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Last updated:
June 16, 2022
Years published: 1988, 1989, 1996, 2003, 2004, 2010, 2017, 2022
NORD gratefully acknowledges David Fajgenbaum, MD, MBA, MSc, University of Pennsylvania and Mileva Repasky, MS, Castleman Disease Collaborative Network, for assistance in the preparation of this report.
Castleman disease describes a group of rare disorders with a wide range of symptoms. People with these conditions have enlarged lymph nodes that have a similar appearance when reviewed under the microscope. Castleman disease is first classified based on the number of regions of enlarged lymph nodes that have 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 subtypes of MCD. One subtype is caused by human herpesvirus-8 (HHV-8; also known as Kaposi sarcoma–associated herpesvirus). These cases are called HHV-8-associated MCD. The other subtype includes 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 histopathologic variant based on the microscopic appearance. The usefulness of these additional descriptions is unclear.
The spectrum of disease symptoms and severity is very broad, ranging from gradual enlargement of lymph nodes with mild symptoms to sudden, intense onset of symptoms due to life-threatening organ dysfunction caused by elevated cytokines such as interleukin-6 (IL-6). Symptoms of Castleman disease often overlap with symptoms of other more common illnesses. A Castleman disease diagnosis can therefore only be made with a lymph node biopsy that shows characteristic Castleman disease features and when other illnesses have been evaluated and excluded.
Unicentric Castleman Disease (UCD)
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. Most patients with UCD have no symptoms (asymptomatic). UCD symptoms tend to be mild and occur secondary to compression of surrounding structures by rapidly enlarging lymph nodes. 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. Less commonly, some UCD patients experience systemic inflammatory symptoms such as fever, fatigue, excessive sweating, weight loss and skin rash as well as laboratory abnormalities such as low hemoglobin and elevated C-reactive protein. These symptoms are typically seen in MCD. These symptoms usually disappear after surgical excision of the UCD lymph node.
Multicentric Castleman Disease (MCD)
Patients with multicentric Castleman disease (MCD) have enlarged lymph nodes in multiple regions and more severe symptoms than UCD. Some patients are HHV-8 positive (HHV-8 MCD) whereas other patients are HHV-8-negative/idiopathic (iMCD).
Signs and symptoms of iMCD include:
• Flu-like symptoms: fever, fatigue, weight loss, night sweats, loss of appetite, nausea and vomiting
• Abnormally large lymph nodes, typically in the neck, armpit, collarbone and groin
• Enlarged spleen or liver
• Eruptive cherry hemangiomas
• Edema (swelling), ascites (fluid accumulation in the abdomen) and/or other symptoms of fluid accumulation
• Peripheral neuropathy (numbness in the hands and feet)
• Elevated inflammatory markers (C-reactive protein, erythrocyte sedimentation rate)
• Kidney dysfunction
• Low albumin
• Anemia (low amount of red blood cells)
• Low or high platelet counts
• Elevated immunoglobulins or gamma globulins
iMCD patients can be further subdivided into iMCD-TAFRO or iMCD-NOS. iMCD-TAFRO is characterized by thrombocytopenia (low platelet count), anasarca (ascites, swelling), fever or elevated C-reactive protein (inflammation marker), reticulin fibrosis (evaluated in bone marrow biopsy) and organomegaly (hepatomegaly/splenomegaly). iMCD-NOS typically involves thrombocytosis (elevated platelet count) and elevated immunoglobulins with a less intense disease course.
Patients with HHV-8-associated MCD (HHV-8 MCD) also have multiple regions of enlarged lymph nodes and episodic inflammatory symptoms. HHV-8 MCD is most commonly diagnosed in HIV-infected or otherwise immunocompromised individuals so these patients may experience additional symptoms related to their HIV infection or other conditions.
The following disorders may be associated with Castleman disease as secondary characteristics:
iMCD has been diagnosed in some patients with POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder and skin changes) syndrome. (For more information on this disorder, choose “POEMS” as your search term in the Rare Disease Database.)
There is an increased rate of cancer diagnosed in patients with iMCD and HHV-8-associated MCD.
Patients with UCD are at increased risk of developing paraneoplastic pemphigus (PNP), which is a rare autoimmune condition that can be life threatening. PNP involves blisters in the mouth and on the skin that are often misdiagnosed as occurring for another reason. Though the risk of developing PNP is low (<5%) among patients with UCD, it is the deadliest potential complication of UCD and should be evaluated in all UCD patients. Patients with HHV-8-associated MCD are at increased risk of developing Kaposi’s sarcoma, which is a malignant skin tumor that may spread to other parts of the body. Affected individuals may have skin lesions (e.g., papules, plaques, etc.) that may grow and come together (coalesce). In some patients, the lesions may reduce in size and number (regress). On rare occasions these lesions may be painful.
