Castleman Disease 

Updated: Nov 24, 2021
Author: Geneva E Guarin, MD, MBA; Chief Editor: Emmanuel C Besa, MD 

Overview

Practice Essentials

Castleman disease (CD) describes a group of three immunologic disorders that occur in individuals of all ages and share a similar microscopic lymph node appearance, with signs and symptoms related to the release of cytokines, particularly interleukin 6.[1, 2] Dr. Benjamin Castleman first described the constellation of lymph node features observed in CD ("CD-like features") in the 1950s.[3] Approximately 6600-7700 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. [4] 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.

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.[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 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)[8]  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.

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.[9]

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.

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.[10]  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[11] :

  • 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.

Prognosis

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

The prognosis in unicentric Castleman disease (UCD) is excellent. 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 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 is associated with the worst prognosis, with deaths reported within two 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 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. 

Patient Education

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

 

Presentation

History and Physical Examination

The three types of Castleman disease can each cause a variety of signs and symptoms.

Unicentric Castleman disease (UCD) is generally asymptomatic but may present as follows:

  • Localized lymphadenopathy with resultant compressive symptoms [13] : common sites are chest, neck, abdomen, and retroperitoneum; less common sites are axilla, groin, and pelvis
  • Systemic manifestations like those of human herpesvirus 8 (HHV-8)–negative/idiopathic multicentric Castleman disease (iMCD)

The presentation of multicentric Castleman disease spans a wide spectrum of severity, from mild symptoms to life-threatening organ failure. The National Comprehensive Cancer Network (NCCN) criteria for active disease include fever, C-reactive protein > 20 mg/L in the absence of other causes, and 3 or more of the following[14] :

  • Peripheral lymphadenopathy
  • Splenomegaly
  • Edema
  • Pleural effusion
  • Ascites
  • Cough
  • Nasal obstruction
  • Xerostomia
  • Rash
  • Jaundice
  • Autoimmune hemolytic anemia

HHV-8–associated multicentric Castleman disease (HHV-8–associated MCD) involves multicentric lymphadenopathy with characteristic "CD-like" lymph node histopathology and/or the following systemic manifestations, although some cases (< 10%) are asymptomatic:

  • Flulike symptoms (fever, night sweats that soak the sheets, weight loss, loss of appetite, weakness, fatigue)
  • Shortness of breath, cough
  • Nausea and vomiting
  • Numbness and weakness (neuropathy)
  • Leg edema
  • Skin rashes
  • Hemangiomata

For idiopathic multicentric Castleman disease (iMCD), according to the Castleman Disease Collaborative Network (CDCN), at least 2 of following must be present for it to be classified as severe [15] :

  • Eastern Cooperative Oncology Group (ECOG) performance status 2 or above
  • Stage IV kidney dysfunction (estimated glomerular filtration rate < 30 mL/minute/1.73m 2, creatinine > 3 mg/dL)
  • Anasarca and/or ascites, pleural effusion, or pericardial effusion
  • Hemoglobin ≤8 g/dL
  • Pulmonary involvement/interstitial pneumonitis with dyspnea

IMCD involves multicentric lymphadenopathy with characteristic "CD-like" lymph node histopathology and a number of signs and symptoms as defined by the 2017 International Consensus Diagnostic Criteria of iMCD, which may progress or remit/relapse over time:

  • Elevated C-reactive protein (CRP) level and/or erythrocyte sedimentation rate (ESR)
  • Anemia
  • Thrombocytopenia or thrombocytosis
  • Hypoalbuminemia
  • Kidney dysfunction and/or proteinuria
  • Polyclonal hypergammaglobulinemia
  • Flulike signs and symptoms (night sweats, fever, weight loss, fatigue)
  • Large liver and/or spleen
  • Fluid accumulation (edema, anasarca, ascites, pleural effusion)
  • Eruptive cherry hemangiomatosis or violaceous papules
  • Lymphocytic interstitial pneumonitis

There are at least three subtypes of iMCD that demonstrate varying clinical features:

