Identifying Castleman disease from non-clonal inflammatory causes of generalized lymphadenopathy

Idiopathic multicentric Castleman disease (iMCD) is a rare, life-threatening subtype of Castleman disease (CD), which describes a group of rare, polyclonal lymphoproliferative disorders that demonstrate characteristic histopathology and variable symptomatology. iMCD involves a cytokine storm that occurs due to an unknown cause. Rapid diagnosis is required to initiate appropriate, potentially life-saving therapy, but diagnosis is challenging and impeded by clinical overlap with a wide spectrum of inflammatory, neoplastic, and infectious causes of generalized lymphadenopathy. Diagnosis, which requires both consistent histopathologic and clinical criteria, can be further delayed in the absence of close collaboration between clinicians and pathologists. A multimodal assessment is necessary to effectively discriminate iMCD from overlapping diseases. In this review, we discuss a pragmatic approach to generalized lymphadenopathy and clinical, laboratory, and histopathological features that can aid with identifying iMCD. We discuss diagnostic barriers that impede appropriate recognition of disease features, diagnostic criteria, and evidence-based treatment recommendations that should be initiated immediately following diagnosis.