==== Front Chin Med J (Engl)Chin. Med. JCMJChinese Medical Journal0366-6999Medknow Publications & Media Pvt Ltd India CMJ-131-186810.4103/0366-6999.237399CorrespondenceTAFRO Syndrome – A Specific Subtype of Castleman's Disease in China Ma Wan-Lu 1Zhang Lu 2Zhu Tie-Nan 2Zhou Dao-Bin 2Li Jian 2Sun Jian 3Pan Bo-Ju 3Xu Wei-Xing 41 Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100730, China2 Department of Hematology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100730, China3 Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100730, China4 Department of Hematology, Cangzhou Central Hospital, Cangzhou, Hebei 061001, ChinaAddress for correspondence: Dr. Lu Zhang, Department of Hematology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100005, China E-Mail: pumczhanglu@163.com05 8 2018 131 15 1868 1870 28 3 2018 Copyright: © 2018 Chinese Medical Journal2018This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms. ==== Body To the Editor: Castleman's disease (CD) describes a group of lymphoproliferative disorders with heterogeneous clinical manifestations.[1] CD comprises at least two distinct diseases (unicentric CD [UCD] and multicentric CD [MCD]) with respective clinical features and prognoses: UCD often involves one lymph node area with favorable outcome; MCD is a systemic disease with relatively poor prognosis which involves multiple lymph node areas with constitutional symptoms (e.g. fever, night sweats, and weakness) and organ dysfunction. According to pathogenesis, MCD can be further divided into different subtypes based on the status of human herpes virus-8 (HHV-8) infection. Of the HHV-8 negative MCD (also named as idiopathic MCD [iMCD]), there is a peculiar subtype named TAFRO syndrome which constitutes a constellation of unique clinical manifestations (T: Thrombocytopenia, A: Anasarca, F: myelofibrosis, R: Renal dysfunction, and O: Organomegaly). This syndrome, first reported in Japan,[2] has been reported mostly in the Japanese population and occasionally in Caucasians. There is no such case reported in China. We herein report the first patient with TAFRO syndrome in China with confirmed myelofibrosis. In July 2016, a 39-year-old woman was referred to our center with a 3-year history of hepatosplenomegaly and multiple lymphadenopathy. Five months ago, she complained of fatigue, palpitation, and shortness of breath after minor exercise. Her body temperature ranged over 38°C for the recent 2 months, which was diurnal, with an afebrile period early in the morning and a gradually rise through day time, reaching the peak (38–38.5°C) in the late afternoon or evening. Other complaints included night sweats, malaise, lower extremity edema, enlarged lymph nodes at neck, axillary fossa, and inguinal groove. Antibiotics did not work well. Methylprednisolone was administrated in a local hospital for 25 days; therefore, body temperature and edema were both improved. However, abdominal distention was later apparent, and a 10 kg loss of body weight was observed despite increased abdomen circumference. On examination, the patient was febrile with maximum 39.1°C. Petechiae were observed on knees, sacrococcygeal region, and left popliteal fossa. Enlarged lymph nodes were at bilateral submandibular areas, right axillary fossa, and bilateral inguinal grooves. Breath sounds were low in both lower lungs. The liver was palpable 9 cm below the right costal margin with slight tenderness. Splenomegaly was noted with line I 12.2 cm, line II 15 cm, and line III − 3.8 cm without pain while pressed. A shifting dullness and fluid thrill was revealed after the examination of the abdomen. Edema of lower extremity was notable. Laboratory investigation showed the following results (normal reference range in brackets): reticulocyte% 0.79% (0.8–2), hemoglobin 3.7 (11.0–16.0) g/dl, mean corpuscular volume 66.7 (82–97) fl, white blood cell (WBC) 2.61 × 109 (4.0–10.0 × 109)/L, platelet (PLT) 74 × 109 (100–300 × 109)/L, urine occult blood (−), urine protein (+) (0.72 g/24 h), fecal occult blood (−), raised erythrocyte sedimentation rate of over 140 (<20) mm/h, raised C-reactive protein of 106.14–143.9 (0–3) mg/L, alkaline phosphates 210 U/L (35–100), lactate dehydrogenase 277 U/L (0–250), creatinine 25 (60–110) μmol/L, alanine transaminase 25 (10–40) IU/L, albumin 29 (35–55) g/L, serum iron (Fe) 30.7 (9–27) umol/L, ferritin (Fer) 266.3 (24–336) ng/ml, and total iron binding capacity 58.7 (54–77) umol/L. Low