A Complete Overview of Unicentric and Multicentric Castleman Disease

Everything You Need to Know About Castleman Disease

Castleman disease (CD), also known as Castleman syndrome or giant lymph node hyperplasia, is a rare and poorly understood lymphoproliferative disorder that affects the lymph nodes and related tissues. First described by Dr. Benjamin Castleman in the 1950s, Castleman disease encompasses a group of disorders that share similar lymph node histopathology but can vary widely in their clinical presentation and behavior.

Castleman disease is characterized by abnormal cell growth and hyperplasia within the lymph nodes, which can result in a wide range of symptoms, from asymptomatic enlargement of a single lymph node to a life-threatening, multi-organ disease. The condition is broadly categorized into two forms: unicentric Castleman disease (UCD) and multicentric Castleman disease (MCD), each of which has different causes, presentations, and treatments.

In this comprehensive article, we’ll delve into the different types of Castleman disease, their pathophysiology, clinical features, diagnosis, and treatment options.

What is Castleman Disease?

Castleman disease refers to a group of rare lymphoproliferative disorders where the normal architecture of lymph nodes becomes disrupted due to excessive cell proliferation. These disorders can be divided into two main types based on their clinical presentation:

1. Unicentric Castleman Disease (UCD): In this form, the disease is localized to a single lymph node or a single group of lymph nodes. UCD is more common and generally has a better prognosis because it is often cured with surgical removal of the affected lymph node.
2. Multicentric Castleman Disease (MCD): This more aggressive form involves multiple lymph node regions and often results in systemic symptoms. MCD can be life-threatening and requires more intensive treatment. It is further divided into two subtypes:

• Human Herpesvirus-8-associated MCD (HHV-8-associated MCD): This subtype is strongly associated with human herpesvirus-8 (HHV-8) infection, particularly in patients who are HIV-positive.
• Idiopathic MCD (iMCD): In this subtype, the cause is unknown, and HHV-8 infection is absent. Idiopathic MCD can occur in both HIV-positive and HIV-negative individuals.

Pathophysiology of Castleman Disease

The exact mechanisms underlying Castleman disease remain poorly understood, but it is clear that dysregulation of the immune system plays a central role in the pathogenesis. In UCD, local factors within a single lymph node are likely responsible for the abnormal proliferation, whereas in MCD, systemic factors, such as excessive cytokine release, drive the disease.

1. Unicentric Castleman Disease (UCD)

In UCD, the disease is confined to one lymph node or a single group of lymph nodes. The exact cause remains unknown, but localized hyperplasia of lymphoid tissue is characteristic. The overproduction of certain cytokines, particularly interleukin-6 (IL-6), appears to be a key driver of the disease. IL-6 is a pro-inflammatory cytokine that plays a role in immune responses and inflammation, and its overproduction can lead to excessive growth of lymphoid tissue.

2. Multicentric Castleman Disease (MCD)

In MCD, the disease affects multiple lymph node regions and can involve various organs, resulting in systemic inflammation. Excessive cytokine production, especially IL-6, plays a major role in the pathogenesis of MCD. Elevated levels of IL-6 can lead to a “cytokine storm,” driving inflammation and causing the severe systemic symptoms associated with MCD, including fever, weight loss, and multi-organ dysfunction.

• HHV-8-associated MCD: This subtype is closely linked to infection with human herpesvirus-8 (HHV-8). HHV-8 is known to cause Kaposi sarcoma, and in the case of HHV-8-associated MCD, it leads to the proliferation of infected B cells, causing widespread lymph node hyperplasia and systemic symptoms.
• Idiopathic MCD (iMCD): The cause of iMCD is not well understood. Unlike HHV-8-associated MCD, there is no known viral infection driving the disease. However, elevated IL-6 levels are also commonly seen in iMCD, suggesting an autoimmune or autoinflammatory process may be involved. Genetic factors and environmental triggers may also play a role in the pathogenesis of iMCD.

Causes and Risk Factors

The exact cause of Castleman disease remains unknown, but several factors have been implicated in its development, particularly in the different subtypes.

1. Genetic and Environmental Factors

The cause of unicentric Castleman disease is largely unknown, though there may be a genetic predisposition in some individuals. Environmental factors, including chronic infections or immune system dysfunction, could contribute to localized lymph node hyperplasia.

2. Human Herpesvirus-8 (HHV-8)

HHV-8 is a well-established cause of HHV-8-associated multicentric Castleman disease. The virus infects B cells and can trigger their uncontrolled proliferation, leading to the development of the disease. HHV-8-associated MCD is particularly common in individuals with HIV/AIDS, where immune suppression allows the virus to replicate unchecked.