The exact cause of UCD and iMCD is not known. There are no known risk factors; there is no evidence of any food, lifestyle or environmental exposure associated with these diseases. There is no known report of a patient developing UCD or iMCD from contact with another individual with UCD or iMCD. 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 25-50% of all cases of MCD. HHV-8-associated MCD often occurs in individuals infected with human immunodeficiency virus (HIV). The HIV weakens the ability of the immune system to control the HHV-8 infection. The HHV-8 virus causes MCD by making its own IL-6 and causing cells to rapidly multiply.
Approximately 50-75% 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) due to 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 coordinates the immune response to infection. However, IL-6 is not elevated in all patients, and neutralizing IL-6 is not effective for the treatment of all patients.
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 4,300-5,200 cases of CD diagnosed each year in the United States.
Castleman disease can be difficult to diagnose because it is a rare disease and an imitator of many other diseases. Patients can have the same symptoms as other conditions, including common illnesses such as influenza (flu), autoimmune diseases and lymphomas. Due to the complexity of the disease, physicians often need to rule out many other diseases before Castleman disease is suspected. The clinical history and several tests are used to rule out other conditions and confirm a diagnosis of Castleman disease.
According to international, evidence-based guidelines for UCD and iMCD from the Castleman Disease Collaborative Network, these tests should include:
• Lymph node biopsy: a sample of tissue from a lymph node is examined under a microscope to identify features of Castleman disease
• Laboratory tests: complete blood count, inflammation markers (CRP/ESR) and markers of organ function such as liver function tests, albumin, creatinine as well as HIV/HHV8 testing for HHV-8-associated MCD
• Imaging tests: X-rays and PET-CT scans can be used to locate enlarged lymph nodes and activity of those lymph nodes in the body
A diagnostic criterion was recently established for UCD. 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. It is important that a complete excisional lymph node biopsy be performed rather than a fine-needle aspirate or core biopsy.
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.
Diagnostic criteria for iMCD were recently established. The criteria require both 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.
Treatment
Treatments for Castleman disease are specific to the subtype. International, evidence-based guidelines have been developed for UCD and iMCD.
Unicentric Castleman Disease (UCD)
Surgery is considered to be the first-line treatment option for all cases of UCD. Surgical removal of the affected lymph node(s) usually results in cure. However, recurrences of UCD have been reported. Sometimes, removing the enlarged lymph node(s) is not possible. If surgical excision is not possible, treatment is recommended for symptomatic patients. If symptoms are due to compression, rituximab is recommended. If symptoms are due to an inflammatory syndrome, anti-interleukin-6 (IL-6) therapy is recommended. If these treatments are not effective, radiation may be needed.
Idiopathic Multicentric Castleman Disease (iMCD)
First-line treatment for iMCD is anti-IL-6 therapy with siltuximab (or tocilizumab if siltuximab is not available). Siltuximab is the only FDA-approved treatment for iMCD, and patients who respond to siltuximab tend to have long-term responses. For critically ill patients, chemotherapy and corticosteroids are recommended if the patient’s disease is progressing while on siltuxumab. Approximately half of iMCD patients do not improve with anti-IL-6 therapy, and for these patients, other treatments such as rituximab and sirolimus can be used.
HHV-8-Associated Multicentric Castleman Disease (HHV-8 Positive MCD)
Rituximab is often used to eliminate a type of immune cell called the B lymphocyte. It is highly effective for HHV-8-associated MCD, but occasionally antivirals and/or cytotoxic chemotherapies are also needed.
A clinical trial for the medication sirolimus is currently open for iMCD patients who do not improve on siltuximab or tocilizumab. Patients can learn more about this trial at https://cdcn.org/trial/ or clinicaltrials.gov. Patients with iMCD who have not responded to siltuximab may email cstl@pennmedicine.upenn.edu to ask about eligibility for this sirolimus clinical trial.
Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/ All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
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: prpl@cc.nih.gov
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact:
https://www.centerwatch.com/
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
Contact for additional information about Castleman disease:
David Fajgenbaum, MD, MBA, MSc
Assistant Professor of Medicine, University of Pennsylvania
Associate Director, Patient Impact, Orphan Disease Center
Co-Chair, Scientific Advisory Board, Castleman Disease Collaborative Network
Principal Investigator, ACCELERATE Castleman Disease Registry & Biobank
Mailing Address:
University of Pennsylvania, Center for Cytokine Storm Treatment & Laboratory
3535 Market Street, Suite 700
Philadelphia, PA 19104
info@castlemannetwork.org
Phone: (215) 614-0935
Patient questions: (610) 304-0696
Sample Donation
Donating a sample to help advance life-saving research is one of the most important ways that patients can join in the fight against Castleman disease. Patients willing to donate a sample who are newly diagnosed, currently hospitalized or having a relapse or flare of symptoms can call (267) 586-9977 or email the CDCN Biobank coordinator Bridget Austin at Castlebank@uphs.upenn.edu.