  • POEMS-associated, HHV-8–negative MCD: When POEMS (polyradiculoneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell proliferative disorder, and skin changes) syndrome co-occurs with HHV-8–negative MCD, these patients often have unique clinical features and require treatment targeted at controlling the POEMS.
  • TAFRO syndrome, HHV-8–negative MCD (iMCD-TAFRO): Patients will sometimes present with thrombocytopenia, anasarca, myelofibrosis, kidney dysfunction, and organomegaly (TAFRO) without hypergammaglobulinemia. These cases often have mixed or hypervascular (formerly called hyaline vascular) histopathological features and normal gamma globulin levels.
  • 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 subtype, are classified as having iMCD-NOS. These patients often have thrombocytosis, less severe fluid accumulation, hypergammaglobulinemia, and mixed or plasmacytic histopathological features.

Other conditions that can co-occur with iMCD include the following:

  • Amyloidosis, a condition in which abnormal proteins build up in tissues around the body, can occur in Castleman disease. This can lead to kidney damage; heart damage; nerve damage; and intestinal problems, mainly diarrhea. If the Castleman disease is treated successfully, the amyloidosis may improve or disappear.
  • Autoimmune disease
  • Autoimmune cytopenias such as hemolytic anemia and immune thrombocytopenia (ITP)
  • Bronchiolitis obliterans organizing pneumonia
  • Glomerular nephropathy
  • Inflammatory myofibroblastic tumor
  • Polyneuropathy (without POEMS)

The flulike symptoms and acute-phase reaction, with elevation of the ESR and CRP level, elevated fibrinogen, thrombocytosis, and hypergammaglobinemia in HHV-8–associated MCD and iMCD, are believed to be driven by overproduction of interleukin-6 (IL-6).

 

DDx

Diagnostic Considerations

The differential diagnosis of unicentric Castleman disease (UCD) includes other disorders that can present as a solitary enlarged lymph node and/or systemic symptoms. As a general rule, it is unusual for patients with other causes of reactive lymphadenopathy to present with enlargement of a solitary lymph node, or to have lymph node enlargement to sizes greater than 2 to 3 cm, clues that can be helpful when the histologic appearance raises the possibility of UCD. However, the "CD-like" histopathological features can be seen in other disorders.

The differential diagnoses for the hyaline vascular histopathological subtype of UCD include the following:

  • Toxoplasma lymphadenitis
  • Burned-out HIV lymphadenitis
  • Follicular hyperplasia of any cause
  • Non-Hodgkin lymphoma subtypes with nodular growth patterns
  • Follicular dendritic cell (FDC) sarcoma
  • Autoimmune lymphoproliferative syndrome (ALPS)

The differential diagnoses for the plasma cell histopathological subtype of UCD include the following:

The differential diagnosis of  human herpes virus 8–associated multicentric Castleman disease (HHV-8–associated MCD), which presents with the plasmablastic histopathological subtype, includes the same disorders as HHV-8–negative MCD (below) as well as the following:

  • HIV lymphadenitis
  • Kaposi sarcoma inflammatory cytokine syndrome (KICS)
  • Kaposi sarcoma

Diagnosis of HHV-8–negative/idiopathic multicentric Castleman disease (iMCD) requires exclusion of disorders that can mimic iMCD. These include the following[10] :

  • Human herpesvirus 8 (HHV-8)–associated MCD - Can be excluded by negative latency-associated nuclear antigen–1 (LANA-1) staining in a diagnostic lymph node
  • Epstein-Barr virus (EBV)–associated lymphoproliferative disorders (eg, infectious mononucleosis or chronic active EBV infection); however, low levels of EBV are not necessarily exclusionary
  • Inflammation and adenopathy caused by other uncontrolled infections (eg, acute cytomegalovirus, toxoplasmosis, HIV, acute tuberculosis)
  • Systemic lupus erythematosus
  • Adult-onset Still disease
  • ALPS
  • Juvenile idiopathic arthritis
  • Lymphoma
  • Multiple myeloma
  • Primary lymph node plasmacytoma
  • FDC sarcoma
 

Workup

Approach Considerations

The presentation of Castleman disease (CD) varies considerably between the three subtypes.