3. Immune Dysregulation

In both iMCD and HHV-8-associated MCD, immune dysregulation plays a key role in driving the disease. Elevated levels of IL-6 and other inflammatory cytokines are characteristic of MCD, leading to widespread lymph node hyperplasia and systemic inflammation.

4. HIV Infection

In patients with HIV, the immune system is compromised, making them more susceptible to infections like HHV-8. HIV-positive individuals are at higher risk for developing HHV-8-associated MCD. However, iMCD can occur in both HIV-positive and HIV-negative individuals.

Symptoms of Castleman Disease

The clinical presentation of Castleman disease can vary significantly depending on the subtype. UCD often presents with localized symptoms, while MCD tends to cause systemic, life-threatening symptoms.

1. Unicentric Castleman Disease (UCD)

Patients with UCD typically have localized symptoms related to the enlarged lymph node. Common features include:

• Painless lymph node enlargement: Usually in the chest, abdomen, or neck.
• Pressure effects: Large lymph nodes can compress nearby structures, leading to symptoms such as difficulty breathing, cough, or abdominal discomfort.
• General well-being: Most patients with UCD feel well, and systemic symptoms are uncommon.

2. Multicentric Castleman Disease (MCD)

MCD presents with more severe symptoms due to widespread lymph node involvement and systemic inflammation. Common features include:

• Generalized lymphadenopathy: Multiple regions of enlarged lymph nodes.
• Fever: Often high-grade and associated with night sweats.
• Fatigue: Severe fatigue is a common complaint in patients with MCD.
• Weight loss: Unintentional weight loss due to systemic inflammation.
• Organomegaly: Enlargement of the liver (hepatomegaly) or spleen (splenomegaly) is common in MCD.
• Edema: Fluid retention in the legs or abdomen due to low levels of albumin.
• Neurological symptoms: In some cases, MCD can cause neuropathy or other neurological complications.
• Anemia: MCD often causes anemia, thrombocytopenia, and hypoalbuminemia.

3. Complications

MCD can lead to life-threatening complications, including multi-organ failure, secondary infections, and certain cancers, such as Kaposi sarcoma (especially in HHV-8-associated MCD) or lymphoma. Early diagnosis and treatment are critical to avoid these severe outcomes.

Diagnosis of Castleman Disease

The diagnosis of Castleman disease can be challenging due to its rarity and variable presentation. A combination of clinical evaluation, imaging studies, histopathological examination, and laboratory tests is essential for accurate diagnosis.

1. Clinical Evaluation

The first step in diagnosing Castleman disease is a detailed clinical evaluation, including a thorough history and physical examination. The presence of enlarged lymph nodes, systemic symptoms (in MCD), and any associated conditions (such as HIV or HHV-8 infection) should raise suspicion for Castleman disease.

2. Imaging Studies

Imaging is essential for identifying the location and extent of lymph node enlargement and organ involvement. Common imaging modalities include:

• CT scan: A CT scan of the chest, abdomen, and pelvis is typically performed to assess the size and distribution of lymphadenopathy and to rule out other causes of lymph node enlargement, such as lymphoma.
• PET-CT: Positron emission tomography (PET) can be used to assess the metabolic activity of lymph nodes and help distinguish between benign and malignant causes of lymphadenopathy.

3. Lymph Node Biopsy

A lymph node biopsy is the definitive diagnostic test for Castleman disease. Histopathological examination of the biopsy will reveal characteristic features depending on the subtype:

• Hyaline vascular variant: This variant is more common in UCD and is characterized by small, tightly packed follicles with a “lollipop” appearance, due to the presence of penetrating blood vessels.
• Plasma cell variant: This variant is more common in MCD and is characterized by the proliferation of plasma cells, often accompanied by systemic inflammation.

4. Laboratory Tests

Several laboratory tests can help support the diagnosis and assess the severity of Castleman disease, particularly in MCD. These tests include:

• Elevated IL-6 levels: High levels of IL-6 are commonly seen in MCD and can help confirm the diagnosis.
• Inflammatory markers: Elevated C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) are common in MCD due to systemic inflammation.
• Complete blood count (CBC): Anemia, thrombocytopenia, and leukopenia can be seen in MCD.
• HIV and HHV-8 testing: Testing for HIV and HHV-8 is critical in patients with MCD to identify the underlying cause of the disease.

