Castleman disease and TAFRO syndrome

Abstract

Although Castleman disease was first described in 1956, this disease includes various conditions, including unicentric Castleman disease with hyaline vascular histology, human herpesvirus-8 (HHV-8) related multicentric Castleman disease, idiopathic multicentric Castleman disease, and mimics of Castleman disease associated with other conditions. To date, Castleman disease remains incompletely understood due to its rareness and difficulties in clinical and pathological diagnosis. TAFRO syndrome was reported in Japan in 2010. Because lymph node histology is similar in patients with TAFRO syndrome and Castleman disease, TAFRO syndrome is described as a related disorder of Castleman disease. Clinically, however, these conditions differ markedly. Although elevated interleukin-6 (IL-6) expression is characteristic of Castleman disease, increased expression of IL-6 may occur in patients with other diseases, making elevated IL-6 unsuitable for differential diagnosis. Further understanding of these disorders requires the identification of novel disease-specific biomarkers. This review article therefore outlines the characteristics of Castleman disease and TAFRO syndrome.

Keywords: Anasarca; Cytokine storm; HHV-8; IL-6; POEMS syndrome; Thrombocytopenia.

Fig. 1

Classification of types of Castleman disease. Castleman disease is clinically classified as unicentric Castleman disease (UCD) and multicentric Castleman disease (MCD) and was histopathologically classified as hyaline vascular, plasma cell, mixed, hyper-vascular, and plasmablastic types. Most patients with UCD have hyaline vascular histology, with the remainder having plasma cell histology. MCD is etiologically classified as human herpesvirus 8 (HHV-8)-related, HHV-8-unrelated (idiopathic MCD [iMCD]), and other, including POEMS syndrome, TAFRO syndrome, IgG4-related disease, malignancies (lymphoma, cancer, and sarcoma), autoimmune diseases (systemic lupus erythematosus, Sjögren’s syndrome, and vasculitis), and infections (e.g., tuberculosis)

Fig. 2

Cytokine storm and hyper-IL-6 syndrome. Hyper-IL-6 syndrome occurs frequently in patients with HHV8-related MCD and iMCD-NOS and in PC-type UCD. Clinical symptoms and lymph node histology due to hyper-IL6 syndrome have also been observed in patients with POEMS syndrome; TAFRO syndrome; idiopathic portal hypertension (IPH); various malignancies, such as lymphoma and cancer; various autoimmune diseases, such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and Sjögren’ s syndrome (SjS); some infections, such as with tuberculosis (Tbc) and COVID-19; and some iatrogenic conditions, such as chimeric antigen receptor T-cell (CAR-T) therapy and treatment with blinatumomab. Although some patients with IgG4-related disease (IgG4-RD) demonstrate hyper-IL-6 syndrome, most do not. Other than hyper-IL-6 syndrome, hemophagocytic lymphohistiocytosis (HLH), hemophagocytic syndrome (HPS), some severe infections, adult-onset Still disease, and auto-inflammatory syndrome causes hyper-cytokine storm. In contrast, HV-type UCD is not associated with cytokine storm