KSHV‐associated multicentric Castleman disease: A tangle of different entities requiring multitarget treatment strategies

Multicentric Castleman Disease (MCD) is a lymphoproliferative disorder presenting with heterogeneous pathological and clinical features. It comprises disease entities with a complex aetiology and overlapping pathogenesis. MCD can be found in association with HIV infection, plasma‐cell dyscrasias, Kaposi sarcoma (KS), B‐cell lymphomas including primary effusion lymphoma (PEL) and its solid variant, and Hodgkin lymphoma. In KSHV‐associated MCD cases, a common association is KS and a specific variant of lymphoma referred to as “plasmablastic lymphoma,” also called “large B‐cell lymphoma arising in KSHV‐associated MCD” lacking EBV infection. MCD is often referred to as human interleukin‐6 (hIL‐6) syndrome, since an overproduction of IL‐6 occurs in MCD‐associated diseases as well as in MCD itself. hIL‐6 and a viral IL‐6 (vIL‐6) homolog encoded by KSHV can independently or together lead to flares of KSHV‐associated MCD. Recently, a new clinical entity was proposed to describe a severe systemic infection/reactivation of KSHV: KSHV inflammatory syndrome (KICS). KICS may contribute in inducing the inflammatory symptoms seen in some patients with severe KS or PEL. The precise relationship of KICS to KSHV‐associated MCD is unclear and it is possible that KICS may be prodromal symptoms to frank KSHV‐associated MCD. Options for treatment of KSHV‐associated MCD and related diseases include monoclonal antibodies, chemotherapy, immune modulators, virus‐activated cytotoxic therapy and antiviral therapies. A comprehensive understanding of the intricacies of the HIV‐KSHV coinfection will probably lead to additional advances in therapy and managements for these disorders.