Unicentric CD (UCD) should be suspected in patients who present with enlargement of a single lymph node or single region of lymph nodes (ex: right cervical chain). These patients may also experience flulike symptoms and have elevated inflammatory markers such as C-reactive protein (CRP). The diagnosis is made by histologic examination of an excised lymph node. Imaging should be performed to confirm that there is only a single lymph node or single region of enlarged lymph nodes (unicentric) and to select the best lymph node for surgical excision.

Histopathologically, the lymph nodes demonstrate a contellation of "CD-like" features along a spectrum, including small or large germinal centers, follicular dendritic cell (FDC) prominence, hypervascularity, polyclonal plasmacytosis, and/or expansion of polyclonal B cells and T cells. Lymph node features of the different histopathological subtypes of UCD are as follows:

  • Hyaline vascular –  Atrophic germinal centers, onion-skinning mantle zones, hypervascularization, and FDC prominence. [8]
  • Plasma cell – Hyperplastic germinal centers as well as occasional atrophic germinal centers and interfollicular plasmacytosis
  • Mixed – Lymph nodes demonstrate features of both the hyaline vascular and plasma cell subtypes

Human herpesvirus 8 (HHV-8)–associated multicentric Castleman disease (MCD) should be suspected in patients who present with enlargement of multiple regions of lymph nodes, flulike symptoms, elevated inflammatory markers such as C-reactive protein (CRP), and organ dysfunction. Symptoms may appear gradually over the course of months or erupt over the course of days. The diagnosis is made by histologic examination of an excised lymph node. Imaging should be performed to confirm that there are multiple regions of enlarged lymph nodes (multicentric) and to select the best lymph node for surgical excision. 

Histopathologically, the lymph nodes in HHV-8–associated MCD demonstrate a contellation of "CD-like" features, including small or large germinal centers, hypervascularity, lambda-restricted polyclonal plasmacytosis, increased plasmablasts, and/or expansion of polyclonal B cells and T cells. IgH gene rearrangement studies should be performed on the lymph node specimen to rule out a clonal disorder (eg, occult lymphoma). Latency-associated nuclear antigen–1 (LANA-1) staining for HHV-8 by immunohistochemistry should be performed on all cases to confirm that HHV-8 is the pathological driver.

HHV-8-negative/idiopathic MCD (iMCD) should be suspected in patients who present with enlargement of a multiple regions of lymph nodes, flulike symptoms, elevated inflammatory markers such as C-reactive protein (CRP), and organ dysfunction. Symptoms may appear gradually over the course of months or erupt over the course of days.

In 2017, an international panel published diagnostic criteria for iMCD.[10] For diagnosis, patients must meet both major criteria (characteristic lymph node histopathology and multicentric lymphadenopathy) and at least 2 of the 11 minor criteria, including at least 1 laboratory abnormality. Imaging should be performed to confirm that there are multiple regions of enlarged lymph nodes (multicentric) and to select the best lymph node for surgical excision. Histopathologically, the lymph nodes demonstrate a contellation of "CD-like" features along a spectrum, including small or large germinal centers, FDC prominence, hypervascularity, polyclonal plasmacytosis, and/or expansion of polyclonal B cells and T cells. IgH gene rearrangement studies should be performed on the lymph node specimen to rule out a clonal disorder (eg, occult lymphoma).

LANA-1 staining for HHV-8 by IHC should be performed on all cases and should be negative, confirming that HHV-8 is NOT the pathological driver. In addition, diagnosis requires exclusion of infectious, malignant, and autoimmune disorders that can mimic idiopathic MCD (see DDx).

The clinical minor diagnostic criteria comprise the following:

  • Constitutional symptoms
  • Hepatosplenomegaly
  • Anasarca, edema or effusions
  • Eruptive cherry hemangiomatosis or violaceous papules
  • Lymphocytic interstitial pneumonitis (LIP)

The laboratory minor criteria comprise the following:

  • Elevated CRP and/or ESR level
  • Anemia
  • Thrombocytopenia or thrombocytosis
  • Hypoalbuminemia
  • Kidney dysfunction
  • Polyclonal hypergammaglobulinemia

 

Imaging Studies

Imaging is primarily helpful in determining whether the patient has UCD or a form of MCD and in assessing response to therapy.

Whole-body imaging should be performed on all patients with suspected UCD or a form of MCD.

