Castleman's disease: one disease, multiple etiologies

Abstract

Castleman disease (CD) comprises a heterogeneous group of rare lymphoproliferative disorders characterized by similar morphological features in nodal biopsies. Since Benjamin Castleman's initial description in 1956, our understanding of CD has progressed substantially. The intricate mechanisms underlying the four recognized subtypes of multicentric CD (MCD) have been studied thoroughly during recent decades. Major disease contributors include the identification of certain viral infections, namely human herpes virus-8 (HHV-8) and HIV; and the discovery of molecular and genetic mechanisms driving disease development and progression and the consequent development of biological targeted therapies, notably siltuximab and rituximab. The CD has been associated with autoimmune, autoinflammatory, and hematological disorders. Along with epidemiological data, the current classification of CD encompasses unicentric CD and MCD. MCD is further subdivided into HHV-8-associated MCD, polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin (POEMS)-associated MCD, and idiopathic MCD (iMCD), which includes thrombocytopenia, anasarca, fever, reticulin TAFRO-iMCD, and iMCD-not-otherwise-specified (iMCD-NOS). While these subtypes share common histological and similar clinical manifestations, they represent distinct conditions. In this review, we discuss the differences in epidemiology, pathophysiology, histology, clinical presentation, and treatment for all distinct CD subtypes. We focus on the role of viral infections in CD development and epidemiology. We finally end by acknowledging areas where further research is needed to uncover the complex nature of CD.