Castleman Disease

• Castleman disease is a rare condition affecting lymph nodes, and actually is a group of related conditions.
• Castleman disease is not cancer, although some of the methods used to treat Castleman disease also are used to treat cancers.
• There are two main forms of Castleman disease, unicentric (localized) and multicentric (found in different sites throughout the body).
• Signs and symptoms of Castleman disease occur most often with the multicentric form and can include
  • fever,
  • night sweats,
  • loss of appetite,
  • nausea,
  • vomiting, and
  • fatigue.
• The diagnosis of Castleman disease involves examination of a tissue sample (biopsy) by a pathologist.
• Treatment for Castleman disease is complex, and can involve a number of different types and classes of medications such as chemotherapy drugs, immunotherapy drugs, immunomodulator drugs, anti-viral drugs, and corticosteroids.
• Surgery may be used to treat unicentric Castleman disease or to help relieve symptoms in the multicentric form.
• Radiation therapy is another form of treatment sometimes used to destroy the abnormal tissue in Castleman disease.
• Giant lymph node hyperplasia and angiofollicular lymph node hyperplasia (AFH) are other names for Castleman disease.

Castleman disease is a rare disease of lymph nodes and similar tissues. Sometimes referred to as Castleman's disease, it is actually a group of so-called lymphoproliferative disorders, meaning disorders that are accompanied by abnormal growth (or proliferation) of the lymphatic tissue. The lymphatic (or lymphoid) tissue consists of different types of cells that are involved in the immune response, predominantly white blood cells known as lymphoctyes. Lymphatic tissue is found in lymph nodes, the tonsils, thymus, spleen, bone marrow, and gastrointestinal (GI) tract.

Abnormal growth of lymphoid tissue also is characteristic of lymphoma, a type of cancer, but Castleman disease is not cancer. Other names for Castleman disease are giant lymph node hyperplasia and angiofollicular lymph node hyperplasia (AFH).

Even though Castleman disease is not considered to be cancer, one type of this disease (multicentric Castleman disease, see below) behaves very much like lymph node cancer (lymphoma), and can lead to serious health risks.

There are no predictable signs and symptoms that suggest a person has Castleman disease. Some people with the condition do not show any signs or symptoms, while others will have a variety of symptoms.

Castleman disease has two forms, unicentric and multicentric.

Unicentric Castleman disease symptoms and signs

• Unicentric Castleman disease is localized and generally does not cause symptoms, although some affected people may have the symptoms associated with the multicentric form.
• People with unicentric Castleman disease have enlargement of lymph nodes in one area of the body.
• This form is much more common than multicentric Castleman disease, and is more likely to affect younger people.

Multicentric Castleman symptoms and signs

• Multicentric Castleman disease is more widespread, with abnormal enlargement of lymph nodes in locations throughout the body.
• In addition to noticeable swollen lymph nodes, other symptoms may be present, including:
  • Fever
  • Loss of appetite
  • Night sweats
  • Weight loss
  • Weakness
  • Fatigue
  • Shortness of breath
  • Cough
  • Numbness of extremities
  • Swollen legs
  • Rash or skin changes
  • Nausea
  • Vomiting

Castleman disease occurs when there is abnormal growth of the type of white blood cell known as lymphocytes. However, the exact reasons for this abnormal growth are not well understood. Elevated levels of a chemical associated with the normal immune response, known as interleukin-6 (IL-6), often is found in people with multicentric Castleman disease. People with multicentric Castleman disease often are found to have a virus known as human herpesvirus-8 (HHV-8), also known as Kaposi sarcoma herpesvirus (KSHV). HHV-8 is often found in the lymph node cells in people with multicentric Castleman disease, especially in those who are HIV positive. This may be the reason for the elevated levels of IL-6.

HHV-8 has not been seen in all cases of multicentric Castleman disease, and many people become infected with HHV-8 and do not develop Castleman disease, so the exact relationship between the viral infection and the condition is not fully understood.

No, Castleman disease is not considered to be an inherited condition.

The two types of Castleman disease are 1) unicentric, and 2) multicentric Castleman disease, as described previously.

Since Castleman disease is not a cancer, there is not a formal staging system (the stage of a cancer refers to the extent to which it has spread in the body). The two types - multicentric and unicentric (see above) - refer to the extent of disease in the body.