In UCD, a single persistently enlarged lymph node associated with moderate to intense post-contrast enhancement is often found on computed tomography (CT). In such cases, FDG-positron emission tomography (PET) should be considered to establish that the disease is limited to a single site with a relatively lower standardized uptake value (SUV) in other nodes.

In HHV-8-associated MCD and HHV-8-negative MCD, multiple enlarged mediastinal and hilar lymph nodes (1 to 3 cm diameter) may be found along with peripheral lymphadenopathy. HHV-8-associated MCD and HHV-8-negative MCD are both PET avid usually with a relatively low standardized uptake value (SUV) of 2.5-5.[16] Imaging cannot be used to differentiate HHV-8-associated MCD from HHV-8-negative MCD.

In patients with HHV-8-associated MCD and HHV-8-negative MCD, the chest radiograph may show bilateral reticular or ground-glass opacities, mediastinal widening, and/or bilateral pleural effusions.

Lung parenchymal findings may be seen on CT, including subpleural nodules, interlobular septal thickening, peribronchovascular thickening, ground-glass opacities, and patchy rounded areas of consolidation. Small to moderate bilateral pleural effusions may also be present. CT scanning of the neck, abdomen, and pelvis, with and without contrast, may also be helpful.

Imaging may be used to assess whether the UCD was completely resect and no residual disease exists as well as to assess whether the multicentric lymphadenopathy of HHV-8-associated MCD or HHV-8-negative MCD have improved.

Laboratory Studies

Laboratory findings are quite variable across the three subtypes of CD (UCD, HHV-8-associated MCD, HHV-8-negative/idiopathic iMCD) and even within the three clinical subtypes of HHV-8-negative/idiopathic iMCD (POEMS associated iMCD, TAFRO syndrome iMCD, iMCD-NOS). Characteristic findings include the following:

  • Complete blood cell (CBC) count – Anemia (usually mild to moderate, occasionally, the hemoglobin level is < 8 g/dL), thrombocytosis or thrombocytopenia
  • Liver function tests (LFT) – Hypoalbuminemia and elevated alkaline phosphatase
  • Serum protein electrophoresis, with immunofixation and quantitative immunoglobulins – Polyclonal hypergammaglobulinemia
  • C-Reactive Protein (CRP) - Usually elevated
  • Erythrocyte sedimentation rate (ESR) – Usually elevated
  • Fibrinogen – Usually elevated
  • Creatinine and blood urea nitrogen – Usually elevated
  • Serologies for hepatitis B, human herpesvius–8 (HHV-8), and HIV; with quantitative assays if initial results are positive
  • Interleukin-6 (IL-6) and lactate dehydrogenase (LDH) – Usually elevated
  • Vascular endothelial growth factor (VEGF) – May be elevated
  • Autoantibodies, such as ANA - May be elevated

Lymph Node Biopsy

Excisional lymph node biopsy is the preferred method of lymph node biopsy and is used to establish diagnosis.[15]  The other methods of lymph node biopsy are not recommended. Fine needle aspiration is not typically suitable for initial diagnosis. Core needle biopsy has limited accuracy. 

 

Treatment

Approach Considerations

Treatment varies depending on the subtype of Castleman disease.

Unicentric Castleman disease

For unicentric Castleman disease (UCD), surgical removal of the enlarged lymph node is usually curative and is considered the gold standard for treatment. Systemic symptoms and laboratory abnormalities, if present, tend to resolve with complete resection of the enlarged lymph node or solitary region of lymph nodes. Recurrences of UCD have been rarely reported and are usually related to incomplete initial resection or missed lymph nodes at the initial evaluation, though not all UCD recurrences are in the same anatomical location. In rare cases, patients with UCD may have persistent inflammatory symptoms (but not laboratory markers) even after complete surgical resection.

Occasionally, a large UCD mass may be unresectable due to size or location. This is frequently encountered in the setting of a mediastinal mass that is very close to a main bronchus or major blood vessels. In these patients, initial debulking of the mass with systemic therapy, as described for human herpesvirus 8 (HHV-8)–negative/idiopathic multicentric Castleman disease (iMCD), followed by safer surgical intervention should be considered.

