Castleman

Castleman disease is a group of rare disorders characterized by an overactive immune system. Typically, the immune system activates to combat threats like bacteria or viruses and then returns to a resting state, ready for future challenges. However, in Castleman disease, the immune system remains persistently active, causing chronic inflammation that can damage multiple organs and even be fatal.

Lymph nodes are small organs that work with the immune system to filter substances. During illnesses, lymph nodes ramp up their efforts to eliminate bacteria, viruses, and other cells produced by the body to fight these threats. This can cause an overgrowth of cells within the lymph nodes, leading to their enlargement.

In Castleman disease, one or more lymph nodes become swollen and show tissue changes when examined under a microscope or with various staining techniques.

Different Types of Castleman Disease

Castleman disease is classified as unicentric or multicentric, depending on the number of regions in the body with enlarged lymph nodes. Each type requires different treatments.

Unicentric Castleman Disease (UCD)

Unicentric Castleman disease, also known as localized Castleman disease, results in the enlargement of one or more lymph nodes in a single body region. The exact cause of UCD is unknown.

Multicentric Castleman Disease (MCD)

Multicentric Castleman disease leads to the enlargement of lymph nodes in multiple body regions and can be further classified into three categories:

• POEMS-associated MCD: This rare blood disorder sometimes occurs with MCD and is named after its associated signs and symptoms, including polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, and skin changes.
• HHV-8-associated MCD: Human herpesvirus-8 (HHV-8) is a common virus, and individuals with HIV or other conditions that compromise their immune system are at higher risk for HHV-8-associated MCD.
• Idiopathic MCD (iMCD): This is the most common form of MCD with unknown causes. It is subcategorized into three types: iMCD associated with TAFRO, iMCD with idiopathic plasmacytic lymphadenopathy (iMCD-IPL), and iMCD not otherwise specified (iMCD-NOS).

Is Castleman Disease a Cancer?

Researchers are still working to determine how to classify Castleman disease. Some autoimmune conditions, cancers, or infections can cause lymph node changes or symptoms similar to those seen in Castleman disease. It is currently uncertain whether Castleman disease should be considered an autoimmune disease, cancer, or infectious disease.

Who Does Castleman Disease Affect?

Castleman disease can affect people of any age. UCD is more commonly diagnosed in people in their 30s and 40s, while MCD tends to occur in individuals in their 50s and 60s. UCD affects all genders equally, while MCD is slightly more common in men and individuals assigned male at birth (AMAB).

How Common is Castleman Disease?

Castleman disease is rare, with approximately 4,300 to 5,200 new cases diagnosed in the United States each year. Around 75% of these cases are UCD, while the remaining 25% are MCD.

Symptoms and Causes

What Causes Castleman Disease?

The causes of UCD are unknown. HHV-8 infection is associated with MCD, and the risk of developing HHV-8-associated MCD is higher in individuals with HIV or other conditions that weaken the immune system. Researchers are exploring potential causes of UCD and iMCD, including other infections, gene mutations, and autoimmune responses.

What are the Symptoms of Castleman Disease?

Symptoms vary depending on the type of Castleman disease. UCD may not cause noticeable symptoms, with enlarged lymph nodes being the primary sign. UCD may be discovered incidentally during imaging for other health issues. If symptoms do occur, they are often due to an enlarged lymph node pressing on nearby organs.

MCD is more likely to cause noticeable changes, including fever, night sweats, nausea, vomiting, unexplained weight loss, fatigue, enlarged lymph nodes, splenomegaly (enlarged spleen), hepatomegaly (enlarged liver), numbness in extremities, ankle and foot swelling, abdominal swelling, anemia (low red blood cell count), and low platelet count (thrombocytopenia).

Diagnosis and Tests

How is Castleman Disease Diagnosed?

Diagnosing Castleman disease can be challenging because its symptoms can overlap with other common conditions. Healthcare providers often conduct various tests to rule out these conditions and perform additional tests to determine the specific type of Castleman disease.

