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International, evidence-based consensus diagnostic criteria for HHV-8-negative/idiopathic multicentric Castleman disease

David C. Fajgenbaum, Thomas S. Uldrick, Adam Bagg, Dale Frank, David Wu, Gordan Srkalovic, David Simpson, Amy Y. Liu, David Menke, Shanmuganathan Chandrakasan, Mary Jo Lechowicz, Raymond S.M. Wong, Sheila Pierson, Michele Paessler, Jean-François Rossi, Makoto Ide, Jason Ruth, Michael Croglio, Alexander Suarez, Vera Krymskaya, Amy Chadburn, Gisele Colleoni, Sunita Nasta, Raj Jayanthan, Christopher S. Nabel, Corey Casper, Angela Dispenzieri, Alexander Fosså, Dermot Kelleher, Razelle Kurzrock, Peter Voorhees, Ahmet Dogan, Kazuyuki Yoshizaki, Frits van Rhee, Eric Oksenhendler, Elaine S. Jaffe, Kojo S.J. Elenitoba-Johnson and Megan S. Lim

Key points

  • An international panel established the first ever diagnostic criteria for iMCD based on review of 244 clinical cases and 88 tissue samples.

  • The criteria require multicentric lymphadenopathy with defined histopathology, 2 or more clinical/lab changes, and exclusion of iMCD mimics.

Abstract

Human Herpesvirus-8(HHV-8)-negative, idiopathic multicentric Castleman disease (iMCD) is a rare and life-threatening disorder involving systemic inflammatory symptoms, polyclonal lymphoproliferation, cytopenias, and multiple organ system dysfunction due to a cytokine storm often including interleukin-6. iMCD accounts for one-third to one-half of all cases of MCD and can occur in individuals of any age. Accurate diagnosis is challenging, as no standard diagnostic criteria or diagnostic biomarkers currently exist, and there is significant overlap with malignant, autoimmune, and infectious disorders. An international working group comprising 34 pediatric and adult pathology and clinical experts in iMCD and related disorders from eight countries, including two physicians that are also iMCD patients, was convened to establish iMCD diagnostic criteria. The working group reviewed data from 244 cases, met twice, and refined criteria over 15 months (June 2015 - September 2016). The proposed consensus criteria require both Major Criteria (characteristic lymph node histopathology and multicentric lymphadenopathy), at least 2 of 11 Minor Criteria with at least 1 laboratory abnormality, and exclusion of infectious, malignant, and autoimmune disorders that can mimic iMCD. Characteristic histopathologic features may include a constellation of regressed or hyperplastic germinal centers, follicular dendritic cell prominence, hypervascularization, and polytypic plasmacytosis. Laboratory and clinical Minor Criteria include elevated C-reactive protein or erythrocyte sedimentation rate; anemia; thrombocytopenia or thrombocytosis; hypoalbuminemia; renal dysfunction or proteinuria; polyclonal hypergammaglobulinemia; constitutional symptoms; hepatosplenomegaly; effusions or edema; eruptive cherry hemangiomatosis or violaceous papules; and lymphocytic interstitial pneumonitis. iMCD consensus diagnostic criteria will facilitate consistent diagnosis, appropriate treatment, and collaborative research.

  • Submitted October 20, 2016.
  • Accepted January 5, 2017.