NORD gratefully acknowledges David Fajgenbaum, MD, MBA, MSc, University of Pennsylvania and the Castleman Disease Collaborative Network, for assistance in the preparation of this report.
Castleman disease describes a group of disorders with a wide range of symptoms that each has enlarged lymph nodes that share similar appearances when reviewed under the microscope. Castleman disease is first classified based on the number of regions of enlarged lymph nodes that demonstrate these abnormal features. Unicentric Castleman disease (UCD) involves a single enlarged lymph node or single region of enlarged lymph nodes whereas multicentric Castleman disease (MCD) involves multiple regions of enlarged lymph nodes. There are two sub-types of MCD. A subset of MCD is caused by human herpesvirus-8 (HHV-8; also known as Kaposi sarcoma–associated herpesvirus). These cases are called HHV-8-associated MCD. There are also MCD patients who are negative for the HHV-8 virus, and the cause is unknown. These cases are called HHV-8 negative or “idiopathic” MCD (iMCD).
Castleman disease can also be described as hyaline-vascular, plasmacytic, or mixed based on the microscopic appearance. The usefulness of this sub-typing is unclear.
UCD is characterized by a single enlarged lymph node or multiple enlarged lymph nodes in a single region of the body, such as the chest, abdomen, or neck. In most cases of UCD, individuals exhibit no symptoms (asymptomatic). Occasionally, patients experience symptoms due to the size and location of the growth. For example, a growth may form next to a vein, resulting in a bulge and possible obstruction in the involved blood vessel. Occasionally, individuals with UCD may exhibit a variety of symptoms including fever, fatigue, excessive sweating, weight loss, skin rash, early destruction of red blood cells, leading to unusually low levels of circulating red blood cells (hemolytic anemia), and/or abnormally elevated amounts of certain immune factors in the blood (hypergammaglobulinemia). These symptoms are typically seen in MCD. These symptoms usually disappear after surgical excision of the UCD lymph node.
Both HHV-8-associated MCD and iMCD are characterized by multiple regions of enlarged lymph nodes and episodic inflammatory symptoms, such as fever, weight loss, skin rash, destruction of red blood cells, leading to unusually low levels of circulating red blood cells (hemolytic anemia), and/or abnormally increased amounts of certain immune factors in the blood (hypergammaglobulinemia). Many individuals with MCD may exhibit an abnormally large liver and spleen (hepatosplenomegaly).
HHV-8–associated MCD is most commonly diagnosed in HIV-infected or otherwise immunocompromised individuals. Thus, HHV-8-associated MCD patients may experience additional symptoms related to their HIV infection or other conditions.
The exact cause of UCD and iMCD is not known. Viruses, genetic mutations acquired over the course of life, and inflammation have all been proposed as possible causes of UCD. Recent research suggests that acquired genetic mutations are the likely cause of UCD.
HHV-8 is the well-established cause of HHV-8-associated MCD, which accounts for approximately 50% of all cases of MCD. HHV-8-associated MCD often occurs in individuals infected with human immunodeficiency virus (HIV). The HIV weakens the immune system’s ability to control the HHV-8 infection. The HHV-8 virus causes MCD by making its own IL-6 and causing cells to proliferate.
Approximately 50% of MCD cases are negative for HHV-8 and the cause is unknown or “idiopathic.” Recently, four possible causes have been hypothesized: a virus, genetic mutation acquired over the course of life, an inherited genetic mutation, or autoimmunity. Some researchers speculate that increased production of interleukin-6 (IL-6) for one of the above causes may be involved in the development of iMCD. IL-6 is a substance normally produced by cells within the lymph nodes (plasma cells) and in healthy individuals serves to coordinate the immune response to infection. However, IL-6 is not elevated in all cases, and neutralizing IL-6 is not effective for the treatment of all cases.
UCD and iMCD affect males and females in equal numbers, and there are no known factors that increase the risk of UCD or iMCD. HHV-8-associated MCD affects males at an increased rate compared to females. All types of Castleman disease may affect individuals of any age. Persons with HIV are at increased risk of developing HHV-8-associated MCD. It is estimated that there are approximately 5,000 individuals diagnosed each year and 30,000 individuals in the United States afflicted with one of the forms of Castleman disease.