Human herpesvirus 8 (HHV-8)–associated multicentric Castleman disease (MCD)

In HHV-8–associated MCD, treatment with rituximab is highly effective. For patients with concomitant HIV infection and a low CD4 count and/or higher HIV load, antiretroviral therapy (ART) should be included with the rituximab.[17] For HIV-negative patients, there may also be a role for concomitant antiviral therapy with ganciclovir. Treatment with rituximab should be repeated upon relapse. Rituximab may be administered or without steroids and/or chemotherapy. However, rituximab therapy occasionally worsens Kaposi sarcoma, which must be carefully considered in HIV-positive patients with a high viral load, low CD4 count, and active Kaposi sarcoma.[18, 17] For HHV-8–associated MCD patients with evidence of life-threatening organ failure or poor performance status, liposomal doxorubicin or etoposide can be added.

HHV-8–negative MCD

Siltuximab (Sylvant) is the only drug approved by the US Food and Drug Administration (FDA) for HHV-8–negative MCD. Siltuximab is a monoclonal antibody that binds interleukin-6 (IL-6). Where available, siltuximab is the preferred therapy, based on its benefit in the only randomized trial[19] and its approval by the FDA; National Comprehensive Cancer Network (NCCN) guidelines recommend siltuximab as the preferred primary treatment.[20] If siltuximab is not available, tocilizumab (anti–IL-6 receptor therapy) may be used in its place. Anti–IL-6 treatment is continued until progression of disease in order to maintain the response and prevent an early relapse.

Of note, after siltuximab is administered, laboratory tests for IL-6 levels become uninterpretable, because the assays detect complexed IL-6 and drug. Therefore, IL-6 levels should not be used to guide or contribute to treatment decisions for at least 18-24 months after the last dose of siltuximab.

Also, 66% of patients in the clinical trial did not respond to siltuximab treatment, approximately half of whom did not have elevated IL-6 levels. Optimal treatment for siltuximab non-responders is not known, but the following agents have been used:

  • Other immunomodulatory therapies (eg, tocilizumab, sirolimus, corticosteroids, cyclosporine, anakinra, thalidomide, intravenous immunoglobulin [IVIg], bortezomib [21, 22] )
  • Targeted B cell depletion with rituximab
  • Cytotoxic chemotherapies (cyclophosphamide, etoposide, [23] adriamycin, vinblastine, or combinations such as rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone [R-CHOP] cyclophosphamide, vincristine, and prednisone [CVP]): Cytotoxic chemotherapy has been used as single agents or in combination, yielding symptomatic relief and a partial response in many patients. However, symptoms recur when treatment is stopped, necessitating intermittent maintenance therapy, often lifelong.

Unicentric Castleman Disease

Surgery is usually curative. In patients whose lesions cannot be completely resected, outcomes remain favorable. Partially resected masses may remain stable and asymptomatic for many years.

Patients with unresectable diseases with compressive symptoms can be treated as described for HIV-negative MCD (below).

Systemic steroids can provide symptomatic relief but do not predictably reduce tumor size.

Radiation therapy with 30-45 Gy can result in complete and partial remission rates of 40% and 10%, respectively, but can cause radiation-induced fibrosis that makes subsequent surgical intervention more difficult.[24]

Multicentric Castleman Disease

The National Comprehensive Cancer Network (NCCN) recommends siltuximab as a preferred primary treatment for patients with HIV-negative HHV-8-negative/idiopathic multicentric Castleman disease (iMCD) with plasmacytic or mixed pathology.[20]

 

 

Long-Term Monitoring

Disease response is assessed by evaluating lymph node size via imaging, as well as biochemical values. The following markers of inflammatory response and organ function can be evaluated33:

  • C-reactive protein
  • Hemoglobin
  • Albumin
  • Glomerular filtration rate

The frequency of monitoring depends on the severity of presentation, as follows[15] :

  • For severe presentation, initially monitoring should be daily
  • For less severe presentation, weekly assessment of clinical symptoms and laboratory values is necessary, then biweekly until maximum benefit has occurred

Radiological evaluation of lymph nodes with computed tomography is as follows[15] :

  • Begin at 6 weeks after treatment initiation
  • Repeat every 3 months until maximum response is achieved, then reduce to every 6 to 12 months
 

Medication

Medication Summary

Siltuximab is the only agent approved by the US Food and Drug Administration for use in Castleman disease—specifically, for idiopathic multicentric Castleman disease. It is also listed as the preferred primary treatment in National Comprehensive Cancer Network guidelines.[20]  Rituximab and tocilizumab have been used off-label for multicentric Castleman disease.