Differential Diagnosis

Several conditions can mimic the symptoms of Castleman disease, particularly when it presents with lymphadenopathy and systemic symptoms. It is essential to consider other diagnoses, including:

• Lymphoma: Both Hodgkin and non-Hodgkin lymphomas can present with similar lymph node enlargement and systemic symptoms. A biopsy is required to differentiate between Castleman disease and lymphoma.
• Autoimmune diseases: Conditions such as systemic lupus erythematosus (SLE) or sarcoidosis can cause lymph node enlargement and systemic symptoms similar to MCD.
• Chronic infections: Infections like tuberculosis or Epstein-Barr virus (EBV) can also cause lymphadenopathy and must be ruled out.

Treatment of Castleman Disease

The treatment of Castleman disease depends on the subtype, with different approaches required for unicentric and multicentric forms.

1. Unicentric Castleman Disease (UCD)

Surgical removal of the affected lymph node is the treatment of choice for UCD. Complete excision of the lymph node often results in a cure, and patients typically do not require additional therapy. For patients who cannot undergo surgery due to the location of the lymph node or other health conditions, radiation therapy may be considered.

2. Multicentric Castleman Disease (MCD)

The treatment of MCD is more complex and depends on the underlying cause (HHV-8-associated or idiopathic) as well as the severity of the disease.

• HHV-8-associated MCD: The primary treatment for HHV-8-associated MCD is antiviral therapy combined with immunomodulatory agents. Rituximab, a monoclonal antibody that targets CD20-positive B cells, is commonly used to control the disease by depleting B cells infected with HHV-8. Antiviral medications such as ganciclovir or valganciclovir are also used to control HHV-8 replication, particularly in patients with HIV.
For patients with HIV, antiretroviral therapy (ART) is essential to suppress HIV replication and boost immune function. ART, combined with rituximab, has dramatically improved outcomes for patients with HIV-associated MCD.

• Idiopathic MCD (iMCD): The treatment of iMCD often involves immunosuppressive and anti-cytokine therapies to control systemic inflammation. Siltuximab, an IL-6 inhibitor, is approved for the treatment of iMCD and is effective in controlling symptoms and reducing lymph node size. Tocilizumab, another IL-6 receptor antagonist, is also used in the management of iMCD.
For patients who do not respond to anti-IL-6 therapies, other immunosuppressive agents such as rituximab, cyclophosphamide, or corticosteroids may be used. These therapies help control the immune system and prevent disease progression.

3. Supportive Care

Supportive care is crucial for managing the symptoms and complications of MCD. This may include:

• Treatment of anemia: Blood transfusions or erythropoietin may be needed to manage anemia.
• Management of organomegaly: Enlarged organs, such as the spleen or liver, may require additional treatment if they cause discomfort or dysfunction.
• Infection prevention: Patients with MCD, particularly those on immunosuppressive therapy, are at increased risk of infections. Vaccinations and prophylactic antibiotics may be necessary to reduce the risk of opportunistic infections.

Prognosis and Complications

The prognosis for Castleman disease varies widely depending on the subtype and response to treatment.

1. Unicentric Castleman Disease (UCD)

The prognosis for UCD is generally excellent. Most patients are cured with surgical removal of the affected lymph node, and recurrence is rare. Long-term outcomes are generally favorable, and patients can expect a normal life expectancy following successful treatment.

2. Multicentric Castleman Disease (MCD)

The prognosis for MCD is more variable and depends on the underlying cause, disease severity, and response to treatment. Patients with HHV-8-associated MCD generally have a better prognosis with appropriate antiviral therapy and immunomodulatory treatment. However, patients with idiopathic MCD may have a more unpredictable course, with the potential for relapses and complications.

Complications of MCD include:

• Infections: Immunosuppressive therapy and HIV-related immune suppression increase the risk of opportunistic infections.
• Organ dysfunction: Persistent inflammation can lead to multi-organ dysfunction, particularly affecting the liver, kidneys, and lungs.
• Secondary malignancies: Patients with MCD are at increased risk of developing certain cancers, including lymphoma and Kaposi sarcoma.

Conclusion

Castleman disease is a rare and complex lymphoproliferative disorder that presents in both localized (unicentric) and systemic (multicentric) forms. While unicentric Castleman disease is typically curable with surgery, multicentric Castleman disease can be life-threatening and requires a multifaceted treatment approach. Understanding the different subtypes, their pathophysiology, and the available treatment options is essential for providing optimal care to affected patients.

For medical students and doctors, Castleman disease represents an important but rare differential diagnosis in patients presenting with lymphadenopathy and systemic symptoms. Advances in immunotherapy and antiviral treatments offer hope for improved outcomes, particularly for patients with multicentric disease.