gammaglobulin levels were noted: immunoglobulin G (IgG) 5.29 g/L (7–17), IgM 0.37 g/L (0.4–2.3), IgA 0.82 g/L (0.7–4). IgG subtypes: IgG1 4800 mg/L (4900–11400), IgG2 821 (1500–6400), IgG3 101 (200–1100), and IgG4 31 (80–1400). Serology examinations for infection including tuberculin and blood cultures were negative. Antinuclear antibody, anti-dsDNA, and anti-SSA antibody were negative. Rheumatoid factor, serum protein electrophoresis, serum immunofixation electrophoresis, and blood free light chain were negative. Coombs test, sucrose hemolysis test, Ham and cobra venom factor hemolysis tests were negative. PLT-associated antibody was positive. Interleukin 6 (IL-6) was 133 pg/ml (<5.9), tumor necrosis factor α 13.7 pg/ml (<8.1), IL-10 6.9 pg/ml (<9.1), and IL-8 407 pg/ml (<62). Vascular endothelial growth factor was 484 pg/ml (<600). Echocardiogram showed normal cardiac function with a mild aortic insufficiency. A computed tomography scan revealed bilateral pleural effusion, enlarged lymph nodes in the mediastinum, hilum of lung, neck, axillary fossa, inguinal groove as well as in the retroperitoneal region, hepatosplenomegaly and ascites. Peripheral blood smear: erythrocytes ranging in size with some irregular shape, the central indifference zone of red blood cell expanding, WBC morphology normal and PLTs rare. Bone marrow aspiration showed neutrophilic and megakaryocytic hyperplasia. Bone marrow biopsy revealed fibrosis with positive reticulin stain [Figure 1d]. The biopsy of the enlarged lymph node in the right axillary fossa showed a histological picture consisted with CD of the hyaline-vascular (HV) variant [Figure 1a and 1b]; immunohistochemical stain for HHV-8 was negative [Figure 1c]. A diagnosis of idiopathic (HHV-8 negative) MCD (HV variant) was therefore made. With the constellation of manifestations of thrombocytopenia (T), anasarca (A), myelofibrosis (F) and proteinuria and organomegaly (O), a final diagnosis of TAFRO syndrome was thus confirmed. Figure 1 Lymph node biopsy showed Castleman disease of hyaline-vascular variant. Regressed germinal center was observed (H and E, original magnification ×100) (a). Vascularity was prominent which suggested a hyaline-vascular variant (H and E, original magnification ×200) (b). Negative HHV-8 LANA stain of this patient (LANA, original magnification ×200) (c). Positive reticulin stain (d). HHV-8: Human herpes virus-8. Along with supportive treatment (e.g. transfusion), two courses of TCP (thalidomide 100 mg qn, cyclophosphamide 300 mg/m2 qw and prednisone 1 mg/kg d1–2 qw) regimens were administrated with aspirin 100 mg qd to prevent thromboembolism. After the treatment, her enlarged lymph nodes, liver and spleen partly shrank with abdomen circumference decreased. However, due to neutropenia, cyclophosphamide was discontinued at the accumulation dosage of 1.6 g (her neutrophil count recovered after the discontinuation of cyclophosphamide). Despite the above-mentioned improvement, unfortunately, her PLT and hemoglobin levels were not improved. Without effective means to improve her anemia (other than transfusion), the general status of the patient deteriorated. The patient died with cardiac arrest which was possibly due to severe anemia 2 months after diagnosis. TAFRO syndrome is a unique subtype of HHV-8 negative MCD (iMCD) with high mortality,[3] first reported by Takai et al. in 2010.[2] In the beginning, TAFRO stood for Thrombocytopenia (T), Anasarca (A), Fever (F), Reticulin fibrosis (R), and Organomegaly (O) which was consistent with the clinical presentation of our patient.[4] In 2012, a diagnostic criterion was proposed for TAFRO syndrome at the Fukushima and Nagoya meeting, and some slight changes were made for the acronyms: F presented myelofibrosis and R for renal dysfunction.[4] This criterion was composed of 11 items [Table 1] which included both clinical and laboratory parameters. Rather than a “diagnostic criterion,” these 11 items can be more properly referred as the clinical manifestations of TAFRO syndrome. Moreover, the diagnosis of TAFRO syndrome is a clinical diagnosis which does not require to fulfill all the 11 criteria. However, with a thorough review of the reported cases so far, it is worth mentioning that once an iMCD patient fulfills at least 4 of 5 key components (T, A, F, R, O) and has other manifestations listed in Table 1, a diagnosis of TAFRO syndrome should be highly suspected. Table 1 Diagnostic criteria for