Validated international definition of the thrombocytopenia, anasarca, fever, reticulin fibrosis, renal insufficiency, and organomegaly clinical subtype (TAFRO) of idiopathic multicentric Castleman disease

Abstract

Thrombocytopenia, anasarca, fever, reticulin fibrosis, renal insufficiency, and organomegaly (TAFRO) syndrome is a heterogeneous entity manifesting with a constellation of symptoms described above that can occur in the context of idiopathic multicentric Castleman disease (iMCD) as well as infectious diseases, malignancies, and rheumatologic disorders. So, iMCD-TAFRO is an aggressive subtype of iMCD with TAFRO syndrome and often hyper-vascularized lymph nodes. Since we proposed diagnostic criteria of iMCD-TAFRO in 2016, we have accumulated new insights on the disorder and additional cases have been reported worldwide. In this systematic review and cohort analysis, we established and validated a definition for iMCD-TAFRO. First, we searched PubMed and Japan Medical Abstracts Society databases using the keyword "TAFRO" to extract cases. Patients with possible systemic autoimmune diseases and hematologic malignancies were excluded. Our search identified 54 cases from 50 articles. We classified cases into three categories: (1) iMCD-TAFRO (TAFRO syndrome with lymph node histopathology consistent with iMCD), (2) possible iMCD-TAFRO (TAFRO syndrome with no lymph node biopsy performed and no other co-morbidities), and (3) TAFRO without iMCD or other co-morbidities (TAFRO syndrome with lymph node histopathology not consistent with iMCD or other comorbidities). Based on the findings, we propose an international definition requiring four clinical criteria (thrombocytopenia, anasarca, fever/hyperinflammatory status, organomegaly), renal dysfunction or characteristic bone marrow findings, and lymph node features consistent with iMCD. The definition was validated with an external cohort (the ACCELERATE Natural History Registry). The present international definition will facilitate a more precise and comprehensive approach to the diagnosis of iMCD-TAFRO.

Figure 1:. Concepts of TAFRO syndrome and iMCD-TAFRO

TAFRO syndrome is a heterogenous clinical entity with a constellation of non-specific clinical symptoms including thrombocytopenia (T), anasarca (A), fever (F), reticulin fibrosis or renal insufficiency (R), and organomegaly (O). Due to its heterogeneity, TAFRO syndrome includes various clinical conditions such as malignancies, rheumatologic disorders, infections, and POEMS syndrome. The figure conceptualizes five different classifications related to TAFRO syndrome and iMCD-TAFRO. The present study included cases with iMCD-TAFRO, TAFRO with possible iMCD without lymph node biopsy and other co-morbidities (TAFRO with possible iMCD), and TAFRO without histologically proven iMCD and other co-morbidities (TAFRO without iMCD and other co-morbidities). Attention needs to be paid not to confuse TAFRO syndrome and iMCD-TAFRO. Abbreviation: iMCD-TAFRO, TAFRO clinical subtype of idiopathic multicentric Castleman disease; iMCD-NOS, idiopathic multicentric Castleman disease not otherwise specified.

Figure 2:. Performance of the Present Definition to Distinguish iMCD-TAFRO from iMCD-NOS in ACCELERATE Natural History Registry Cohort

36 cases met the present definition for iMCD-TAFRO, and the rest of the 32 cases were noted as iMCD-NOS among the 68 pathology-reviewed, expert-confirmed cases of iMCD in ACCELERATE that primarily come from the United States. All patients noted as iMCD-TAFRO had thrombocytopenia, anasarca, and fever or elevated CRP, as well as renal dysfunction or reticulin fibrosis or hyperplasia of the bone marrow. Of note, of the four iMCD-NOS patients with low platelets, two met TARO criteria but not F criteria, though both had elevated ESR, suggesting inflammation, and two met TAFO criteria but not R criteria, though neither had a bone marrow report to confirm the presence of reticulin fibrosis or hyperplasia. Abbreviation: C-reactive protein; iMCD-TAFRO, TAFRO clinical subtype of idiopathic multicentric Castleman disease; iMCD-NOS, idiopathic multicentric Castleman disease not otherwise specified.