TAFRO syndrome: An atypical variant of KSHV ‐negative multicentric C astleman disease

Castleman disease (CD) was first described as a solitary lesion, occurring most often in the mediastinum 1, which can be separated into two types, that is, the plasma cell (PC) and the hyaline vascular (HV) types, based upon morphologic features. The PC type demonstrates predominantly follicular hyperplasia and interfollicular sheets of mature PCs, and is associated with a clinical syndrome that includes hypergammaglobulinemia, hypoalbuminemia, anemia, low serum iron, and fever. The HV type demonstrates follicular hyperplasia and prominent interfollicular vascularity, with vessels radially entering the lymphoid follicles and frequently showing hyalinization (Fig. 1). The latter type is usually not associated with clinical symptoms. Schematic representation of histologic characteristics of different types of CD and multicentric CD (MCD). (a) CD HV type consists of follicular hyperplasia with a HV pattern, interfollicular vascularity, vessels radially entering the lymphoid follicle and vessels showing hyalinization. (b) CD PC type is characterized by follicular hyperplasia with an interfollicular sheet of mature PCs. (c) TAFRO – idiopathic (i)MCD is characterized by an atrophic GC along with high endothelial venules in the GC and interfollicular zone, and only small numbers of PCs observed in the interfollicular zone. (d) iMCD-NOS consists of a hyperplastic GC and sheets of proliferating PCs. (e) KSHV-associated MCD consists of a GC with vascular transformation, and large KSHV/latency-associated nuclear antigen positive cells displaying plasmablastic features present at the boundary between the GC and the MZ. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] With the delineation of a multicentric variant, the so-called multicentric Castleman disease (MCD), CD has evolved from a localized, reversible disease, to a generalized disease that is rapidly progressive and fatal. Idiopathic MCD (iMCD), also termed Kaposi sarcoma-associated herpesvirus (KSHV)-negative MCD, exhibits systemic lymphadenopathy, marked hyperimmunoglobulinemia, severe inflammation, and thrombocytosis 2. The affected lymph nodes show a common PC type or mixed type (variant of the PC type and HV type). Also, iMCD can be divided in two clinical forms: a self-limiting multicentric form and a more generalized, progressive and often fatal form. Another progressive form of MCD is represented by KSHV-associated MCD, which has been described histologically as a plasmablastic variant of MCD. This variant is characterized by the presence of plasmablasts scattered in the mantle zones (MZ) of the follicles and has most frequently been observed in HIV-infected individuals 3. Recently, a limited series of iMCD cases in Japan sharing multiple features including thrombocytopenia (T), anasarca (A), fever (F), reticulin fibrosis (R), and organomegaly (O) has been described as TAFRO (or Castleman-Kojima) syndrome 4. In this issue of the American Journal of Hematology, Iwaki et al. report on the clinicopathological findings of 25 patients, the largest TAFRO syndrome case series to date, including the first report of cases from the USA 5. The unanswered question is whether TAFRO syndrome is an independent entity, or indeed an atypical MCD variant 6, 7, that is associated with other disorders such as autoimmune, IgG4-related, hematologic, or infectious diseases. Recently, Kojima et al. 8 classified Japanese iMCD cases into 2 variants, idiopathic plasmacytic lymphoadenpathy (IPL)-type and non-IPL type, on the basis of their clinicopathological findings. The IPL type is characterized by hyperimmunoglobulinemia and PC-type histology. In contrast, the non-IPL type is associated with pleural effusion, ascites, thrombocytopenia, less hyperimmunoglobulinemia, and HV type or mixed-type histology. According to these features, TAFRO syndrome seems to correspond to non-IPL type of iMCD cases. Moreover, affected lymph nodes in TAFRO syndrome histologically show proliferation of small vessels and mature PCs in the interfollicular area, atrophic germinal centers (GC), and an expanded or disrupted pattern of follicular dendritic cell networks by CD21 immunostaining, which are similarly observed in HV type or mixed type of CD 5, 7 (Fig. 1). Importantly, plasmablasts are absent and KSHV infection is also consistently lacking in affected lymph nodes of TAFRO syndrome. Finally, the pathogenesis of TAFRO syndrome has been considered to be an immunological disorder induced by a cytokine storm with IL-6 and VEGF, similar to the pathogenesis of MCD cases. Dysregulated and overproduced IL-6 results in constitutional symptoms (e.g., fever), laboratory abnormalities (e.g., hypergammaglobulinemia), stimulates B-cell proliferation and induces VEGF-related angiogenesis. In Western countries, KSHV infection induces viral IL-6 expression and might cause IL-6 overproduction in most MCD cases, especially in the setting of HIV infection. However, the cytokine storm with IL-6 overproduction found in Japanese MCD cases is considered to be induced without viral infections. In conclusion, TAFRO syndrome is probably not an independent autoimmune clinicopathological entity, but rather an atypical variant of KSHV-negative MCD. Lymph node biopsy and assessment of the levels of IL-6 and VEGF in serum/plasma and effusions are important in the diagnosis of this syndrome, and can help distinguish CD from patients presenting with lymphadenopathy in systemic autoimmune disease 9. In particular, the histological findings of involved lymph nodes are quite unique and as illustrated in Fig. 1 might help us make a definitive diagnosis. Additional studies are anticipated to help further refine and manage the evolving heterogeneous group of patients that manifest with MCD.