1. What is Castleman disease?
  2. What are the different types of Castleman disease?
  3. What causes Castleman disease?
  4. How prevalent is Castleman disease and what are the demographics?
  5. What are risk factors for developing Castleman disease?
  6. Is Castleman disease a form of cancer?
  7. What are the symptoms of Castleman disease?
  8. What abnormal laboratory values are typically seen in Castleman disease?
  9. What lymph node changes are seen in Castleman disease?
  10. How is Castleman disease diagnosed?
  11. What are some of the possible causes of HHV-8-negative or "idiopathic" MCD (iMCD)?
  12. What is the relationship between iMCD and risk of cancer?
  13. What are the treatment options for Castleman disease?
  14. What is the typical prognosis and survival for Castleman disease patients? What is the risk of recurrence?
  15. What is the CDCN doing to combat Castleman disease? 
  16. How can I help accelerate finding a cure for Castleman disease?
  17. Am I safe to get pregnant?

1. What is Castleman disease?

Castleman disease (CD) describes a group of rare and poorly-understood hyperinflammatory disorders that occur in people of all ages, cause lymph node enlargement, and can cause dysfunction of multiple organ systems. CD can occur in a single lymph node (unicentric) or multiple lymph nodes (multicentric). 

CD patients have symptoms very similar to patients with lymphoma. CD is as common as ALS. The multicentic subtype, MCD, is as deadly as cancer (average for all cancers combined). 

Inflammation is the body’s normal response by the immune system to fight off infection. This response utilizes a complex and interconnected network of cells and chemical messengers (cytokines) to fight these infections off. In CD patients, these inflammatory cells are signaled to activate and produce cytokines for an unknown reason. This abnormal cytokine production leads to lymph node enlargement and organ dysfunction. 

Unicentric Castleman disease (UCD) involves a single enlarged lymph node (or single region of enlarged lymph nodes) and typically presents with discomfort associated with the enlarged lymph node but can occasionally involve some systemic MCD-like symptoms (see below). Surgical removal of the enlarged node usually eliminates CD from the patient resulting in no further complications or relapses. However, a minority of patients will not have a complete resolution of symptoms. There are no known cases reported of UCD becoming or transitioning into MCD.

Multicentric Castleman disease (MCD) involves multiple enlarged lymph nodes and can cause multi-organ system impairment due to cytokine release by activated inflammatory cells. MCD can range in seriousness from mild fatigue in some patients to severe episodes of life-threatening organ failure and death in other patients. MCD can be caused by infection with Human Herpes Virus-8 ("HHV-8-associated MCD") or can occur for unknown reasons (HHV-8-negative or idiopathic "iMCD").  It is extremely important to differentiate this disease into either UCD, HHV-8-associated MCD, or iMCD because they can have different symptoms, treatments, and prognoses.

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2. What are the different types of Castleman disease?

CD is first classified based on the number of lymph node regions that are affected (UCD vs MCD). A patient with a single enlarged lymph node, which is found to have Castleman disease features under the microscope after biopsy, is diagnosed with UCD. A patient with enlarged lymph nodes in multiple locations, Castleman disease features under the microscope on biopsy, and the corresponding symptoms, is diagnosed with MCD.

MCD is sub-classified based on the presence or absence of human herpesvirus-8 (HHV-8). If a patient’s lymph node or blood sample is found to be HHV-8 positive, then he/she is considered to have HHV-8-associated MCD. HHV-8-associated MCD patients are often also HIV-positive, but there are also HIV-negative individuals with HHV-8-associated MCD. If the patient is HIV-negative and his/her lymph node and blood sample are HHV-8-negative, that patient is considered to have HHV-8-negative or idiopathic MCD (iMCD). (The term “idiopathic” is often given to diseases for which the cause is unknown.)

The "histopathological subtype," such as hyaline vascular, plasmacytic, mixed, and plasmablastic, refers to how the patient’s lymph node appears under a microscope when it’s biopsied. However, it means very little for determining prognosis and treatment. Different pathological features can be found in the same patient and these features can change. The most important distinctions are:

  1. Is there one enlarged lymph node (UCD) or many enlarged lymph nodes in multiple regions of the body (MCD)?

  2. If MCD, is the patient HHV-8-positive or HHV-8-negative?
 

 

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3. What causes Castleman disease?

