title: International, evidence-based consensus diagnostic criteria for HHV-8-negative/idiopathic multicentric Castleman disease.
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 caused by 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, because 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 8 countries, including 2 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 to 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.
authors.affiliation: Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
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authors.lastname: Fajgenbaum
authors.affiliation: National Cancer Institute, National Institutes of Health, Bethesda, MD.
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Uldrick
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
authors.forename: Adam
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authors.lastname: Bagg
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
authors.forename: Dale
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authors.affiliation: Department of Laboratory Medicine, University of Washington, Seattle, WA.
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authors.affiliation: Division of Haematology, North Shore Hospital, Auckland, New Zealand.
authors.forename: David
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authors.affiliation: Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
authors.forename: Amy Y
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authors.affiliation: Division of Hematology, Department of Medicine, and Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN.
authors.forename: David
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authors.lastname: Menke
authors.affiliation: Department of Medicine, Emory University School of Medicine, Atlanta, GA.
authors.forename: Shanmuganathan
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authors.lastname: Chandrakasan
authors.affiliation: Department of Medicine, Emory University School of Medicine, Atlanta, GA.
authors.forename: Mary Jo
authors.initials: MJ
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authors.affiliation: Sir Y.K. Pao Centre for Cancer and Department of Medicine & Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong.
authors.forename: Raymond S M
authors.identifier: 0000-0002-9011-4268
authors.initials: RS
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authors.affiliation: Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
authors.forename: Sheila
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authors.lastname: Pierson
authors.affiliation: Department of Pathology, Children's Hospital of Philadelphia, Philadelphia, PA.
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authors.affiliation: Department of Hematology, Hôpital Saint Éloi University Hospital, Montpellier, France.
authors.forename: Jean-François
authors.initials: JF
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authors.affiliation: Department of Hematology, Takamatsu Red Cross Hospital, Takamatsu, Kagawa, Japan.
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authors.affiliation: Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
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authors.affiliation: Division of Pulmonary, Allergy, and Critical Care, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
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authors.lastname: Krymskaya
authors.affiliation: Department of Pathology, Weill Cornell Medical College, New York, NY.
authors.forename: Amy
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authors.affiliation: Departamento de Oncologia Clínica e Experimental, Universidade Federal de São Paulo, São Paulo, Brazil.
authors.forename: Gisele
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authors.affiliation: Division of Hematology/Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
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authors.lastname: Nasta
authors.affiliation: Department of Pediatrics, Texas Children's Hospital, Houston, TX.
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authors.affiliation: Department of Medicine, Brigham and Women's Hospital, Boston, MA.
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authors.lastname: Dispenzieri
authors.affiliation: Department of Oncology, Oslo University Hospital-Norwegian Radium Hospital, Oslo, Norway.
authors.forename: Alexander
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authors.lastname: Fosså
authors.affiliation: Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Dermot
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authors.affiliation: Center for Personalized Therapy and Clinical Trials Office, UC San Diego Moores Cancer Center, La Jolla, CA.
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authors.affiliation: Department of Organic Fine Chemicals, The Institute of Scientific and Industrial Research, Osaka University, Osaka, Japan.
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authors.forename: Frits
authors.initials: F
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authors.affiliation: Department of Clinical Immunology, Hôpital Saint-Louis, Paris, France.
authors.forename: Eric
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authors.affiliation: National Cancer Institute, National Institutes of Health, Bethesda, MD.
authors.forename: Elaine S
authors.initials: ES
authors.lastname: Jaffe
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
authors.forename: Kojo S J
authors.initials: KS
authors.lastname: Elenitoba-Johnson
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
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authors.initials: MS
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mesh_terms: D005871:Castleman Disease / Q000175:diagnosis* / Q000209:etiology*; D003937:Diagnosis, Differential; D019288:Herpesvirus 8, Human; D006801:Humans; D038622:Internationality; D017410:Practice Guidelines as Topic