Castleman Disease

Updated: Feb 01, 2018
  • Author: Neetu Radhakrishnan, MD; Chief Editor: Emmanuel C Besa, MD  more...
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Overview

Practice Essentials

Castleman disease (CD) describes a group of three immunological disorders that occur in individuals of all ages and share a similar microscopic lymph node appearance. Dr. Benjamin Castleman first described the constellation of lymph node features observed in CD ("CD-like features") in the 1950s. [1] Approximately 6,600-7,700 patients are estimated to be diagnosed with CD every year in the United States. There is significant variability in clinical features, treatments, and survival across the three subtypes.

The three subtypes are as follows:

  • Unicentric CD (UCD) involves a single region of enlarged lymph nodes that demonstrate CD-like features under the microscope. Patients may be asymptomatic or present with a variety of signs and symptoms (see Presentation).
  • Human herpesvirus 8 (HHV-8)–associated multicentric Castleman disease (HHV-8-associated MCD) involves multiple regions of enlarged lymph nodes with CD-like features, flulike symptoms, abnormal blood counts, and dysfunction of vital organs (see Presentation) due to uncontrolled infection with HHV-8. Uncontrolled HHV-8 infection leads to excessive production of inflammatory cytokines. HHV-8-associated MCD often occurs in immunocompromised individuals, such as those with human immunodeficiency virus (HIV) infection. [2] Patients are at increased risk of developing Kaposi sarcoma, non-Hodgkin lymphoma, and Hodgkin lymphoma.
  • HHV-8–negative/idiopathic multicentric Castleman disease (iMCD) involves multiple regions of enlarged lymph nodes with CD-like features, flulike symptoms, abnormal blood counts, and dysfunction of vital organs (see Presentation) due to an unknown cause. Cytokines, such as interleukin-6 (IL-6) are also elevated in iMCD. iMCD patients are negative for HHV-8 and HIV. These patients are at increased risk of developing non-Hodgkin lymphoma, Hodgkin lymphoma, and POEMS syndrome. The cause of iMCD is not known, but hypothesized etiologies include acquired mutations in a clonal cell population, inherited mutations leading to autoimmunity or autoinflammation, or a pathogen.

A variety of laboratory tests and imaging studies are indicated for the assessment of CD and determination of the correct subtype, but all three subtypes require histologic examination of a needle biopsy specimen from an enlarged lymph node for diagnosis (see Workup).

Treatment varies depending on the subtype of CD. Surgical removal of the involved node or region of lymph nodes is usually curative in UCD, but is not effective in HHV-8–associated MCD or iMCD. Rituximab is often effective in the treatment of HHV-8–associated MCD. The IL-6 inhibitor siltuximab is often effective for the treatment of iMCD and is approved by the US Food and Drug Administration. See Treatment and Medication.

The Castleman Disease Collaborative Network is "a global initiative dedicated to accelerating research and treatment for Castleman disease." Its goals include the following:

Patients, physicians, and researchers can contact the Castleman Disease Collaborative Network with questions.

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Pathophysiology

The pathophysiology of Castleman disease (CD) varies between subtypes.

Unicentric CD (UCD) pathophysiology is poorly understood. The lymph node is characterized by abnormal features that include small or large germinal centers, follicular dendritic cell (FDC) prominence, hypervascularity, polyclonal plasmacytosis, and/or expansion of polyclonal B cells and T cells. Patients sometimes experience inflammatory symptoms, which are believed to be caused by elevated IL-6 levels in the blood. These symptoms typically resolve after lymph node excision.

HHV-8–associated MCD pathophysiology is well understood: Immunocompromise due to HIV or other causes enables the uncontrolled infection and replication of HHV-8 in lymph node plasmablasts and B cells, which signal for viral IL-6 and other proinflammatory cytokines.  Depletion of B cells with rituximab typically results in resolution of symptoms.

HHV-8-negative/idiopathic MCD (iMCD) pathophysiology is poorly understood. Patients experience atypical, CD-like lymphoproliferation, which occurs along with systemic inflammatory symptoms (fevers, weight loss, fatigue, night sweats), abnormal blood cell counts, and multiple organ system dysfunction. The pathophysiology of the disease is caused by excess IL-6 in a portion of patients. [3, 4, 5]  Inhibition of IL-6 with siltuximab is effective in approximately 34-44% of patients. The pathophysiology in the remaining patients who do not improve with IL-6 inhibition is not known but is suspected to involve cytokines or mechanisms other than IL-6 excess.

Microscopic features of Castleman disease

Patients with UCD, HHV-8–associated MCD, and iMCD can experience a spectrum of lymph node features.

The hyaline vascular histopathological subtype is used to describe lymph node features including atrophic germinal centers, onion-skinning mantle zones, hypervascularization, and FDC prominence. It is most commonly seen in UCD (approximately 90% in some studies) [6]  but can also be seen in iMCD. In iMCD, "hypervascular" is used to describe this constellation of features.

