Practice Essentials
Castleman disease (CD) describes a group of four immunologic disorders that occur in individuals of all ages, genders, and ethnicities, and that share characteristic microscopic changes in lymph node appearance. [1] Dr. Benjamin Castleman first described the constellation of lymph node features observed in CD ("CD-like features") in the 1950s. [2] Clinical features, which are related to the release of cytokines, particularly interleukin-6 (IL-6), vary significantly across the four subtypes of CD, as do laboratory abnormalities, treatments, and survival rates. [3] Approximately 4300-5200 patients are estimated to be diagnosed with CD every year in the United States.
The four subtypes are as follows:
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Unicentric CD (UCD) involves a single enlarged lymph node or multiple enlarged lymph nodes within a single lymph node region that demonstrate CD-like features under the microscope. Patients may be asymptomatic or present with a variety of signs and symptoms (see Presentation).
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Human herpesvirus 8 (HHV-8)–associated multicentric Castleman disease (HHV-8–associated MCD) involves multiple regions of enlarged lymph nodes. HHV-8–associated MCD is due to uncontrolled infection with HHV-8, with resulting excessive production of inflammatory cytokines. Patients present with CD-like features, flulike illness, abnormal blood counts, and dysfunction of vital organs (see Presentation). HHV-8 is a common virus that does not cause clinical illness in the overwhelming majority of infected individuals. HHV-8–associated MCD often occurs in immunocompromised individuals, such as those with human immunodeficiency virus (HIV) infection. [4] Patients with HHV-8–associated MCD are at increased risk of developing Kaposi sarcoma, non-Hodgkin lymphoma, and Hodgkin lymphoma.
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POEMS-associated, HHV-8–negative MCD: POEMS (polyradiculoneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell proliferative disorder, and skin changes) syndrome that co-occurs with HHV-8–negative MCD often results in unique clinical features and requires treatment targeted at controlling the POEMS.
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HHV-8–negative/idiopathic multicentric Castleman disease (iMCD) involves multiple regions of enlarged lymph nodes with CD-like features, flulike illness, abnormal blood counts, and dysfunction of vital organs (see Presentation) due to an unknown cause. Cytokines, such as 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, and Hodgkin lymphoma. iMCD can be further subclassified into three clinical groups: iMCD with TAFRO syndrome (iMCD-TAFRO), which is characterized by Thrombocytopenia, Anasarca, Fever, Renal dysfunction or Reticulin fibrosis, and Organomegaly; iMCD with idiopathic plasmacytic lymphadenopathy (iMCD-IPL), characterized by thrombocytosis, hypergammaglobulinemia, and a more chronic disease course; and iMCD not otherwise specified (iMCD-NOS), which is diagnosed in iMCD patients without TAFRO syndrome or iMCD-IPL. 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. All four subtypes require the following tests:
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Complete excisional lymph node biopsy, with microscopic examination to identify features of CD (see Workup).
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Laboratory tests: Complete blood count, inflammation markers (CRP/erythrocyte sedimentation rate [ESR]), and markers of organ function such as liver function tests, albumin, creatinine as well as HIV/HHV8 testing for HHV-8–associated MCD.
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Imaging tests, such as x-rays and PET-CT scans, to identify enlarged lymph nodes and activity of those lymph nodes.
Treatment varies depending on the subtype of CD. International, evidence-based guidelines exist for UCD and iMCD. 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.
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.
POEMS-associated MCD pathophysiology is somewhat understood: monoclonal plasma cell populations responsible for causing POEMS syndrome also produce inflammatory cytokines that cause an MCD-like syndrome. Therapies targeted at plasma cells are generally effective.
HHV-8–negative/idiopathic MCD (iMCD) pathophysiology is poorly understood. Patients experience atypical CD-like lymphoproliferation, which occurs along with systemic inflammatory signs and 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. [5, 6, 7] 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
Patients with UCD, HHV-8–associated MCD, and iMCD can experience a spectrum of lymph node features that range from hyaline vascular (or hypervascular) to plasmacytic (or plasmablastic) with a mixed subtype in the middle.
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) [8] but can also be seen in iMCD. In iMCD, "hypervascular" is used to describe this constellation of features.
