Multicentric Castleman’s Disease

Synonyms

1

Overview

Multicentric Castleman disease (MCD) is an uncommon lymphoproliferative disorder that share common lymph node histological features that occur systemically (multicentric).

MCD involves hyperactivation of the immune system, excessive release of proinflammatory chemicals (cytokines), proliferation of immune cells (B cells and T cells), and multiple organ system dysfunction. Castleman disease must be distinguished from other disorders that can demonstrate "Castleman-like" lymph node features, including reactive lymph node hyperplasia, autoimmune disorders, and malignancies. While not officially considered a cancer, the overgrowth of lymphocytes with this disease is similar to lymphoma and more research is needed to search for small populations of neoplastic cells. Castleman disease is a focus of intense ongoing research.

Symptoms

MCD clinical features range from waxing and waning mild lymphadenopathy with B-symptoms to more severe cases involving intense inflammation, generalized lymphadenopathy, hepatosplenomegaly, vascular leak syndrome with anasarca, pleural effusions, and ascites, organ failure, and even death. The most common 'B Symptoms' of MCD are high fevers, night sweats, weight loss, and loss of appetite. Acute episodes can display significant clinical overlap with acute viral illnesses, autoimmune diseases, hematologic malignancies, and even sepsis. Laboratory findings commonly include low red cell count, low or high platelet counts, low albumin, high gamma globulin levels, elevated C-reactive protein levels, elevated erythrocyte sedimentation rate, IL-6, vascular endothelial growth factor (VEGF), and fibrinogen; positive anti-nuclear antibody, anti-erythrocyte autoantibodies, and anti-platelet antibodies; and proteinuria and polyclonal marrow plasmacytosis.

Diagnosis

MCD is diagnosed when a lymph node biopsy reveals regression of germinal centers, abnormal vascularity, and a range of hyaline vascular changes and/or polytypic plasma cell proliferation. These features can also be seen in other disorders involving excessive cytokine release, so they must be excluded before a Castleman disease diagnosis should be made.

It is essential for the biopsy sample to be tested for HHV-8 with latent associated nuclear antigen (LANA) by immunohistochemistry or PCR for HHV-8 in the blood.

Treatment

HHV-associated-multicentric

There is no standard therapy for multicentric Castleman disease. Treatment modalities change based on HHV-8 status, so it is essential to determine HHV-8 status before beginning treatment. For HHV-8-associated MCD the following treatments have been used rituximab, antivirals such as ganciclovir, and chemotherapy.

Treatment with the antiherpesvirus drug ganciclovir or the anti CD20 B cell monoclonal antibody, rituximab, may markedly improve outcome. These drugs target and kill B cells via the B cell specific CD20 marker. Since B cells are required for the production of antibodies, the body's immune response is weakened whilst on treatment and the risk of further viral or bacterial infection is increased. Due to the uncommon nature of the condition there are not many large scale research studies from which standardized approaches to therapy may be drawn, and the extant case studies of individuals or small cohorts should be read with caution. As with many diseases, the patient's age, physical state and previous medical history with respect to infections may impact the disease progression and outcome.

HHV-8-negative multicentric

For HHV-8-negative MCD (idiopathic MCD), the following treatments have been used corticosteroids, immunomodulators, rituximab, monoclonal antibodies against IL-6 such as tocilizumab and Siltuximab, and thalidomide.

Prior to 1996 MCD carried a poor prognosis of about 2 years, due to autoimmune hemolytic anemia and non-Hodgkin's lymphoma which may arise as a result of proliferation of infected cells. The timing of diagnosis, with particular attention to the difficulty of determining the cause of B symptoms without a CT scan and lymph node biopsy, may have a significant impact on the prognosis and risk of death. Left untreated, MCD usually gets worse and becomes increasingly difficult and unresponsive to current treatment regimens.

Siltuximab (Sylvant), a monoclonal antibody that binds interleukin-6, preventing it from binding to the IL-6 receptor, was approved by the U.S. Food and Drug Administration for the treatment of multicentric Castleman disease on April 23, 2014. Preliminary data suggest that treatment siltuximab may achieve tumour and symptomatic response in 34% of patients with MCD.

Other treatments for multicentric castleman disease include the following:

• Corticosteroids
• Chemotherapy
• Thalidomide