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?
  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 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?
  15. What is the CDCN doing to combat Castleman disease? 
  16. How can I help accelerate finding a cure for Castleman disease?
  17. Can you provide a glossary of terms?

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?

The cause of HHV-8-associated MCD is HHV-8 (human herpesvirus-8). In these cases, HIV infection or another cause of immunodeficiency (e.g., a genetic disorder, immunosuppressive medications) predisposes the patient to HHV-8 infection. 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 causes of UCD and iMCD are 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?

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 and MCD is more common in 40-60 year olds.

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5. What are risk factors for developing Castleman disease?

There are no known risk factors for UCD or iMCD, though the possibility of a genetic predisposition is being investigated. Risk factors for HHV-8-associated MCD include infection with HIV and other causes of immunodeficiency (e.g., genetic disorders, immunosuppressing medications, organ transplantation) that predispose individuals to infection with HHV-8, the cause of HHV-8-associated MCD.

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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 MCD, the more severe form of CD, sometimes have symptoms and signs indistinguishable from an aggressive lymphoma.

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 usually 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 organs. 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 laboratory values are typically seen in Castleman disease?

UCD: Most 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:

  • 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

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: Hyaline-Vascular (HV), Plasma Cell (PC), Mixed, and Plasmablastic.

HV: This is 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).

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.

Mixed: This displays features of both the HV and PC variants.

Plasmablastic: Displays features similar to PC, but with even greater vascularization and 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. Three hypotheses responsible for causing iMCD hypercytokinemia are listed below:

  1. Systemic inflammatory disease hypothesis: This proposes the involvement of autoimmune/autoinflammatory mechanisms via autoantibody antigenic stimulation or a germ-line genetic aberration in innate immune regulation. (I.e., there is a genetic defect in the ability to turn off the immune system or there are antibodies that constantly stimulate the immune system to stay active. If this is the case, iMCD would be reclassified as an autoimmune or autoinflammatory disorder.)

  2. Paraneoplastic syndrome hypothesis: This suggests that pro-inflammatory cytokines are being secreted by tumor cells either within the Castleman disease lymph nodes or from tumor cells associated with a simultaneously-present cancer. If this is the cases, iMCD would be reclassified as a paraneoplastic syndrome.

  3. Virally-driven hypothesis: This proposes that iMCD patients may be infected with an undiscovered non-HHV-8 virus that’s causing hypercytokinemia similar to the way 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 2 years of iMCD diagnosis. 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 iMCD patients. Further research is needed to better understand the relationship between 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 often enough to eliminate UCD. If removal is not possible or curative, the below MCD 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. Below are four main treatment categories (not listed in any kind of order):

  • Conventional anti-inflammatory (e.g., corticosteroids) and immunosuppressive therapy (e.g. cyclosporine, rituximab): Corticosteroids can improve symptoms during acute exacerbations of iMCD, but most patients relapse when they are tapered. 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) 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., siltuximab, tocilizumab): Over the last decade, treatments directly targeting IL-6 (the cytokine that’s often elevated in MCD patients) have been employed. Tocilizumab, which has been approved to treat iMCD in Japan, has demonstrated to be effective at inducing and maintaining remission of MCD symptoms. Siltuximab, which has been recently approved by the US Food & Drug Administration and European Medicines Agency, has also demonstrated similar effectiveness. Both drugs, generally require life-long administration and are 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.

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

UCD: The average length of survival after diagnosis is greater than 10 years. Life expectancy is usually unchanged in UCD.

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.

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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 400+ 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 a 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)

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 registry 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?

Join the registry, biobank, or become a Castleman disease warriorClick here to GET INVOLVED!!

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17. Can you provide a glossary of terms?

 Please refer to the below glossary for a listing of terms used throughout this site:

Autoimmune disease: a disease in which the immune system attacks normal healthy tissue, mistaking it for a foreign organism.

Autoinflammatory disease: a disease in which the immune system causes hyperinflammation due to genetic mutations that prevent it from being able to turn off inflammation.

B-cell: a type of lymphocyte whose primary function is to transform into plasma cells to produce antibodies that help neutralize foreign organisms; B cells also produce cytokines that regulate other immune system functions. 

Benign: a term used to refer to tumor cells that are non-malignant. Lymph nodes of Castleman disease patients have been considered to be "benign" for many years, but this is a misnomer because the lymph nodes of Castleman disease patients are not tumors. The cells within the lymph node are proliferating due to high levels of cytokines, not because they are benign tumors or because there are malignant cells.

Cytokine: a chemical substance that immune cells use to communicate with other immune cells. For instance, immune cells may release a cytokine called interleukin-1 (IL-1) to alert the other cells of the immune system that they may need to fight off an invading bacteria or virus.

Human herpesvirus-8 (HHV-8): also known as Kaposi’s sarcoma-associated herpesvirus, HHV-8 is one of seven currently known cancer-causing viruses (oncoviruses). Because most healthy immune systems are able to prevent the spread of this virus, HHV-8 usually only causes problems in individuals with immunosuppressed or weakened immune systems (e.g., HIV infected). In HHV-8-associated MCD, HHV-8 signals for the release of cytokines by the body that result in MCD. HHV-8 lives in the body’s B-cells, so destruction of these B-cells with Rituxan (rituximab) is a very effective treatment strategy in HHV-8-associated MCD.

Hypercytokinemia: a state of elevated levels of cytokines in the blood.

Hyperinflammatory disorder: a disorder involving the excessive activation of immune cells and subsequent release of inflammatory chemical messengers (cytokines). There are a variety of triggers for the immune cell activation such as foreign organisms, autoimmune mechanisms, and organ transplant rejection.

Interleukin-6 (IL-6): one type of cytokine, which is found and used by every healthy immune system. It is often found to be abnormally elevated in Castleman disease as a source of hyperinflammation and is thus a therapeutic target. This is what siltuximab and tocilizumab block.

Lymph node: one of many small organs that are distributed throughout the body with the function of filtering the blood for foreign particles and serving as the location that activated immune cells go to to work together. Lymph nodes get enlarged during states of inflammation. This is where many lymphocytes, including B-cells, T-cells, and plasma cells are concentrated.

Lymphocyte: a type of white blood cell (immune cell) used to fight infections but can occasionally drive diseases by attacking normal tissue directly or releasing cytokines. Includes B-cells, T-cells, and plasma cells. The lymph node is the home base for these cell types.

Lymphoproliferative disorder: a disorder involving the abnormally rapid production (proliferation) of lymphocytes. This typically refers to diseases where the proliferation is due to a malignant mutation, such a lymphoma or multiple myeloma. Castleman disease is often considered to be a lymphoproliferative disorder because lymphocytes proliferate due to cytokine signaling, but researchers are beginning to think it should be more appropriately considered as a hyperinflammatory disorder.

Neoplastic: a term used to refer to tumor cells that are malignant or cancerous.

Paraneoplastic syndrome: a disease in which cancerous cells release substances or cause the release of substances that generate a separate set of symptoms in the patient not directly associated with the malignancy.

Plasma cell: a type of lymphocyte that produces large quantities of antibodies, which are proteins used by the immune system to destroy bacteria and viruses; B-cells become plasma cells during their final stage of maturation.

T-cell: a type of lymphocyte involved in killing other cells infected with organisms.

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