The plasma cell histopathological subtype is used to describe lymph node features including hyperplastic germinal centers as well as occassional atrophic germinal centers and interfollicular plasmacytosis. It is most commonly seen in iMCD, but it can also be seen in UCD.

The mixed histopathological subtype is used to describe cases in which lymph nodes demonstrate features of both the hyaline vascular and plasma cell subtypes.

The plasmablastic histopathological subtype is found in HHV-8–associated MCD. These cases have plasmablasts and stain positive for latency-associated nuclear antigen–1 (LANA-1) by immunohistochemistry.

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Etiology

The etiologies differ between the three subtypes of Castleman disease.

The etiology of UCD is unknown, but a subset of UCD cases may be the result of somatic mutations in monoclonal cell populations, likely lymph node stromal cells. Alternatively, UCD may occur due to exaggerations of the types of reactive changes that can be seen in response to normal antigenic stimuli.

Active HHV-8 infection is the well-established etiology of HHV-8–associated MCD. HHV-8 is a gamma herpesvirus similar to Epstein-Barr virus (EBV) that has been found in both endemic and HIV-associated Kaposi sarcoma (KS). The HHV-8 virus is pathologically responsible for all symptoms and signs of the disease. [7]

The etiology of HHV-8–negative/idiopathic MCD (iMCD) is not known. The heterogeneity and overlapping clinical and pathologic abnormalities with a wide range of other immunologic disorders suggest that multiple processes—each involving immune dysregulation and a common pathway of increased cytokine levels—may give rise to iMCD in different subsets of patients. Four candidate etiological drivers of iMCD pathogenesis have been proposed: autoimmune mechanisms, autoinflammatory mechanisms, neoplastic mechanisms, and/or infectious mechanisms.

There are at least three clinical subgroups of HHV-8–negative MCD that may each arise from different etiologies than those proposed above:

  • POEMS-associated, HHV-8–negative MCD: Polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, and skin changes (POEMS) is a paraneoplastic syndrome that can co-occur with HHV-8–negative MCD. Both POEMS and HHV-8–negative MCD are thought to be caused by cytokine production from monoclonal plasma cells that have undergone genomic events, such as translocations or deletions.
  • TAFRO syndrome, HHV-8–negative/idiopathic MCD (iMCD-TAFRO): Thrombocytopenia, anasarca, myelofibrosis, renal dysfunction, and organomegaly (TAFRO) often occurs in HHV-8-negative MCD cases. These cases often have mixed or hypervascular (formerly called hyaline vascular) histopathological features and normal gamma globulin levels. The etiology and pathological cell types are completely unknown.
  • Not otherwise specified (NOS), HHV-8–negative/idiopathic MCD (iMCD-NOS): HHV-8–negative MCD patients, who do not have POEMS syndrome or the TAFRO clinical subtype, are considered iMCD-NOS. These patients often have thrombocytosis, hypergammaglobulinemia, and mixed or plasmacytic histopathological features. The etiology and pathological cell types are completely unknown.
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Epidemiology

Castleman disease is rare. An estimated 6500 to 7700 new cases are diagnosed each year in the United States; aproximately 1000 of those are HHV-8–associated multicentric Castleman disease (HHV-8–associated MCD) and 1000 are HHV-8–negative MCD. [8]  UCD, HHV-8–associated MCD, and HHV-8–negative MCD can affect individuals of all ages, including children.

UCD is slightly more common in women and younger individuals.

HHV-8–associated MCD is more common in men and individuals with HIV infection.The incidence of HHV-8–associated MCD has increased with better antiretroviral therapy (ART) for the management of HIV infection. On multivariate analysis, risk factors for the development of HHV-8–associated MCD included the following [9] :

  • Nadir CD4 count higher than 200/µL
  • Increased age
  • No previous ART exposure
  • Nonwhite ethnicity

HHV-8–negative/idiopathic MCD is slightly more common in men. There are no known risk factors.

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Prognosis

The prognosis of Castleman disease varies, depending on the subtype.

The prognosis in unicentric Castleman disease (UCD) is excellent. Patients are usually cured after lymph node excision. Patients who are not able to have complete surgical excision of the enlarged lymph node or region of lymph nodes may require medical management. Development of lymphoma and/or paraneoplastic pemphigus are two rare co-morbidities that can be deadly for UCD patients. No cases of UCD have ever been reported to develop into HHV-8–negative MCD.

HHV-8–associated MCD patients have a good prognosis when treated with rituximab, with greater than 90% 5-year overall survival. In patients who do not respond to rituximab alone, chemotherapy agents may be added to control the disease.

The prognosis for HHV-8–negative MCD patients is not as good as that for patients with HHV-8–associated MCD. According to studies performed prior to the advent of anti–IL-6 therapy, approximately 65% of patients survive for 5 years after diagnosis. This is worse than lymphoma, breast cancer, and prostate cancer. 

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Patient Education

Patient education information and a patient forum are available through the Castleman Disease Collaborative Network.

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