Very little research had been done into CD prior to 2012 when the CDCN was founded. Therefore, very little is known about how it works.

HHV-8-associated MCD is cause by an infection with HHV-8 (human herpesvirus-8) that gets out of control. Many of these patients' immune systems have been significantly compromised or suppressed by HIV infection or another cause of immunodeficiency (e.g., a genetic disorder, immunosuppressive medications) that predisposes the patient to the HHV-8 infection getting out of control. HHV-8 then replicates in the lymph nodes and signals for the release of an excessive amount of cytokines, such as interleukin-6 (IL-6). In all healthy individuals, cytokines, including IL-6, are used by the immune system to fight infections and keep the body healthy. However, when too many cytokines are released (hypercytokinemia), an overabundance of inflammatory cells are signaled to replicate and organs are damaged by the immune activation. The virus initiates and drives the production of molecules that lead to flu-like symptoms, lymph node enlargement, drops in blood counts, and dysfunction of vital organs, such as the kidneys, liver, heart, and lungs. 

The causes of UCD and iMCD are completely unknown. iMCD patients also exhibit elevated levels of cytokines, such as IL-6, but the cause of its release is not known. Click here for a list of the current hypotheses for what causes iMCD.

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4. How prevalent is Castleman disease and what are the demographics?

The exact number of people diagnosed with CD each year is not known. Recent estimates suggest the incidence of Castleman disease (UCD, HHV-8-associated MCD, and iMCD combined) to be approximately 6,500 to 7,700 new cases per year in the US. MCD is estimated to account for one in three CD cases, with about one-third of those being HHV-8-associated MCD and the other two-thirds being iMCD.

CD can occur in males and females at any age, including young children, but UCD is more common in 20-30 year olds, HHV-8-associated MCD and iMCD are more common in 40-60 year olds. UCD is slightly more common in females, while HHV-8-associated MCD and iMCD are slightly more common in males.

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5. What are risk factors for developing Castleman disease?

Again, very little is known about this disease. To date, no risk factors for UCD or iMCD have been identified, though the possibility of a genetic predisposition is being investigated.

Risk factors for HHV-8-associated MCD include anything that significantly suppresses the immune system therefore predisposing individuals to uncontrolled HHV-8-infection including HIV, genetic disorders, immunosuppressing medications, and organ transplantation.

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6. Is Castleman disease a form of cancer?

Currently, CD is not considered to be a form of cancer, but more research is needed to confirm this. Patients with HHV-8-associated MCD and iMCD sometimes have signs and symptoms that are difficult to distinguish from an aggressive lymphoma.

CD is considered to be a lymphoproliferative disorder (lymphocytes proliferate and produce cytokines that cause systemic inflammation). Lymphoproliferative disorders can be cancers, autoimmune/autoinflammatory diseases, or infectious diseases. Research is currently underway by the CDCN to uncover this. Cancer involves genetic changes to healthy cells during one's lifetime that turn those healthy cells into cancer cells. Autoimmune and autoinflammatory disorders involve genetic changes that individuals are born with. Infectious diseases are caused by infectious agents like viruses.

HHV-8-associated MCD is caused by HHV-8 and is therefore a virally-caused lymphoproliferative disorder.

There are also a number of case reports of CD patients being subsequently diagnosed with a hematologic malignancy. In iMCD patients, malignancies are diagnosed at an increased frequency within two years of their iMCD diagnosis. One explanation is that these malignant cells may have been present all along and actually secreted the IL-6 or other cytokine that was responsible for the patient’s iMCD. Alternative hypotheses for the frequent association between iMCD and malignancy include:

  1. iMCD is a "pre-lymphoma" that eventually transforms into cancer.

  2. Excessive cytokine release promotes malignant transformation.

  3. iMCD treatments cause or increase susceptibility to secondary malignancies.

