TAFRO syndrome: New subtype of idiopathic multicentric Castleman disease

Abstract

Castleman disease (CD) describes a group of three rare and poorly understood lymphoproliferative disorders that have heterogeneous clinical symptoms and common lymph node histopathological features. Unicentric CD (UCD) involves a single region of enlarged nodes. Multicentric CD (MCD) involves multiple regions of enlarged lymph nodes, constitutional symptoms, and organ dysfunction due to a cytokine storm often including interleukin 6. MCD is further divided into Human Herpes Virus-8 (HHV-8)-associated MCD, which occurs in immunocompromised individuals, and HHV-8-negative/idiopathic MCD (iMCD). Recently, iMCD has been further sub-divided into patients with TAFRO syndrome, which involves thrombocytopenia (T), anasarca (A), fevers (F), reticulin myelofibrosis (R), organomegaly (O), and normal or only slightly elevated immunoglobulin levels, and those who do not have TAFRO syndrome. Non-TAFRO iMCD patients typically have thrombocytosis, less severe fluid accumulation, and hypergammaglobulinemia. iMCD patients with TAFRO syndrome may have a worse prognosis, but more research is needed.

FIGURE 1

Clinical spectrum of iMCD. iMCD includes a broad spectrum of clinical and laboratory abnormalities. iMCD patients tend to experience either TAFRO syndrome abnormalities (top) or IPL/non-TAFRO abnormalities (bottom). Constitutional symptoms, renal dysfunction, and hepatosplenomegaly do not tend to segment to TAFRO or IPL. iMCD: Idiopathic multicentric Castleman disease; TAFRO: Thrombocytopenia, anasarca, fevers, reticulin myelofibrosis, organomegaly; IPL: Idiopathic plasmacytic lymphadenopathy.

FIGURE 2

Histological findings of TAFRO-iMCD lymph nodes (A-F) and bone marrow (G-J). (A) The biopsy of a mildly enlarged lymph node shows atrophic germinal centers and intact sinuses (H&E staining); (B) Marked proliferation of high endothelial venules were observed in the germinal centers and interfollicular zone; (C) Atrophic germinal centers with endothelial cells demonstrating enlarged nuclear proliferation without prominent penetrating hyalinized blood vessels (H&E staining); (D) The interfollicular zone is expanded and there is proliferation of highly dense endothelial venules with enlarged nuclei (H&E staining); (E) There are small numbers of CD138-positive plasma cells in the interfollicular zone (CD138 staining); (F) CD21 immunostaining shows expanded or disrupted patterns of follicular dendritic cell networks (CD21 immunostaining); (G) Fifty-nine percent (13/22) of cases show hypercellular marrow (H&E staining); (H) Megakaryocytes tended to be hyperplastic (H&E staining); (I) Megakaryocytes were slightly atypical, with multiple and widely separated nuclei. Marked plasmacytosis was not observed (H&E staining); (J) Silver stain shows very loose network of reticulin fibers (Silver staining). iMCD: Idiopathic multicentric Castleman disease; TAFRO: Thrombocytopenia, anasarca, fevers, reticulin myelofibrosis, organomegaly; H&E: Hematoxylin and eosin. Reprinted from Iwaki et al. [27] with permission.