Recent advances in Kaposi sarcoma herpesvirus-associated multicentric Castleman disease

Abstract

Purpose of review: The discovery of Kaposi sarcoma herpesvirus (KSHV) led to recognition of KSHV-associated multicentric Castleman disease (MCD) as a distinct lymphoproliferative disorder. The pathogenesis of KSHV-MCD is attributed to proliferation of KSHV-infected B cells, production of KSHV-encoded viral interleukin 6 by these cells, and dysregulation of human interleukin 6 and interleukin 10. This article reviews advances in the field of disease pathogenesis and targeted therapies.

Recent findings: Our understanding of the pathogenesis of KSHV-MCD has increased in recent years and improved therapies have been developed. Recent studies demonstrate that the anti-CD20 monoclonal antibody, rituximab, as well as virus-activated cytotoxic therapy using high-dose zidovudine and valganciclovir, can control symptoms and decrease adenopathy. With treatment, 1-year survival now exceeds 85%. Interestingly, even in the absence of pathologic findings of MCD, KSHV-infected patients may have inflammatory symptoms, excess cytokine production, and elevated KSHV viral load similar to KSHV-associated MCD. The term KSHV-associated inflammatory cytokine syndrome has been proposed to describe such patients.

Summary: Recent advances in targeted therapy have improved outcomes in KSHV-MCD, and decreased need for cytotoxic chemotherapy. Improved understanding of the pathogenesis of KSHV-MCD and KSHV-associated inflammatory cytokine syndrome is needed, and will likely lead to additional advances in therapy for these disorders.

FIGURE 1.

Computerized tomography in Kaposi sarcoma herpesvirus-multicentric Castleman disease. (a) Coronal image of neck showing bilateral diffuse cervical adenopathy, red arrow points to example of enlarged lymph node on right. (b) Coronal image of torso, demonstrating dramatic splenomegaly, measuring 25 cm (upper limit of normal = 12 cm).

FIGURE 2.

Lymph node histopathology in Kaposi sarcoma herpesvirus-multicentric Castleman disease. (a) Regressed germinal center with expansion of plasmacytic cells in the mantle zone. Immunohistochemical staining for KSHV latency associated nuclear antigen (LANA) shows a proportion of the cells are KSHV infected. 20X magnification. (b) Immunohistochemical staining for viral interleukin-6 (vIL-6) shows a proportion of cells in the mantle zone express vIL-6. 20X magnification. (c) Immunohistochemistry demonstrating a high proportion of cells expressing CD20 (stained brown), with strongest expression in the germinal center, and a mixture of CD20 positive and negative cells in the mantle zone. 40X magnification. (d) Lymph node biopsy showing spindle cell expansion with leaky vascularity representing Kaposi sarcoma (black arrow), as well as typical finding of KSHV-MCD (red arrow) in the same lymph node. 10X magnification Images and pathology samples from patients on National Cancer Institute Institutional Review Board approved KSHV-MCD Natural History Protocol (NCT00099073). All patients gave written informed consent in accordance with the Declaration of Helsinki.