  4. An unidentified virus may be responsible for both the iMCD and the malignancy.

We suggest that a search for an underlying malignancy be conducted in all newly diagnosed iMCD patients. Further research is needed to better understand the relationship between iMCD and malignancies.

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7. What are the symptoms of CD?

UCD: Patients often show no symptoms except for the discomfort associated with the enlarged lymph node as well as symptoms that may be related to the enlarged lymph node pushing on nearby structures. Patients can occasionally present with systemic MCD-like symptoms. Other UCD patients can go on to develop paraneoplastic pemphigus, which is a very serious disorder requiring prompt treatment.

MCD: Patients can present with a wide range of symptoms from mild flu-like episodes to severe, life-threatening multi-organ failure. Some of the systemic symptoms include:

  • Fever and night sweats

  • Fatigue

  • Loss of appetite

  • Cachexia (weakness and wasting of the body, muscle atrophy, unintended weight loss)

  • Nausea and vomiting

  • Numbness in the hands and feet

  • Enlarged liver and/or spleen

  • Eruption of cherry hemangiomas (cherry red papules that form from an abnormal growth of blood vessels on the skin)

  • Edema (swelling), ascites (fluid accumulation in the abdomen), and/or other symptoms of fluid overload (extensive fluid accumulation, if present, may result in a net weight gain despite cachexia)

  • Decreased urine output and systemic toxicity due to kidney failure

  • Bruising, easy bleeding, and risk of infection due to bone marrow failure

8. What abnormal laboratory values are typically seen in Castleman disease?

UCD: Most UCD patients do not experience a change in blood test results, but some may experience similar changes to those seen in MCD (see below).

MCD: Individuals will often demonstrate several of the following abnormal blood test results (also listed on the Diagnostic Criteria):

  • Elevated erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and fibrinogen

  • Low hemoglobin (anemia), low platelet count (thrombocytopenia)

  • Elevated lymphocytes and plasma cells (polyclonal lymphocytosis and plasmacytosis)

  • Elevated BUN and creatinine (decreased kidney function)

  • Proteinuria (protein in urine)

  • Low albumin (hypoalbuminemia)

  • Elevated gamma globulin (hypergammaglobulinemia)

  • Elevated IL-6 and vascular endothelial growth factor (VEGF)

  • Autoimmune antibodies, such as antinuclear antibodies (ANA), anti-erythrocyte antibodies, and anti-platelet antibodies

Patients with the TAFRO subtype of iMCD may have a low platelet count (Thrombocytopenia), swelling in their abdomen and extremities due to fluid accumulation (Anasarca), a specific finding in the bone marrow called reticulin staining (Fibrosis), kidney (Renal) failure, and/or an enlarged liver an/or spleen (Organomegaly) in addition to other symptoms of HHV-8-negative (iMCD). Other iMCD patients often have elevated platelet counts, less severe fluid accumulation, and elevated gamma globulin levels. 

 

9. What lymph node changes are seen in Castleman disease?

CD lymph nodes demonstrate several characteristics on biopsy which can be divided into one of four variants: 

  1. Hyaline-Vascular (HV): Characterized by widened mantle zones composed of concentric rings of small lymphocytes in an "onion skin" pattern around small atrophic germinal centers with penetrating hyalinized vessels and dysplastic follicular dendritic cells (FDCs).
  2. Plasma Cell (PC): The germinal centers are hyperplastic rather than atrophic, the interfollicular region contains sheets of plasma cells and vascular proliferations, the FDC network is normal, and there is preserved lymph node architecture. 
  3. Mixed: Displays features of nboth the HV and PC variants.
  4. Plasmablastic: Displays features similar to the PC variant but with even greater vascularization and also notable for the presence of immature plasmablasts. This is only found in HHV-8-associated MCD.

The reliability and significance of these variants is unclear, as there are reports of transitions between HV and PC variants on subsequent biopsies as well as the simultaneous presence of both types in separate lymph nodes within the same patient. Also, these same features can be seen in other diseases that behave similarly to Castleman disease, which makes diagnosis extremely challenging. See table below (FAQ #10) for a list of other diseases and conditions that can demonstrate similar “Castleman disease-like” lymph node features.

