Castleman Disease: Unraveling Diagnostic Challenges Through Clinical and Pathologic Perspectives

Castleman disease (CD) comprises a heterogenous group of rare nonmalignant lymphoproliferative disorders. CD is classified as unicentric (UCD) and multicentric CD (MCD) depending on the number of lymph node region involvement. Oligocentric CD (OligoCD) is a recently validated provisional subtype with intermediate clinical features and outcomes. MCD is further subcategorized by etiology into three distinct entities: (1) human herpesvirus 8 (HHV-8) associated (HHV-8+) MCD, (2) idiopathic MCD (iMCD), (3) polyneuropathy, organomegaly, endocrinopathy, monoclonal proteins, and skin changes (POEMS)-associated MCD. Idiopathic MCD itself encompasses three clinical subtypes: iMCD-TAFRO (thrombocytopenia, anasarca, fever, reticulin fibrosis/renal dysfunction, and organomegaly), idiopathic plasmacytic lymphadenopathy (iMCD-IPL), and iMCD-NOS (not otherwise specified). Recent advances suggest that CD comprises biologically distinct entities with unique genetic landscapes, cellular origins, and mechanisms underlying interleukin-6 production. MCD is thought to arise from multifactorial mechanisms, including autoimmune dysregulation, chronic inflammatory processes, and paraneoplastic phenomena. The diagnosis of CD remains challenging due to its overlapping features with a broad range of reactive and malignant disorders, as well as its potential coexistence with other underlying conditions. This review focuses on the cell origins and biological mechanisms underlying CD, with particular emphasis on distinguishing CD from conditions with overlapping features, thereby enhancing our understanding of its pathogenesis and disease biology.