HHV-8-negative, idiopathic multicentric Castleman disease: novel insights into biology, pathogenesis, and therapy

Blood. 2014 May 8;123(19):2924-33. doi: 10.1182/blood-2013-12-545087. Epub 2014 Mar 12.


Multicentric Castleman's disease (MCD) describes a heterogeneous group of disorders involving proliferation of morphologically benign lymphocytes due to excessive proinflammatory hypercytokinemia, most notably of interleukin-6. Patients demonstrate intense episodes of systemic inflammatory symptoms, polyclonal lymphocyte and plasma cell proliferation, autoimmune manifestations, and organ system impairment. Human herpes virus-8 (HHV-8) drives the hypercytokinemia in all HIV-positive patients and some HIV-negative patients. There is also a group of HIV-negative and HHV-8-negative patients with unknown etiology and pathophysiology, which we propose referring to as idiopathic MCD (iMCD). Here, we synthesize what is known about iMCD pathogenesis, present a new subclassification system, and propose a model of iMCD pathogenesis. MCD should be subdivided into HHV-8-associated MCD and HHV-8-negative MCD or iMCD. The lymphocyte proliferation, histopathology, and systemic features in iMCD are secondary to hypercytokinemia, which can occur with several other diseases. We propose that 1 or more of the following 3 candidate processes may drive iMCD hypercytokinemia: systemic inflammatory disease mechanisms via autoantibodies or inflammatory gene mutations, paraneoplastic syndrome mechanisms via ectopic cytokine secretion, and/or a non-HHV-8 virus. Urgent priorities include elucidating the process driving iMCD hypercytokinemia, identifying the hypercytokine-secreting cell, developing consensus criteria for diagnosis, and building a patient registry to track cases.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Castleman Disease / blood*
  • Castleman Disease / etiology*
  • Castleman Disease / therapy
  • Cytokines / blood*
  • HIV-1 / physiology
  • Herpesvirus 8, Human / physiology
  • Humans
  • Inflammation Mediators / blood*
  • Models, Biological


  • Cytokines
  • Inflammation Mediators