title: Clinicopathologic analysis of TAFRO syndrome demonstrates a distinct subtype of HHV-8-negative multicentric Castleman disease.
abstract: Multicentric Castleman disease (MCD) describes a heterogeneous group of disorders involving systemic inflammation, characteristic lymph node histopathology, and multi-organ dysfunction because of pathologic hypercytokinemia. Whereas Human Herpes Virus-8 (HHV-8) drives the hypercytokinemia in a cohort of immunocompromised patients, the etiology of HHV-8-negative MCD is idiopathic (iMCD). Recently, a limited series of iMCD cases in Japan sharing a constellation of clinical features, including thrombocytopenia (T), anasarca (A), fever (F), reticulin fibrosis (R), and organomegaly (O) has been described as TAFRO syndrome. Herein, we report clinicopathological findings on 25 patients (14 males and 11 females; 23 Japanese-born and two US-born), the largest TAFRO syndrome case series, including the first report of cases from the USA. The median age of onset was 50 years old (range: 23-72). The frequency of each feature was as follows: thrombocytopenia (21/25), anasarca (24/25), fever (21/25), organomegaly (25/25), and reticulin fibrosis (13/16). These patients frequently demonstrated abdominal pain, elevated serum alkaline phosphatase levels, and acute kidney failure. Surprisingly, none of the cases demonstrated marked hypergammoglobulinemia, which is frequently reported in iMCD. Lymph node biopsies revealed atrophic germinal centers with enlarged nuclei of endothelial cells and proliferation of endothelial venules in interfollicular zone. 23 of 25 cases were treated initially with corticosteroids; 12 patients responded poorly and required further therapy. Three patients died during the observation period (median: 9 months) because of disease progression or infections. TAFRO syndrome is a unique subtype of iMCD that demonstrates characteristic clinicopathological findings. Further study to clarify prognosis, pathophysiology, and appropriate treatment is needed.
authors.affiliation: Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and, Pharmaceutical Sciences, Okayama, Japan.|Department of Cellular Transplantation Biology (Hematology/Oncology and Respiratory Medicine), Division of Cancer Medicine, Graduate School of Medical Sciences Kanazawa University, Kanazawa, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Iwaki
authors.affiliation: Department of Medicine, Division of Hematology & Oncology, Raymond & Ruth Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: David C
authors.initials: DC
authors.lastname: Fajgenbaum
authors.affiliation: Department of Medicine, Division of Hematology & Oncology, Raymond & Ruth Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Nabel
authors.affiliation: Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and, Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Gion
authors.affiliation: Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and, Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Eisei
authors.initials: E
authors.lastname: Kondo
authors.affiliation: Division of Rheumatology, Kanazawa University Hospital, Kanazawa, Japan.
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Kawano
authors.affiliation: Department of Hematology, Chugoku Central Hospital, Fukuyama, Japan.
authors.forename: Taro
authors.initials: T
authors.lastname: Masunari
authors.affiliation: Department of Hematologic Oncology, National Hospital Organization Shikoku Cancer Center, Matsuyama, Japan.
authors.forename: Isao
authors.initials: I
authors.lastname: Yoshida
authors.affiliation: Division of Clinical Infection Control and Prevention, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Moro
authors.affiliation: Division of Hematology, Niigata City General Hospital, Niigata, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Nikkuni
authors.affiliation: Division of Hematology, Niigata City General Hospital, Niigata, Japan.
authors.forename: Kazue
authors.initials: K
authors.lastname: Takai
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Kameda Medical Center, Kamogawa, Japan.
authors.forename: Kosei
authors.initials: K
authors.lastname: Matsue
authors.affiliation: Department of Hematology, National Hospital Organization Hokkaido Cancer Center, Sapporo, Japan.
authors.forename: Mitsutoshi
authors.initials: M
authors.lastname: Kurosawa
authors.affiliation: Department of Hematology, Eiju General Hospital, Tokyo, Japan.
authors.forename: Masao
authors.initials: M
authors.lastname: Hagihara
authors.affiliation: Department of Hematology, National Hospital Organization Nishigunma National Hospital, Shibukawa, Japan.
authors.forename: Akio
authors.initials: A
authors.lastname: Saito
authors.affiliation: Department of Hematology and Medical Oncology, Fujita Health University School of Medicine, Toyoake, Japan.
authors.forename: Masataka
authors.initials: M
authors.lastname: Okamoto
authors.affiliation: Division of Pathophysiology, Okayama University Graduate School of Health Sciences, Okayama, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Yokota
authors.affiliation: Department of Pathology, Tokai University School of Medicine, Kanagawa, Japan.
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Hiraiwa
authors.affiliation: Department of Pathology, Tokai University School of Medicine, Kanagawa, Japan.
authors.forename: Naoya
authors.initials: N
authors.lastname: Nakamura
authors.affiliation: Cellular Transplantation Biology, Division of Medicine, Kanazawa University Institutes of Medical, Pharmaceutical, and Health Sciences, Kanazawa, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Nakao
authors.affiliation: Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and, Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Yoshino
authors.affiliation: Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and, Pharmaceutical Sciences, Okayama, Japan.|Division of Pathophysiology, Okayama University Graduate School of Health Sciences, Okayama, Japan.
authors.forename: Yasuharu
authors.initials: Y
authors.lastname: Sato
mesh_terms: D000328:Adult; D000368:Aged; D005871:Castleman Disease / Q000473:pathology*; D005260:Female; D019288:Herpesvirus 8, Human / Q000502:physiology; D006801:Humans; D008198:Lymph Nodes / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D010950:Plasma Cells / Q000473:pathology*; D010976:Platelet Count; D013577:Syndrome; D013921:Thrombocytopenia / Q000209:etiology / Q000473:pathology*; D055815:Young Adult