Multicentric Castleman’s Disease (MCD) is a rare and poorly understood disorder that straddles the intersections of hematology, oncology, rheumatology, and virology, and that can be fatal if improperly treated. MCD describes a heterogeneous group of disorders with various etiologies that demonstrate episodic systemic inflammatory symptoms, reactive proliferation of morphologically benign lymphocytes, and multiple organ system impairment as a result of excessive interleukin (IL)-6 and other proinflammatory cytokines (Fajgenbaum DC, et al. Blood. 2014;123:2924-2933). The incidence of MCD has not yet been established, but in a recent study, the number of new cases of Castleman’s disease in the United States was estimated to be 4353 annually, which included 1000 cases of MCD. At the ASH 2014 Special Program, David Fajgenbaum presented “An Overview of MCD and an Update on Pathogenesis.”
Human herpesvirus (HHV)-8 is the well-established cause of hypercytokinemia in all HIV-positive patients with MCD, as well as in some HIV-negative patients, said Fajgenbaum. Among patients with HHV-8 and MCD, HIV infection or another cause of immunodeficiency enables HHV-8 to escape from the host’s immune control, lytically replicate in lymph node plasmablasts, and signal the release of viral IL-6, human IL-6, and several other proinflammatory proteins. These proinflammatory proteins induce B-cell and plasma-cell proliferation, vascular endothelial growth factor (VEGF) secretion and angiogenesis, and an acute phase reaction.
In addition, there are patients with HIV-negative and HHV-8–negative MCD that is referred to as idiopathic MCD (iMCD). The etiology of iMCD proinflammatory hypercytokinemia is not known and may be viral, inflammatory, or neoplastic. Although no survival data are currently available for patients with iMCD, a 2011 review identified a 46% 3-year disease-free survival rate among HIV-negative, HHV-8 unknown MCD case reports, and a 10-year overall survival rate of 40%. No official criteria currently exist for the diagnosis of iMCD, and no disease-specific histopathologic features or biomarkers have been identified. The diagnosis is made when Castleman’s lymph node histopathologic features and clinical correlates are observed and all other infectious, autoimmune, and neoplastic diseases known to demonstrate these features have been systematically excluded.
Considering the heterogeneity of the clinical, histologic, and laboratory presentations of iMCD, Fejgenbaum proposed that iMCD represents a common end point that can be reached through multiple processes, each involving immune dysregulation and a common pathway of elevated proinflammatory cytokine release. He hypothesized that 1 or more of the following 3 candidate processes are responsible for iMCD hypercytokinemia, including (1) autoimmune/autoinflammatory mechanisms via autoantibody antigenic stimulation or a germ-line genetic aberration in innate immune regulation (systemic inflammatory disease hypothesis), (2) ectopic cytokine secretion by malignant or benign tumor cells within the lymph nodes or extranodal (paraneoplastic syndrome hypothesis), and (3) viral signaling by a non–HHV-8 virus (virally driven hypothesis).