The plasmacytic histopathological subtype is used to describe lymph node features including hyperplastic germinal centers as well as occasional atrophic germinal centers and interfollicular plasmacytosis. It is most commonly seen in iMCD, but it can also be seen in UCD. In HHV-8–associated MCD, “plasmablastic” is used to describe this constellation of features, which also includes plasmablasts and positive staining for latency-associated nuclear antigen–1 (LANA-1) by immunohistochemistry.
The mixed histopathological subtype is used to describe cases in which lymph nodes demonstrate features of both the hyaline vascular and plasma cell subtypes.
Etiology
The etiologies differ between the four 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. [9]
Monoclonal plasma cell populations are responsible for causing POEMS-associated MCD.
The etiology of HHV-8–negative/idiopathic MCD (iMCD) is not known. The heterogeneity of clinical features and pathologic abnormalities, which overlap with a wide range of other immunologic disorders, suggests 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 etiologic drivers of iMCD pathogenesis have been proposed: autoimmune, autoinflammatory, neoplastic, and/or infectious mechanisms.
There are at least three clinical subgroups of iMCD that may each arise from different etiologies than those proposed above:
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TAFRO syndrome, HHV-8–negative/idiopathic MCD (iMCD-TAFRO): Thrombocytopenia, anasarca, fever, myelofibrosis, renal dysfunction or reticulin fibrosis, and organomegaly (TAFRO) often occurs in HHV-8–negative MCD. 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 unknown.
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iMCD with idiopathic plasmacytic lymphadenopathy (iMCD-IPL): These patients often have thrombocytosis, hypergammaglobulinemia, mixed or plasmacytic histopathological features, and a more chronic disease course. The etiology and pathological cell types are unknown.
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Not otherwise specified (NOS), HHV-8–negative/idiopathic MCD (iMCD-NOS): HHV-8–negative MCD patients who do not have iMCD-TAFRO or iMCD-IPL are considered to have iMCD-NOS. The etiology and pathological cell types are unknown.
Epidemiology
Castleman disease is rare. An estimated 4300-5200 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. [10] UCD, HHV-8–associated MCD, and HHV-8–negative MCD can affect individuals of all ages (including young children), genders, and ethnicities.
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 [11] :
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Nadir CD4 count higher than 200/µL
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Older age
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No previous ART exposure
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Nonwhite ethnicity
HHV-8–negative/idiopathic MCD is similarly common in men and women. There are no known risk factors.
Prognosis
The prognosis of Castleman disease varies, depending on the subtype.
Unicentric Castleman disease (UCD) carries an excellent prognosis. The reported 10-year survival rate after complete resection is more than 95%. [12] In unresectable cases, the reported survival at 20 months after radiotherapy is 82%. [12] Overall, incomplete resection is associated with poorer outcomes. [12] Development of lymphoma and/or paraneoplastic pemphigus (PNP) are two rare comorbidities that can be deadly for UCD patients. Though the risk of developing (PNP) is low (< 5%), it is the most deadly potential complication and should be evaluated in all UCD patients at the time of diagnosis and following diagnosis to ensure that treatment is rapidly initiated if it presents. Treatment of PNP often includes chemotherapy and immunosuppressive drugs. No cases of UCD have ever been reported to develop into HHV-8–negative MCD.
HHV-8–associated MCD was historically associated with a poor prognosis, with most patients dying within 2 years of diagnosis. [12] However, patients have a good prognosis when treated with rituximab, with greater than 94% 2-year survival. [12] In patients who do not respond to rituximab alone, chemotherapy agents such as doxorubicin and etoposide may be added to control the disease.
The prognosis for iMCD patients is worse than 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. A study in 2021 found a 75% 5-year overall survival rate among iMCD patients. There is reasonable hope that the survival rates are currently greatly improved due to the new breakthroughs in treatment (such as anti-IL6 blockade). The Castleman Disease Collaborative Network is currently leading a global patient research study to collect data to update these numbers. Patients can enroll at www.CDCN.org/ACCELERATE
Patient Education
Patient education information and a patient forum are available through the Castleman Disease Collaborative Network.