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10. How is Castleman disease diagnosed?

Diagnosis of CD is difficult because CD symptoms are similar to those of other diseases, the CD lymph node features are found in other inflammatory disorders, and there are no specific tests to confirm the presence of CD. The first-ever diagnostic criteria for idiopathic multicentric Castleman disease (iMCD) was published in 2016 in the top hematology journal in the world, Blood! You can review details of the diagnostic criteria here or read the full article here: http://www.bloodjournal.org/content/129/12/1646.long Ultimately, a diagnosis is usually given when an enlarged lymph node is biopsied and found to have one of the four  “Castleman disease-like” lymph node appearances described above (FAQ #9) and the patient has several of the symptoms and laboratory values described above (FAQs #7 and #8). In order for a diagnosis to be made, all other possible causes of those “Castleman disease-like” features have been ruled out. Below is a table of diseases and conditions that have been reported to cause “Castleman disease-like” lymph node features. These diseases should be ruled out before CD is confirmed.

Neoplastic

Inflammatory

Infectious/Toxin Ingestion

Non-Hodgkin Lymphoma

Systemic Lupus Erythematous

Epstein-Barr Virus

Cutaneous Lymphoma

Rheumatoid Arthritis

HIV

Hodgkin Lymphoma

Sjogren Syndrome

Hydrochoride Ingestion

Cardiac Myxoma

Relapsing Polychondritis

 

Multiple Myeloma

Systemic IgG4 Plasmacytic Syndrome

 

Clear Cell Meningioma

Systemic/Cutaneous Plasmacytosis

 

Choroid Meningioma

 

 

Giant Cell Carcinoma of lung

 

 

Calcifying Fibrous Pseudotumor

 

 

Inflammatory Myofibroblastic Tumor

 

 

Diagnosis is further complicated by the fact that several disorders are reported to occur simultaneously with CD. These disorders may or may not be the cause of CD. A list of these disorders is provided below.

Neoplastic

Inflammatory

Infectious

POEMS Syndrome

Adult Onset Still’s Disease

Human Herpes Virus 6

Paraneoplastic Pemphigus

Systemic Juvenile Idiopathic Arthritis

Hepatitis B Virus

Melanoma

Sarcoidosis

Toxoplasma

Angioimmunoblastic T-cell Lymphoma

Amyloidosis

Mycobacterium Tuberculosis

Indolent T-Lymphoblastic Proliferation

Pure Red Cell Aplasia

Cytomegalovirus

Inflammatory Hepatocellular Adenoma

Acquired Factor VIII Deficiency

Toxoplasma

 

Myasthenia Gravis

 

 

Familial Mediterranean Fever

 

 

Glomerulonephritides

 


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11. What are some of the possible causes of HHV-8-negative or idiopathic MCD (iMCD)?

It has been recently proposed that there may be multiple causes of iMCD, with each cause involving an imbalance in the immune system and a common pathway leading to the release of pro-inflammatory cytokines.

Four hypotheses have been proposed as potential causes of iMCD and are currently under intense investigation:

  1. Autoimmune hypothesis: There may be antibodies directed against healthy tissue in the patient that stimulate the immune system to be overactive thus causing the release of inflammatory molecules or "cytokines" that lead to iMCD symptoms.

  2. Autoinflammatory hypothesis: There may be a genetic defect in the ability to turn off the immue system, which leads to hyper-activity.

  3. Paraneoplastic syndrome hypothesis: There may be acquired oncogenic ("cancer-causing") mutations that cause cytokines to be secreted by either cells within CD lymph nodes or from cells associated with a simultaneously-present cancer.

  4. Pathogen hypothesis: There may be an undiscovered pathogen (i.e. a virus other than HHV-8) that is causing uncontrolled immune activation and cytokine release similar to the way that HHV-8 does in HHV-8-associated MCD.

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12. What is the relationship between iMCD and risk of cancer?

