Unraveling TAFRO Syndrome: An In-Depth Look at the Pathophysiology, Management, and Future Perspectives

Abstract

TAFRO syndrome is a rare and aggressive inflammatory entity characterized by thrombocytopenia, anasarca, fever, renal failure, reticulin fibrosis, and organomegaly. This entity supposes a diagnostic and therapeutic challenge due to its significant overlap with Castleman's disease. However, distinct clinical and histological features warrant its classification as a separate subtype of idiopathic multicentric Castleman's disease (iMCD). While recent modifications have been made to the diagnostic criteria for iMCD, these criteria lack specificity for this particular condition, further complicating diagnosis. Due to its inflammatory nature, several complex molecular signaling pathways are involved, including the JAK-STAT pathway, NF-kB, and signal amplifiers such as IL-6 and VEGF. Understanding the involvement of immune dysfunction, some infectious agents, genetic mutations, and specific molecular and signaling pathways could improve the knowledge and management of the condition, leading to effective treatment strategies. The current therapeutic approaches include corticosteroids, anti-IL6 drugs, rituximab, and chemotherapy, among others, but response rates vary, highlighting the need for personalized strategies. The prognosis is uncertain due to diagnostic difficulties, emphasizing the importance of early intervention and appropriate targeted treatment. This comprehensive review examines the evolving landscape of TAFRO syndrome, including the pathophysiology, diagnostic criteria, treatment strategies, prognosis, and future perspectives.

Keywords: TAFRO; anasarca; fever; organomegaly; renal failure; reticulin fibrosis; thrombocytopenia.

Figure 4

Proposed algorithm for the treatment of TAFRO syndrome. HSCT: hematopoietic stem cell transplantation.

Figure 1

Pathophysiology, etiological factors, and potential therapeutic targets in TAFRO syndrome. EBV: Epstein—Baar virus; HHV8: Human herpes virus 8; CMV: cytomegalovirus; AI: autoimmune; TNF: tumor necrosis factor; IL: interleukin; MAPK: MAP kinase; VEGF: vascular endothelial growth factor; PI3K: phosphoinositide 3-kinase; AKT: protein kinase B; NFkB: nuclear factor kappa-light-chain-enhancer of activated B cells; Rc: receptor.

Figure 2

Proposed algorithm for the diagnosis of TAFRO syndrome. CD: Castleman-like features on lymph node biopsy; OM: organomegaly; MF: myelofibrosis; PRI: progressive renal insufficiency; SLE: systemic lupus erythematosus; SS: Sjögren’s syndrome; POEMS: polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes; TTP/HUS: thrombotic thrombocytopenic purpura/hemolytic uremic syndrome. * Pleural effusion, ascites and/or edema. ^¶ <100,000/μL and no myelosuppression. ^§ Fever > 37.5 °C and CRP ≥ 2 mg/dL.

Figure 3

Histologic specimens of bone marrow and lymph node in a patient with TAFRO syndrome. (A) Bone marrow, Hematoxylin-eosin (HE). Megakaryocytic hyperplasia with signs of dysplasia (×5). (B) Bone marrow. Reticulin fibrosis. Reticulin staining (×1). (C) Lymph node. Hyperplasia of dendritic cells labeled with CD23 (×5). (D) Lymph node, HE. Vessels entering the germinal center and lymphocytes in a single file. Typical “lollipop” lesions (×5).