associated with systemic inflammatory symptoms such as fever, weight loss, and fatigue.
Further subdivided into:
- HHV-8-associated MCD (typically in HIV-positive patients)
- Idiopathic MCD (iMCD) (no evidence of HHV-8 or HIV)
- POEMS-associated MCD (seen in patients with POEMS syndrome)

2. Histopathological Classification:

Regardless of clinical type, lymph node biopsy in CD may show one of the following patterns:

A. Hyaline Vascular Type:

Most common in UCD.
Characterized by small hyalinized follicles and prominent vascular proliferation.

B. Plasma Cell Type:

Common in MCD.
Shows hyperplastic germinal centers and sheets of plasma cells in interfollicular zones.

C. Mixed Type:

Features of both hyaline vascular and plasma cell types.

3. Etiologic Classification (Specific to MCD):

Subtype	Association
HHV-8-associated MCD	HIV-positive or immunocompromised
Idiopathic MCD (iMCD)	Unknown cause, often autoimmune-like
POEMS-associated MCD	Linked to POEMS syndrome

Epidemiology and Risk Factors

Epidemiology:

1. General Prevalence:

Castleman Disease (CD) is rare, with an estimated incidence of:
- UCD: ~15–30 cases per million per year.
- MCD: Less common but more severe; precise global incidence is unclear due to underdiagnosis.

2. Age and Gender:

Unicentric CD (UCD):
- Can occur at any age.
- Most commonly diagnosed in young adults (20–40 years).
- Slight female predominance.
Multicentric CD (MCD):
- Typically affects middle-aged to older adults.
- HHV-8-associated MCD is more frequent in HIV-positive men, especially in their 30s–50s.
- Idiopathic MCD (iMCD) affects both genders equally.

3. Geographical Distribution:

HHV-8-associated MCD is more common in areas with high HIV or HHV-8 prevalence, such as:
- Sub-Saharan Africa
- Parts of the Mediterranean
- Some regions in Asia and Latin America

Risk Factors:

1. Viral Infections:

Human Herpesvirus 8 (HHV-8):
- Strongly associated with HHV-8-associated MCD.
- Viral IL-6 mimics human IL-6, driving disease pathogenesis.
HIV Infection:
- Increases the risk of HHV-8 infection and MCD development.

2. Immunosuppression:

Immunocompromised individuals, especially those with HIV/AIDS or on immunosuppressive therapy, are at higher risk of MCD.

3. Autoimmune Conditions (iMCD):

Some idiopathic MCD cases may be associated with autoimmune or autoinflammatory processes.
Exact triggers are unclear but may involve dysregulated cytokine production, especially IL-6.

4. POEMS Syndrome:

A rare paraneoplastic disorder involving polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, and skin changes.
Associated with a subset of MCD cases.

Clinical Features

Unicentric Castleman Disease (UCD):
Usually asymptomatic or causes localized symptoms due to an enlarged lymph node (e.g., neck mass, cough, abdominal discomfort). Systemic symptoms are rare.
Multicentric Castleman Disease (MCD):
Causes systemic symptoms such as fever, night sweats, fatigue, weight loss, and generalized lymphadenopathy. Patients may also have hepatosplenomegaly, anemia, elevated inflammatory markers, and polyclonal hypergammaglobulinemia.

POEMS-associated MCD includes additional features like polyneuropathy, endocrine disorders, and skin changes.

Investigations

Blood Tests:
Show anemia, elevated inflammatory markers (CRP, ESR), high IL-6, and polyclonal hypergammaglobulinemia—especially in Multicentric CD (MCD).
Viral Testing:
Check for HIV and HHV-8 to assess risk for HHV-8–associated MCD.
Imaging:
CT or PET-CT scans help identify lymphadenopathy, organ enlargement, and distinguish between Unicentric (UCD) and Multicentric (MCD) types.
Lymph Node Biopsy (Excisional):
Essential for diagnosis; shows hyaline vascular, plasma cell, or mixed patterns.

Bone Marrow Biopsy:
Done in MCD to assess plasma cell involvement or POEMS syndrome features.

Treatment

Unicentric Castleman Disease (UCD):
- Surgical excision is the treatment of choice and usually curative.
- Radiotherapy is used if surgery isn’t possible.
Multicentric Castleman Disease (MCD):
- HHV-8–associated MCD:
  - Rituximab (with or without chemotherapy)
  - Antiviral therapy and HIV treatment (cART) if HIV-positive
- Idiopathic MCD (iMCD):
  - Anti–IL-6 therapy (Siltuximab or Tocilizumab)
  - Corticosteroids or immunosuppressants if needed
- POEMS-associated MCD:
  - Treat underlying plasma cell disorder (e.g., chemotherapy or stem cell transplant)
Supportive care includes managing anemia, infections, and inflammation.

Treatment is tailored based on disease type and underlying causes.

Prognosis & Follow-up

Unicentric Castleman Disease (UCD):
- Excellent prognosis with surgical removal (5-year survival >95%).
- Rarely recurs.
- Follow-up: Annual clinical checks; imaging only if needed.

Multicentric Castleman Disease (MCD):
- Variable prognosis, depending on the subtype:
  - HHV-8–associated: Improved with rituximab and HIV therapy.
  - Idiopathic MCD: May relapse or progress; response to IL-6 therapy varies.
  - POEMS-associated: Outcome depends on treatment of plasma cell disorder.
- Follow-up: Every 3–6 months with physical exams, labs (CBC, CRP, IL-6), and imaging.

Castleman Disease in HIV and HHV-8 Infection

HHV-8–associated Multicentric Castleman Disease (MCD) is common in HIV-positive individuals.
Caused by HHV-8 infection of B-cells, leading to overproduction of viral IL-6 and systemic inflammation.
Symptoms: Fever, night sweats, lymphadenopathy, hepatosplenomegaly, and cytopenias.
Diagnosis: Lymph node biopsy and detection of HHV-8 (via PCR or immunohistochemistry).
Treatment:
- cART (HIV control)
- Rituximab (first-line therapy)
- Chemotherapy for severe or refractory cases

Prognosis: Good with proper treatment; poor if untreated or immunosuppressed.