Hematologic malignancies are diagnosed at an increased frequency within two years of iMCD diagnosis. The exact reason for this increased risk is not known. These malignant cells may have been present all along and actually secreted the IL-6 that was responsible for the preceding iMCD symptoms and diagnosis. Alternative explanations for the frequent association between iMCD and malignancy include 1) that iMCD is a "pre-lymphoma" that eventually transforms, 2) excessive cytokine release promotes malignant transformation, 3) iMCD treatments cause or increase susceptibility to secondary malignancies, or 4) an unidentified virus may be responsible for both the iMCD and the malignancy. We suggest that a search for an underlying malignancy be conducted in all newly diagnosed HHV-8-negative (iMCD) patients. Further research is needed to better understand the relationship between HHV-8-negative (iMCD) and malignancies.

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13. What are the treatment options for Castleman disease?

UCD: Surgical removal of the enlarged lymph node is the first line of therapy against UCD. If removal is not possible or curative, the below iMCD treatments may also be used to treat UCD.

MCD: Treatment for MCD (both HHV-8-associated and idiopathic) is not as straightforward. For reasons not yet understood, many of the options are effective in some patients but ineffective in others.

HHV-8-associated MCD: Treatment of HHV-8-associated MCD with rituximab to deplete B cells is highly effective. If patients relapse, additional administration of rituximab is often effective to induce a subsequent remission. Occasionally, additional treatments, such as cytotoxic chemotherapies are needed. If the patient is HIV positive, then anti-retroviral therapy to control the HIV infection is very important. 

 

HHV-8-negative (iMCD): Treatment should begin with the only FDA-approved therapy for iMCD, the anti-interleukin-6 drug, siltuximab. This drug is well tolerated and highly effective in approximately one-third to one-half of iMCD patients. Administration is considered to be life-long based on what is known about the drug and the disease. For patients that do not improve with siltuximab, the following classes of therapies may be considered:

    • Conventional anti-inflammatory (e.g., corticosteroids) and immunosuppressive therapy (e.g. sirolimus, cyclosporine, rituximab): Corticosteroids can improve symptoms during acute exacerbations of iMCD, but most patients relapse when they are tapered. Sirolimus, which suppresses immune cell proliferation and activation, has been used successfully in iMCD patients not responding to siltuximab. Cyclosporine, which decreases the growth and activity of T-cells, is being used more frequently as some physicians are treating MCD more like a systemic inflammatory disease. Rituximab, which eliminates B-cells, is effective in most cases of HHV-8-associated MCD and some cases of iMCD but typically does not provide long-term disease control in iMCD.
    • Chemotherapy: Chemotherapy regimens that have traditionally been used to treat lymphomas (e.g., cyclophosphamide, doxorubicin, vincristine, and prednisone a.k.a. CHOP, or cyclophosphamide, etoposide, rituximab) have also shown to be effective in the most severely ill MCD patients by eliminating a large portion of their inflammatory cells. However, relapses are common and the side effects are significant.
    • Anti-IL-6 therapy (e.g., tocilizumab): Tocilizumab targets interleukin-6 receptor, so it is occasionally used in place of or following siltuximab therapy. It has been approved to treat iMCD in Japan. Like siltuximab, tocilizumab generally requires life-long administration and is not effective in all patients. 
    • Therapies targeting other cytokines and inflammatory cell pathways: Recently, therapeutic approaches targeting new inflammatory cell pathways related to iMCD have been reported. These potential treatment options need to be further explored, particularly for patients who do not respond to anti-IL-6 therapy. Bortezomib, thalidomide, and anakinra are other drugs that have been used.

To learn more about specific treatments for iMCD visit our Therapeutic Target Dashboard. More information about treatmetns for UCD, HHV-8-positive MCD, and POEMS-associated MCD can be found here

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14. What is the typical prognosis and survival of Castleman disease? What is the risk of recurrence?