TAFRO syndrome 1. Blood count abnormalities: Low platelets and/or red blood cells; thrombocytopenia, microcytic anemia 2. Systemic inflammation: Polyserositis (pleuritic/peritonitis); inflammation of the tissue lining the lungs or abdominal cavities; pleural effusions, ascites 3. Renal dysfunction 4. Myelofibrosis 5. Immunologic disorder: Rheumatoid factor, platelet-associated IgG, antithyroid antibody, and positivity on direct coombs test 6. Antinuclear antibody 7. Rare polyclonal hyper-globulin: <4000 mg/dL 8. Laboratory data abnormalities: Elevated level of alkaline phosphatase and decreased level of lactate dehydrogenase 9. Elevated levels of IL-6 and the vascular endothelial growth factor in serum or effusions 10. Lymphadenopathy: Generally of mild degree (<1.5 cm in diameter) 11. Histology of mixed-type and less frequently HV-type CD IgG: Immunoglobulin G; HV: Hyaline-vascular; CD: Castleman's disease; IL-6: Interleukin-6. As a rare clinical entity, there are only a few cases of TAFRO syndrome reported in English literatures: mostly in the Japanese and occasionally in the Caucasians. Although the Chinese shares similar origin with the Japanese, TAFRO syndrome in Chinese population was not reported so far. Maybe hematologists in China need more time to recognize this disease. We herein report the very first case of TAFRO syndrome in China. Since the patient had pancytopenia and TAFRO syndrome was a possible explanation for this laboratory finding, a bone marrow biopsy was performed, which revealed myelofibrosis which was a key criterion of this syndrome. One important reason that TAFRO syndrome should be distinguished from other MCD patients is its aggressive and lethal characteristics with hardly effective regimens. There was no “standard treatment” for MCD by now. IL-6 targeted therapy seems to be effective, but neither tocilizumab nor siltuximab was approved in China. Rituximab might be effective but was very expensive and not covered by medical insurance in China. Thalidomide-based treatment was a relatively inexpensive treatment option which might still be efficacious in MCD patients.[5] In this patient, who was from the rural area of China, we chose thalidomide-based treatment, trying to provide her with an economical therapy. Unfortunately, this treatment seemed not very helpful. In conclusion, we report the case of TAFRO syndrome in China which might help to enrich the clinical spectrum of this rare and unique subtype of MCD. We anticipate more cases to be reported in the future. Declaration of patient consent The patient was a participant of our registered clinical trial which was approved by the Institutional Ethical Review Board of Peking Union Medical College Hospital (ZS-1159), and informed consent was achieved from the patient and her relative. Financial support and sponsorship This study was supported by the PUMC Science Fund for Distinguished Young Scholars (JQ201508). Conflicts of interest There are no conflicts of interest. Edited by: Yi Cui ==== Refs REFERENCES 1 Srkalovic G Marijanovic I Srkalovic MB Fajgenbaum DC TAFRO syndrome: New subtype of idiopathic multicentric Castleman disease Bosn J Basic Med Sci 2017 17 81 4 doi: 10.17305/bjbms.2017.1930 28135567 2 Takai K Nikkuni K Shibuya H Hashidate H Thrombocytopenia with mild bone marrow fibrosis accompanied by fever, pleural effusion, ascites and hepatosplenomegaly Rinsho Ketsueki 2010 51 320 5 doi: 10.11406/rinketsu.51.320 20534952 3 Masaki Y Nakajima A Iwao H Kurose N Sato T Nakamura T Japanese variant of multicentric Castleman's disease associated with serositis and thrombocytopenia – A report of two cases: Is TAFRO syndrome (Castleman-Kojima disease) a distinct clinicopathological entity? J Clin Exp Hematop 2013 53 79 85 doi: 10.3960/jslrt.53.79 23801138 4 Kawabata H Takai K Kojima M Nakamura N Aoki S Nakamura S Castleman-Kojima disease (TAFRO syndrome): A novel systemic inflammatory disease characterized by a constellation of symptoms, namely, thrombocytopenia, ascites (anasarca), microcytic anemia, myelofibrosis, renal dysfunction, and organomegaly: A status report and summary of Fukushima (6 June, 2012) and Nagoya meetings (22 September, 2012) J Clin Exp Hematop 2013 53 57 61 doi: 10.3960/jslrt.53.57 23801135 5 Ramasamy K Gandhi S Tenant-Flowers M Ceesay M Corderoy S Marcus R Rituximab and thalidomide combination therapy for Castleman disease Br J Haematol 2012 158 421 3 doi: 10.1111/j.1365-2141.2012.09157.x 22583139