Most UCD patients do not experience systemic symptoms. Typically, the enlarged lymph node will be discovered inadvertently, during care for another condition, or because it is impeding on nearby organs. UCD is diagnosed by histopathological examination of the excised lymph node.
There are no official diagnostic criteria for HHV-8-associated MCD. It is generally diagnosed when a patient has multiple regions of enlarged lymph nodes, inflammatory symptoms, biopsy of the lymph node demonstrates “Castleman-like” features under the microscope, and HHV-8 testing is positive. Characteristic “Castleman-like” microscopic features may include a constellation of regressed or hyperplastic germinal centers, follicular dendritic cell prominence, hypervascularization, and polytypic plasmacytosis.
A diagnostic criterion for iMCD was recently established. The criteria require major criteria (characteristic lymph node features on biopsy and multiple regions of enlarged lymph nodes), at least 2 of 11 minor criteria with at least 1 laboratory abnormality, and exclusion of infectious, malignant, and autoimmune disorders that can mimic iMCD. Laboratory and clinical minor criteria include elevated C-reactive protein or erythrocyte sedimentation rate, anemia, thrombocytopenia or thrombocytosis, hypoalbuminemia, renal dysfunction or proteinuria, polyclonal hypergammaglobulinemia, constitutional symptoms, hepatosplenomegaly, effusions or edema, eruptive cherry hemangiomatosis or violaceous papules, and lymphocytic interstitial pneumonitis.
The diagnosis of all forms of Castleman disease should be based upon a thorough clinical evaluation that includes a detailed patient history and a variety of specialized imaging techniques (e.g., computer-assisted tomography [CT scan], magnetic resonance imaging [MRI], and ultrasonography). During CT scanning, a computer and X-rays are used to create a film showing cross-sectional images of an organ’s tissue structure. MRI uses a magnetic field and radio waves to create cross-sectional images of the organ. In ultrasonography, reflected sound waves create an image of the organs in question. These tests can identify enlarged lymph nodes. Then, surgical (excisional) biopsy of the lymph node is needed. Finally, the clinician should integrate the clinical history, imaging results, and microscopic report to make the diagnosis.
For localized (unicentric) disease, surgical removal of the affected lymph node(s) usually results in cure. However, recurrences of UCD have been reported. In some cases, ionizing radiation (radiotherapy) has proven effective.
For iMCD, chemotherapy had been the cornerstone of treatment, but has been largely supplanted by newer, more directed therapies. These include drugs which target and neutralize IL-6 (siltuximab or Sylvant) or the receptor for IL-6 (tocilizumab or Actemra). In 2014, Sylvant (siltuximab) was approved to treat patients with iMCD. This is the first and only FDA-approved drug to treat patients with iMCD. Approximately half of iMCD patients do not improve with IL-6 neutralization. These patients are often treated with chemotherapy or newer treatment options such as rituximab, sirolimus, or anakinra.
Additional symptomatic and supportive therapy may include corticosteroids or autologous bone marrow transplantation (used most frequently for severe disease or iMCD associated with POEMS syndrome).
For HHV-8-associated MCD, rituximab to eliminate a type of immune cell called the B lymphocyte is often used. It is highly effective for HHV-8-associated MCD, but occasionally antivirals and/or cytotoxic chemotherapies are needed.
Tocilizumab (Actemra), manufactured by Roche Pharmaceuticals in the United States, showed substantial efficacy in the treatment of iMCD in a small study from Japan. The drug was approved by the FDA for the treatment of rheumatoid arthritis, and can be prescribed “off label” for the treatment of Castleman. Treatment requires monthly intravenous injections.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government website.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
For information about clinical trials sponsored by private sources, contact:
For information about clinical trials conducted in Europe, contact:
Contact for additional information about Castleman disease:
David Fajgenbaum, MD, MBA, MSc
Assistant Professor of Medicine, University of Pennsyvlabia
Associate Director, Patient Impact, Orphan Disease Center
Co-Chair, Scientific Advisory Board, Castleman Disease Collaborative Network
Principal Investigator, ACCELERATE Castleman Disease Registry & Biobank
Hospital of the University of Pennsylvania
3400 Spruce St, Silverstein 5, Suite S05094
Philadelphia, PA 19104
Phone: (215) 614-0936, Fax: (877) 991-9674
RareConnect offers a safe patient-hosted online community for patients and caregivers affected by this rare disease. For more information, visit www.rareconnect.org.
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