It is impossible to know how this diagnosis will affect your life expectancy, but based on large studies of hundreds of patients the following generalizations can be made:

  • UCD does not usually affect one's life expectancy (>95% will survive for at least 5 years after diagnosis). However, there are UCD patients that develop paraneoplastic pemphigus, lymphomas, or sarcomas, which can be fatal.
  • Approximately 90% of individuals diagnosed with HHV-8-associated MCD will survive for at least 5 years after diagnosis if appropriately treated with B cell depleting therapy (rituximab).
  • Approximately 55-75% of individuals diagnosed with iMCD will survive for at least 5 years after diagnosis. With the advent of therapies, such as siltuximab, which became the first FDA-approved therapy for iMCD in 2014, we expect to see survival rates improve. 

UCD: The average length of survival after diagnosis is greater than 10 years. Life expectancy is usually unchanged in UCD. The risk of recurrence in UCD is rare after a lymph node has been successfully resected. However, there have been some cases of patients with UCD who develop a recurrence in the same or a different region. Sometimes it can be confusing to distinguish whether a patient is having a UCD recurrence or if they were misdiagnosed with UCD and actually have MCD.

MCD: The 5-year overall survival rate in a 2012 study of MCD patients was 65%. Further progress in long-term outcome is anticipated with the advent of anti-IL-6 therapies, such as siltuximab and tocilizumab. Recurrence with both forms of MCD is common and unpredictable.

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15. What is the CDCN doing to combat Castleman disease?

A major reason that patients are dying from CD is that it is so poorly understood by the medical community. We're here to change that. The Castleman Disease Collaborative Network (CDCN) was developed in August 2012 by a group of physicians and researchers dedicated to finding a cure for Castleman disease and supporting patients along the way. So far we have:

  • Connected the global community of 500+ physicians and researchers through the three largest-ever Castleman disease research meetings and an online discussion board

  • Assembled a Scientific Advisory Board of 32 experts from eight countries

  • Engaged patients on the Scientific Advisory Board, Leadership Team, and all research meetings, as well as through the annual Patient Summit, online discussion board, physician referrals, and educational materials

  • Established the current state of medical knowledge for Castleman disease through an article published in the top hematology journal, Blood

  • Worked with the research community to determine high-priority research projects for the International Research Agenda (IRA); 17 of these studies are currently underway and others are waiting for enough funds to be raised to enable them - donate here today!

Progress has been made in patient outcomes over the last 20 years, but more work is needed to extend the lives of patients battling CD. Important next steps for the field and priorities for the CDCN include developing an official international criteria for MCD diagnosis, creating a patient research study with a virtual tissue repository, offering research funding, collecting patient quality-of-life data, and facilitating greater collaboration with rheumatologists, immunologists, and virologists.

 

16. How can I help accelerate finding a cure for Castleman disease?

  1. Share your Castleman disease data: Be sure that you have taken 15-20 minutes to enroll in the ACCELERATE Castleman Disease patient research study, which is collecting data on patients from around the world to identify patterns and information to improve treatment and care.
    • This is a huge opportunity to do your part to help solve the mysteries of CD!
    • NOTE: Password when you sign up must be at least 8 characters long and include:
      • 1 number (0-9)
      • 1 lowercase letter (a-z)
      • 1 uppercase letter (A-Z)
      • 1 symbol character (any character not a number or letter)
      • Ex: Castleman1!!
  2. Share samples: Be sure that you have taken 5 minutes to express interest in contributing samples for ongoing and future research studies, click here
  3. Donate funds for CD research: Research is not possible without funding. You can donate or share the link with friends and family to enable life-saving CD research - https://www.cdcn.org/donate
  4. Join the Warriors: Patients can join the Castleman Warrior team and create their own Warrior fundraising pages to share with family and friends.
  5. Connect: Make sure you have joined the CDCN Patient/Loved One Community, click here to join and gain access to all available information, resources, and peet support groups. 
  6. Let us know how we can help! Email info@castlemannetwork.org or call (610)304-0696 if you would like more information or have any questions.

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17. Am I safe to get pregnant?

No one has ever studied or reported any data on this important question, so unfortunately, we can't provide a definitive answer to this question. This is one of several areas that we're actively researching through our ACCELERATE Registry.

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