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The below content is based on the following review article: Fajgenbaum D, van Rhee F, Nabel C. "HHV-8-negative or idiopathic multicentric Castleman disease: novel insights into biology, pathogenesis, and treatment." Blood. 2014; 123(19): 2924-2933.

Members of the CDCN conducted a systematic literature review of HHV-8-negative MCD, which was published in 2016: Liu A et al "Idiopathic multicentric Castleman's disease: a systematic literature review." Lancet Haematology. 2016.

Castleman Disease Overview

Dr. David Fajgenbaum presents an overview of Castleman disease and an update on pathogenesis at a recent ASH meeting:

 

Multicentric Castleman Disease (MCD)

Multicentric Castleman disease (MCD) is a rare and poorly understood disorder that straddles the intersections of hematology, oncology, rheumatology, and virology, and can be fatal if improperly treated. MCD describes a heterogeneous group of disorders with various etiologies that demonstrate systemic inflammatory symptoms, reactive proliferation of morphologically benign lymphocytes, and multiple organ system impairment as a result of excessive Interleukin-6 (IL-6) and/or other proinflammatory cytokines. The population incidence has not been established; a recent study estimates 4,353 new cases of “Castleman disease” per year in the US, which we approximate to include 1,000 cases of MCD. The two major MCD subtypes are:

  • HHV-8-associated MCD: Human Herpes Virus-8 (HHV-8) is the well-established cause of the hypercytokinemia (highly elevated levels of cytokines) in all HIV-positive MCD patients and in some HIV-negative patients. Among these HHV-8-associated MCD cases, HIV infection or another cause of immunodeficiency enables HHV-8 to escape from host 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, VEGF secretion and angiogenesis, and an acute phase reaction.
  • HHV-8-negative or idiopathic MCD (iMCD):The etiology of iMCD proinflammatory hypercytokinemia is not known. There are three hypothesized mechanisms responsible for its proinflammatory hypercytokinemia, including that iMCD is driven by systemic inflammatory disease mechanisms, paraneoplastic syndrome mechanisms, and/or virally-driven mechanisms. 
    • (1) The Systemic Inflammatory Disease Hypothesis involves (1a) autoantibodies triggering proinflammatory cytokine release by antigen-presenting cells that induce the “hypercytokine-secreting cell” to release IL-6; (1b/c) an error in kinase or inhibitory signaling in an antigen presenting cell or other “hypercytokine-secreting cell” causing IL-6 secretion, or (1d) a defect in the regulation of activated inflammatory cells. Systemic inflammation is perpetuated by positive feedback of IL-6 and possibly further autoantibody stimulation. 
    • (2) The Paraneoplastic Syndrome Hypothesis involves a somatic mutation in benign or malignant cells inside or outside of the lymph node that causes constitutive proinflammatory cytokine release. 
    • (3) The Virally-Driven Hypothesis involves a non-HHV-8 virus (ex: EBV, HHV-6) signaling proinflammatory cytokines. 
  • Regardless of the etiology, the proinflammatory hypercytokinemia is the common pathway that results in the subsequent clinical and histopathological features of iMCD.

Unicentric Castleman Disease (UCD)

UCD typically involves enlargement of a single lymph node or a single region of lymph nodes. Symptoms are related to the discomfort associated with the enlarged lymph node and can occasionally involve some systemic inflammatory symptoms. Surgical removal of the enlarged node usually cures the patient, with no further complications or relapses. There have never been any cases reported of UCD becoming or transitioning into MCD.