Last updated:
5/5/2025
Years published: 1988, 1989, 1996, 2003, 2004, 2010, 2017, 2022, 2025
NORD gratefully acknowledges David Fajgenbaum, MD, MBA, MSc, University of Pennsylvania, Joshua Brandstadter, MD, PhD, MSc, University of Pennsylvania, Madison Ahearn, MHA, Castleman Disease Collaborative Network and Mileva Repasky, MS, Castleman Disease Collaborative Network, for assistance in the preparation of this report.
Castleman disease is a rare blood disease defined by enlarged lymph nodes with a particular appearance when reviewed under the microscope and a broad range of symptoms and laboratory findings. 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 region of enlarged lymph nodes whereas multicentric Castleman disease (MCD) involves multiple regions of enlarged lymph nodes and body-wide inflammation. People with MCD often develop drenching night sweats, fatigue, unexplained weight loss, rash, fevers, shortness of breath, or swelling. The inflammation can take the form of blood count abnormalities, fluid accumulation in the legs, lungs, or abdomen, rash, kidney failure, or other blood test abnormalities. Some MCD cases are related to human herpesvirus-8 (HHV-8; also known as Kaposi sarcoma–associated herpesvirus) but others are HHV-8 negative without an identifiable cause and are called “idiopathic” MCD (iMCD). Some people with iMCD have a particularly severe subtype called “TAFRO” where they have low platelets, kidney failure, enlarged liver and/or spleen and whole-body swelling, among other findings.
Oligocentric Castleman disease (OligoCD) is a newly described subtype of Castleman disease that doesn’t fit into the two previously described subtypes, UCD or MCD. OligoCD involves a few nearby regions of enlarged lymph nodes with milder chronic symptoms than are typically observed in MCD.
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 people 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 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 people with UCD have systemic inflammatory symptoms such as fever, fatigue, drenching night sweats, weight loss and skin rash as well as laboratory abnormalities such as low hemoglobin, low albumin and elevated C-reactive protein. These symptoms are more commonly seen in MCD and usually – but not always – resolve after surgical excision of the UCD lymph node.
People with UCD are at increased risk of developing paraneoplastic pemphigus (PNP) or bronchiolitis obliterans, which are rare autoimmune conditions that can be life threatening though the risk is low (<5%). PNP involves blisters in the mouth and on the skin that are often misdiagnosed as occurring for another reason. Over the long term, UCD can also transform into cancers such as lymphoma or follicular dendritic cell sarcoma.
Oligocentric Castleman Disease (OligoCD)
OligoCD is a newly identified form of Castleman disease involving 2–5 nearby enlarged lymph nodes. Like UCD, people with OligoCD typically present with little to no symptoms or only mild inflammatory signs. Diagnosis requires surgical removal of a lymph node showing Castleman-like features, along with imaging evidence of multiple enlarged nodes, but without meeting criteria for idiopathic multicentric Castleman Disease (iMCD). Treatment usually involves surgical removal of the affected nodes, while rituximab may help in some cases; strong systemic treatments like chemotherapy are generally avoided.
Multicentric Castleman Disease (MCD)
Patients with MCD have enlarged lymph nodes in multiple regions and more severe symptoms than UCD. Some people are HHV-8 positive (HHV-8 MCD) whereas others are HHV-8-negative/idiopathic (iMCD).
Signs and symptoms of iMCD include:
People with iMCD 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.
People 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 immuno-compromised individuals so these people 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 people with POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder and skin changes) syndrome.
There is an increased rate of cancer diagnosed in people with iMCD and HHV-8-associated MCD.
People 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 people, the lesions may reduce in size and number (regress). On rare occasions these lesions may be painful.