Diagnostic measures may include:

• Biopsy: A lymph node biopsy is the definitive method to identify characteristic pathological changes associated with Castleman disease. During a biopsy, a tissue sample is taken from a lymph node or the entire lymph node itself and examined under a microscope to confirm Castleman disease features. Additionally, a test is conducted on the tissue to detect HHV-8 presence, which determines the specific type of Castleman disease.
• Blood and urine tests: These tests are employed to identify signs of MCD. Parameters checked may include blood cell counts to detect anemia, thrombocytosis, or thrombocytopenia. An HIV test may be conducted, as HHV-8-associated MCD often co-occurs with HIV.
• Imaging tests: Procedures like X-rays, CT scans, MRIs, and PET scans are used to locate enlarged lymph nodes within the body and identify other Castleman disease indicators, such as splenomegaly or hepatomegaly.

Management and Treatment

How is Castleman Disease Managed or Treated?

The treatment of Castleman disease depends on the specific type:

Unicentric Castleman Disease (UCD) Treatment

For UCD, the primary treatment involves surgically removing the affected lymph nodes. Depending on the location and size of the lymph nodes, radiation therapy or immunotherapy may be administered prior to surgery to reduce lymph node growth, facilitating their surgical removal. In cases where surgery is not feasible and if the patient is asymptomatic, a “watch and wait” approach may be adopted. If symptoms emerge, treatments intended for multicentric Castleman disease may be recommended.

Multicentric Castleman Disease (MCD) Treatment

MCD is more challenging to treat than UCD, and surgical or radiation therapy is usually not employed due to its widespread nature. Treatment approaches for MCD depend on the presence of HHV-8 and the disease’s severity. Options may include:

• Corticosteroids: These medications reduce inflammation and provide rapid symptom relief, often recommended for critically ill individuals to manage inflammation promptly.
• Chemotherapy Drugs: Anticancer medications that slow excessive cell growth in the lymphatic system. Rituximab is commonly prescribed to treat HHV-8-associated MCD.
• Immunotherapy: The use of humanized monoclonal antibodies to enhance the immune system. Siltuximab, approved by the U.S. Food and Drug Administration (FDA) in 2014, is employed to block the growth-stimulating protein in MCD.
• Antiviral Drugs: These medications are used for treating HIV or HHV-8. If a person has HHV-8-associated MCD in conjunction with another infection, a combination of antiviral drugs and other treatments may be necessary.

Complications

Castleman disease can elevate the risk of developing cancer, particularly lymphoma. MCD can also increase the susceptibility to infections that may harm organs and pose life-threatening risks without prompt treatment. Close monitoring and tailored treatment are essential to prevent complications where possible.

Prevention

No specific risk factors for UCD or iMCD are known. The primary risk factor for HHV-8-associated MCD is having HIV or a weakened immune system. Currently, there are no preventative measures against most forms of Castleman disease.

Outlook / Prognosis

The prognosis for UCD is typically very favorable, and it rarely affects life expectancy. Surgical removal of affected lymph nodes is often curative.

For MCD, the outlook depends on the specific type and disease severity. Some individuals experience intense flares that can be life-threatening, while others have more chronic symptoms. Approximately 65% to 75% of people diagnosed with MCD survive for at least five years. With the advent of breakthrough therapies, there is optimism for continued improvement in the outlook.

The prognosis may vary based on the specific type of Castleman disease and other factors, such as the presence of other medical conditions.

Living With Castleman Disease

When to Call the Doctor:

Seek medical attention if you notice a lump in your neck, armpit, or groin, or experience symptoms of Castleman disease that persist for several weeks. Symptoms can often overlap with those of more common illnesses, and a definitive diagnosis typically requires a lymph node biopsy, which should be conducted after excluding other potential causes of your symptoms.

Questions to Ask Your Doctor:

When discussing your condition with your healthcare provider, consider asking the following questions:

• Which specific type of Castleman disease do I have?
• What tests are recommended for my case?
• What is the most suitable treatment for me?
• What potential side effects may accompany my treatment?
• What symptoms should I be vigilant about that may indicate a Castleman disease-related complication?