Castleman disease is rare, and there are no reliable estimates of its frequency in the population.

The diagnosis of Castleman disease is made by a tissue sampling (biopsy) of an affected lymph node. The tissue sample is examined by a pathologist (a physician specialized in the diagnosis of diseases from tissue samples) under a microscope, and additional special tests may be done on the tissue sample. A number of blood tests that evaluate immune function may also be performed, but the diagnosis itself depends upon identifying the abnormal lymph node tissue.

Treatment for Castleman disease can involve a combination of different approaches, including:

• Surgery to remove involved lymph nodes (see surgery section)
• Medications to reduce the abnormal immune response (see medication section)
• Radiation therapy to destroy areas of affected lymph nodes that cannot be removed surgically

Several different classes of medications have been used to treat Castleman disease.

• Corticosteroid drugs suppress the immune response. They can be useful in people with immune system disorders and some cancers. These drugs may be given alone, or sometimes in combination with the type of chemotherapy drugs used to treat cancers.
• These chemotherapy drugs are most often used in Castleman disease
  • carmustine (BiCNU),
  • cladribine (Leustatin),
  • chlorambucil (Leukeran),
  • cyclophosphamide (Cytoxan),
  • doxorubicin (Adriamycin, Rubex),
  • etoposide (Vepesid),
  • melphalan (Alkeran),
  • vinblastine, and
  • vincristine (Oncovin).
• Chemotherapy and corticosteroids may also be combined with radiation therapy to destroy the abnormal tissue.
• Immunotherapy involves administering drugs that boost or strengthen the body's natural immune response. Immunotherapy drugs include
  • siltuximab (Sylvant), a monoclonal antibody drug that binds to IL-6.
  • Rituximab (Rituxan) is a monoclonal antibody often used to treat lymphoma that is also sometimes used to treat Castleman disease.
  • Tocilizumab (Actemra) is an IL-6 receptor antagonist antibody that also has been used.
• Immunomodulating drugs such as thalidomide (Thalomid) and lenalidomide (Revlimid) are used to treat multiple myeloma and some lymphomas, and also can be helpful for some people with Castleman disease.
• Interferon-alfa (a man-made version of an immune-boosting substance produced by the body) is occasionally used to treat Castleman disease.
• Anti-viral medications such as ganciclovir, valganciclovir, and foscarnet have been successfully used to treat multicentric Castleman disease associated with infection with the virus HHV-8.

Surgical removal of the involved lymph nodes is a helpful way to treat unicentric (localized) Castleman disease. Surgery also may be used in multicentric Castleman disease as a way to control symptoms, although in multicentric Castleman disease, it is not typically possible to remove all of the affected lymph nodes.

A number of different specialists may be involved in the care of a patient with Castleman disease, depending upon the type and extent of the disease, including hematologist-oncologists, radiation therapy specialists, and surgeons. If the patient has HIV-associated Castleman disease, infectious disease specialists will also likely be involved in the patient's care.

Questions to ask the doctor about Castleman disease include the following:

1. What type of Castleman disease do I have?
2. How was the diagnosis established? Was my biopsy read by a pathologist who is an expert on Castleman disease? If not, should I have a second opinion?
3. What additional tests, if any, do I need?
4. Do you have experience treating patients with Castleman disease? Should I get a second opinion from another physicians regarding treatment options?
5. What are all the treatment options, and which do you recommend?
6. What are the side effects of treatment, and how will treatment affect my daily life?
7. What is the likelihood that the treatment will be successful? If the disease returns after treatment, what are my options?
8. What is my prognosis, or outlook for survival?
9. What kind of follow-up care will be required after treatment?
10. Am I eligible for any clinical trials or new treatments?

It is difficult to determine the outlook for any given individual with Castleman disease because the condition takes different forms and is very rare. Estimates of 3-year survival rates are based on whether the affected person is also infected with HIV and upon certain characteristics of the lymph nodes when observed under the microscope. For example, in a group of patients with unicentric Castleman disease who had certain microscopic features in their lymph nodes, 93% were alive 3 years after the diagnosis. In HIV+ patients with multicentric disease, only 28% were alive after 3 years. It is important to note that these survival statistics were based upon a small number of patients who were treated in the past, and treatments are always improving.