The exact cause of UCD, OligoCD and iMCD are 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, OligoCD or iMCD from contact with another individual with UCD, OligoCD or iMCD. Viruses, gene variants acquired over the course of life and inflammation have all been proposed as possible causes of UCD. Recent research suggests that acquired genetic variants are a possible cause of some cases 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). 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 variants acquired over the course of life, an inherited gene variants 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 and in healthy individuals, coordinates the immune response to infection. However, IL-6 is not elevated in all affected people, and neutralizing IL-6 is not effective for the treatment of all patients.
UCD, OligoCD and iMCD affect males and females in equal numbers and there are no known factors that increase the risk of UCD, OligoCD 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. People 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. Affected people can have the same symptoms as in 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:
Diagnostic criteria for iMCD 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)
Surgical removal of enlarged lymph nodes is the first-line treatment option for UCD and is usually curative though rare recurrences do occur. When removal is not safe or possible, treatment approaches differ but reasonable alternatives include active surveillance if asymptomatic, partial surgical resection, treatment with rituximab to shrink the tumor, radiation, embolization, or treatment with anti-IL-6 medication if an inflammatory syndrome is present.
Oligocentric Castleman Disease (OligoCD)
Though more research is needed to better understand OligoCD, treatment should follow a similar course of UCD. The main treatment approach is surgical removal of the enlarged lymph nodes, if possible. B-cell depletion therapies such as rituximab may be helpful for some. Strong, systemic treatments like chemotherapy should be avoided unless absolutely necessary.
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 patients with severe disease manifestations, chemotherapy and high-dose corticosteroids are recommended if the patient’s disease progresses while on siltuxumab. Approximately half of iMCD patients do not improve with anti-IL-6 therapy. For these patients, there is no consensus standard of treatment though rituximab, sirolimus, ruxolitinib, adalimumab, and a combination of thalidomide/cyclophosphamide/dexamethasone have all been 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 ruxolitinib will soon be 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 [email protected] to ask about eligibility for this 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 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:
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
Associate 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
[email protected]
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 [email protected].
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 [email protected].
Family members of deceased patients are also able to enroll in the registry.
JOURNAL ARTICLES
Pierson SK, Brandstadter JD, Torigian DA, et al. Characterizing the heterogeneity of Castleman disease and oligocentric subtype: findings from the ACCELERATE registry. Blood Adv. 2025;9(8):1952-1965. doi:10.1182/bloodadvances.2024014391
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.
Soulier J, et al. Kaposi’s sarcoma-associated herpesvirus-like DNA sequences in multicentric Castleman’s disease. Blood. 1995;86:1276-80.
McCarty MJ, et al. Angiofollicular lymph node hyperplasia (Castleman’s disease). Cancer Treat Rev. 1995;21:291-310.
Shroff VJ, et al. Castleman’s disease presenting in as a pediatric surgical problem. J Pediatr Surg. 1995;30:745-47.
Adelman HJ, et al. Case report: Castleman disease in association with POEMS. Am J Med Sci. 1994;307:112-14.
Johnson WK, et al. Castleman disease mimicking an aggressive retroperitoneal neoplasm. Abdom Imaging. 1994;19:342-44.
Zarate-Osorno A, et al. Hogdkin’s disease with coexistent castleman-like histiologic features. Arch Pathol Lab Med. 1994;118:270-74.
Khan J, et al. Castleman’s disease of the chest. Magnetic resonance imaging features. Chest. 1994;105:1608-10.
Freeman SJ, et al. Case report: cervical Castleman’s disease shown by CT and MRI. Clin Radiol. 1994;49:721-23.
Mandler RN, et al. Castleman’s disease in poems syndrome with elevated interleukin-6. Cancer. 1992;69:2697-703.
Bartkowski DP, et al. Castleman’s disease: an unusual retroperitoneal mass. J Urol. 1988;139:118-120.
Friedman L, et al. Computerized tomography of Castleman’s disease simulating a false renal artery aneurysm: a case report. J Urol. 1987;138:123-24.
Powell RW, et al. Castleman’s disease in children. J Pediatr Surg. 1986;21:678-82.
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