Patient Registry
The ACCELERATE registry is the first-ever global patient registry for Castleman disease. Patients with Castleman disease and parents of children with Castleman disease can enroll at www.CDCN.org/ACCELERATE. For questions about enrollment call 215-614-0209 or email
RareConnect offers a safe patient-hosted online community for patients and caregivers affected by this rare disease. For more information, visit www.rareconnect.org.
TEXTBOOKS
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JOURNAL ARTICLES
van Rhee F, Oksenhendler E, Srkalovic G, et al. International evidence-based consensus diagnostic and treatment guidelines for unicentric Castleman disease. Blood Adv. 2020 Dec 8;4(23):6039-6050. doi: 10.1182/bloodadvances.2020003334.
Van Rhee F, Voorhees P, Dispenzieri A, et al. International, evidence-based consensus treatment guidelines for idiopathic multicentric Castleman disease. Blood. 2018 Nov 15;132(20):2115-2124. doi: 10.1182/blood-2018-07-862334. Epub 2018 Sep 4.
Fajgenbaum DC, Uldrick TS, Bagg A, et al. International, evidence-based consensus diagnostic criteria for HHV-8–negative/idiopathic multicentric Castleman disease. Blood. 2017;129(12):1646-1657.
Liu AY, Nabel CS, Finkelman BS, et al. Idiopathic multicentric Castleman’s disease: a systematic literature review. The Lancet Haematology. 2016;3(4):e163-e175.
Fajgenbaum DC, van Rhee F, Nabel CS. HHV-8-negative, idiopathic multicentric Castleman disease: novel insights into biology, pathogenesis, and therapy. Blood. 2014;123(19):2924-2933.
van Rhee F, Wong RS, Munshi N, et al. Siltuximab for multicentric Castleman’s disease: a randomised, double-blind, placebo-controlled trial. The Lancet Oncology. 2014;15(9):966-974.
Uldrick TS, Polizzotto MN, Yarchoan R. Recent advances in Kaposi sarcoma herpesvirus-associated multicentric Castleman disease. Curr Opin Oncol. 2012;24(5):495-505.
van Rhee F, Stone K, Szmania S, Barlogie B, Singh Z. Castleman disease in the 21st century: an update on diagnosis, assessment, and therapy.Clinical Advances in Hematology & Oncology. 2010;8(7):486-498.
van Rhee F, Fayad L, Voorhees P, et al. Siltuximab, a novel anti-interleukin-6 monoclonal antibody, for Castleman’s disease. J Clin Oncol. 2010;28(23):3701-3708.
Casper C. The aetiology and management of Castleman disease at 50 years: translating pathophysiology to patient care. Br J Haematol. 2005;129(1):3-17.
Nishimoto N, Kanakura Y, Aozasa K, et al. Humanized anti-interleukin-6 receptor antibody treatment of multicentric Castleman disease. Blood 2005;106(8):2627-2632.
Yamasaki S, et al. Detection of human herpesvirus-8 in peripheral blood mononuclear cells from adult Japanese patients with multicentric Castleman’s disease. Br J Haematol. 2003;120:471-77.
Lee FC, Merchant SH, Alleviation of systemic manifestations of multicentric Castleman’s disease by thalidomide. Am J Hematol. 2003;73:48-53.
Iyonaga K, et al. Multicentric Castleman’s disease manifesting in the lung: clinical, radiographic, and pathologic findings and successful treatment with corticosteroid and cyclophosphamide. Intern Med. 2003;42:182-86.
Seirafi PA, et al. Thorascopic resection of Castleman disease: case report and review. Chest. 2003;123:280-82.
Larroche C, et al. Castleman’s disease and lymphoma: report of eight cases in HIV-negative patients and literature review. Am J Hematol. 2002;69:119-26.
Oksenhendler E, et al. High incidence of Kaposi sarcoma-associated herpesvirus-related non-Hodgkin lymphoma in patients with HIV infection and multicentric Castleman disease. Blood. 2002;99:2331-36.
Bowne WB, et al. The management of unicentric and multicentric Castleman’s disease: a report of 16 cases and a review of the literature. Cancer. 1999;85:706-17.
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Bartkowski DP, et al. Castleman’s disease: an unusual retroperitoneal mass. J Urol. 1988;139:118-120.
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