Immunomodulators

Class Summary

Agents that decrease IL-6 production or actions are emerging for MCD.

Siltuximab (Sylvant)

Siltuximab is a monoclonal antibody that binds IL-6 and prevents the binding of IL-6 to both soluble and membrane-bound IL-6 receptors. It is approved by the FDA with an indication for multicentric Castleman disease in patients who are negative for HIV and human herpesvirus-8.

Tocilizumab (Actemra)

Tocilizumab is an IL-6 receptor antagonist. It has been used off-label for multicentric Castleman disease.

Rituximab (Rituxan)

Rituximab is a humanized monoclonal antibody that binds to CD20 antigen, which results in decreased IL-6 production. It has been used off-label for multicentric Castleman disease.

 

Questions & Answers

Overview

What is Castleman disease (CD)?

What are the subtypes of Castleman disease (CD)?

How is Castleman disease (CD) diagnosed?

How is Castleman disease (CD) treated?

What is the Castleman Disease Collaborative Network?

What is the pathophysiology of Castleman disease (CD)?

What are the microscopic features of Castleman disease (CD)?

What causes Castleman disease (CD)?

What are the subgroups of human herpesvirus-8–associated multicentric Castleman disease (HHV-8-associated MCD)?

What are the risk factors for developing HHV-8–associated multicentric Castleman disease (HHV-8-associated MCD)?

How common is Castleman disease (CD) in the US?

What are the sex- and age-related demographics of Castleman disease (CD)?

What is the prognosis of Castleman disease (CD)?

What are the patient education resources for Castleman disease (CD)?

Presentation

What is the clinical presentation of human herpesvirus 8–associated multicentric Castleman disease (HHV-8-associated MCD)?

What is the clinical presentation of unicentric Castleman disease (UCD)?

What are the signs and symptoms of idiopathic multicentric Castleman disease (iMCD)?

What are the clinical features of idiopathic multicentric Castleman disease (iMCD)?

Which conditions co-occur with idiopathic multicentric Castleman disease (iMCD)?

DDX

What is included in the differential diagnosis of human herpesvirus 8–associated multicentric Castleman disease (HHV-8–associated MCD)?

Which disorders can mimic human herpesvirus 8–negative/idiopathic multicentric Castleman disease (HHV-8-associated iMCD)?

What is included in the differential diagnosis of unicentric Castleman disease (UCD)?

What is included in the differential diagnosis of the hyaline vascular histopathological subtype of unicentric Castleman disease (UCD)?

What is included in the differential diagnosis of the plasma cell histopathological subtype of unicentric Castleman disease (UCD)?

Workup

What are the histopathological lymph node features of the unicentric Castleman disease (UCD) subtypes?

What are the approach considerations in the workup of unicentric Castleman disease (UCD)?

How is human herpesvirus 8–associated multicentric Castleman disease (HHV-8-associated MCD) diagnosed?

What are the diagnostic criteria for idiopathic Castleman disease (iCD)?

Which imaging studies are indicated in the workup of Castleman disease (CD)?

Which lab studies are indicated in the workup of Castleman disease (CD)?

What is the role of lymph node biopsy in the workup of Castleman disease (CD)?

Treatment

How is human herpesvirus 8 (HHV-8)–associated multicentric Castleman disease (MCD) treated?

What is the treatment for Castleman disease (CD)?

How is unicentric Castleman disease (UCD) treated?

How is human herpesvirus 8 (HHV-8)–negative Castleman disease (MCD) treated?

What surgical treatment is indicated in unicentric Castleman disease (UCD)?

What long-term monitoring is indicated in Castleman disease (CD)?

Medications

Which medications are indicated in the treatment of Castleman disease (CD)?

Which medications in the drug class Immunomodulators are used in the treatment of Castleman Disease?