Summary of Treatment Approaches: For initial systemic therapy, rituximab monotherapy has been recommended based on encouraging efficacy and safety results, with a high likelihood of initial response and associated long-term, progression-free survival rates reported to be between 60% and 79%.34,50-57,59,77,78 Treatment involves 4 weekly doses at 375 mg/m2 that can be repeated as necessary for subsequent flareups in patients who previously responded favorably to therapy.55,77
In patients who are negative for HIV but who have failed to respond to, or relapse rapidly following rituximab monotherapy, siltuximab monotherapy is recommended. For patients who progress following treatment with siltuximab, single-agent chemotherapy can be utilized with etoposide,5 vinblastine,43 or liposomal doxorubicin47 with or without rituximab. Combination chemotherapy regimens such as rituximab plus CHOP (R-CHOP) and rituximab plus CVP (R-CVP) are options for patients with resistant or rapidly progressive disease.
In patients with HIV-associated MCD who fail to respond to or relapse rapidly following rituximab monotherapy, the use of either single-agent chemotherapy with or without rituximab or antiherpesvirus therapy with high-dose zidovudine and valganciclovir is recommended.67 Given the increased toxicity in patients with HIV infection and MCD, combination therapy with R-CHOP or R-CVP should be reserved for select patients with treatment-resistant, rapidly progressive, or fulminant disease.
In cases of progression following second-line therapy, the use of alternative single-agent or combination chemotherapies with or without rituximab, bortezomib, antiherpesvirus therapies, or IL-6-directed therapy with siltuximab or tocilizumab should be considered. Siltuximab or tocilizumab should be considered for use in patients positive for HIV in the context of a clinical trial.
Corticosteroid pulses may be helpful for acutely symptomatic disease; however, steroids alone are unlikely to induce lengthy remissions, so they should be reserved for short-term symptomatic control.3,32,37-42 The emerging IL-6 and its receptor antibodies appear highly active in clinical trials, although they have not been studied in HIV-associated MCD.60-62,65,79,80 A recommended treatment algorithm is provided in Fig 4.
(To view a larger version of the figure, click here.)
Associated Conditions and Malignancy Risk
HHV-8 plays a critical role in the pathogenesis of both MCD and Kaposi sarcoma, and the clinical association of these diseases was noted prior to the identification of HHV-8 as a common underlying viral pathogen. Patients with HIV-associated MCD have a 72% risk of being diagnosed with Kaposi sarcoma, either concurrently or sequentially, and the 2 diseases may coexist in the same pathological specimen (see Fig 3).33
The association is lower with Kaposi sarcoma negative for HIV, where the dual incidence is reported at 0% to 13%.33,81 Exacerbations of Kaposi sarcoma have been observed with rituximab therapy34,50,51; therefore, vigilance for flareups of Kaposi sarcoma is necessary when using treatments containing rituximab in a patient with both diseases.
Patients with Castleman disease are at increased risk for lymphoma. Non-Hodgkin lymphoma has been reported in approximately 20% of patients with MCD, as well as in patients with UCD.18,32,38,82,83
Among these, large B-cell lymphoma arising in HHV-8-associated MCD is the most common lymphoma subtype. Patients with MCD are also at increased risk for primary effusion lymphoma, which shares a common HHV-8-mediated pathogenesis.
Patients infected with HIV may also develop other HIV-associated lymphomas not directly related to MCD, including plasmablastic lymphoma, Hodgkin lymphoma, and primary lymphoma of the central nervous system. Amyloidosis has also been reported in association with both UCD and MCD.84-88
Although most cases of lymphoma arising in MCD occur in patients with HIV or HHV-8 infection, patients with MCD in the absence of HIV or HHV-8 infection are also at increased risk of lymphoma to a lesser degree.82,89
POEMS syndrome is characterized by a λ light chain restricted monoclonal gammopathy and a progressive polyneuropathy with early sensory symptoms and later more severe motor symptoms, resembling a chronic inflammatory demyelinating polyneuropathy.90,91
MCD is present in 15% to 25% of patients with POEMS syndrome and is included as a major criterion for the diagnosis of POEMS syndrome.7,92 Other common features include osteosclerotic bone lesions, elevated levels of vascular endothelial growth factor, hepatosplenomegaly, lymphadenopathy, endocrinopathy, skin changes, and elevated protein in the cerebrospinal fluid.
Treatment is directed at the plasma cell clone and includes dexamethasone, lenalidomide, and alkylator-based therapy, with high-dose chemotherapy and autologous stem cell transplantation reserved for select cases.
Follicular Dendritic Cell Sarcoma
Follicular dendritic cell sarcoma is a rare malignancy that frequently occurs in lymph nodes, although it may also involve extranodal sites. Follicular dendritic cell sarcoma has been associated with UCD; in such cases, follicular dendritic cell sarcoma is diagnosed either concurrently with or following the diagnosis of UCD.93-100
Optimal therapy is surgical resection, with or without adjuvant radiation therapy or chemotherapy, although data to guide chemotherapy in this population are scant given the rarity of the disease.
Paraneoplastic pemphigus is an autoimmune mucocutaneous blistering disease associated with localized Castleman disease in 18% of cases and can be a devastating disease with a high mortality rate.101
Approximately two-thirds of patients with paraneoplastic pemphigus have either UCD or an associated malignancy (eg, B-cell lymphoma, lymphoplasmacytic lymphoma, chronic lymphocytic leukemia) at the time of diagnosis.102
The disease precedes the diagnosis of UCD or cancer in the remaining cases. UCD should be suspected in any young patient with paraneoplastic pemphigus. Complete resection of UCD results in clinical improvement or complete remission in most patients.