KSHV/HHV8-mediated hematologic diseases

Abstract

Kaposi sarcoma (KS) herpesvirus (KSHV), also known as human herpesvirus 8, is the causal agent of KS but is also pathogenetically related to several lymphoproliferative disorders, including primary effusion lymphoma (PEL)/extracavitary (EC) PEL, KSHV-associated multicentric Castleman disease (MCD), KSHV+ diffuse large B-cell lymphoma, and germinotropic lymphoproliferative disorder. These different KSHV-associated diseases may co-occur and may have overlapping features. KSHV, similar to Epstein-Barr virus (EBV), is a lymphotropic gammaherpesvirus that is preferentially present in abnormal lymphoid proliferations occurring in immunecompromised individuals. Notably, both KSHV and EBV can infect and transform the same B cell, which is frequently seen in KSHV+ EBV+ PEL/EC-PEL. The mechanisms by which KSHV leads to lymphoproliferative disorders is thought to be related to the expression of a few transforming viral genes that can affect cellular proliferation and survival. There are critical differences between KSHV-MCD and PEL/EC-PEL, the 2 most common KSHV-associated lymphoid proliferations, including viral associations, patterns of viral gene expression, and cellular differentiation stage reflected by the phenotype and genotype of the infected abnormal B cells. Advances in treatment have improved outcomes, but mortality rates remain high. Our deepening understanding of KSHV biology, clinical features of KSHV-associated diseases, and newer clinical interventions should lead to improved and increasingly targeted therapeutic interventions.

Graphical abstract

Figure 1.

Oncogenic effects of viral oncoproteins. Latent viral proteins (LANA, vCYC, vFLIP, IRF3, and kaposin B) and messenger RNA (miR-K11) are expressed in PEL and depicted in red. Their effects or interactions with representative cellular proteins (blue) is shown. The pathogenic effects of these viral factors include increased cellular proliferation, inhibition of apoptosis and enhanced cellular survival, and production of human cytokines that may have local and systemic effects. cFLIP, cellular FLIP; huIL-6, human IL-6; IAP, inhibitor of apoptosis; MAPK, mitogen-activated protein kinase.

Figure 2.

Three different presentations of PEL. (A) Isolated malignant ascites in a patient with classic PEL (arrows). (B) EC/solid PEL infiltrating the stomach (arrows). Notice the mass displacing the oral contrast. (C-D) Isolated malignant right-sided pleural effusion (C) with concurrent KS (D). Notice the collapse of the right lung compared with the left (C), with characteristic purple KS lesions located on the side of the face in the same patient (D).

Figure 3.

Histopathology of PEL and MCD. (A) PEL cells are large, with pleomorphic immunoblastic/plasmablastic features. A mitotic figure indicates proliferation of the tumor cells. Immunostaining of a cytospin preparation (insert) with an antibody to LANA shows the characteristic dot pattern in the nucleus (modified Giemsa stain, ×100 original magnification; insert: immunoperoxidase, ×100 original magnification). (B) Follicles in KSHV⁺ MCD are often involuted and hyalinized. There are many plasma cells in the interfollicular area and prominent vascular proliferation. In addition, a number of KSHV⁺ plasmablasts (arrows; insert) are present in mantle cell zones. These plasmablasts are LANA⁺ and vIL-6⁺ (hematoxylin and eosin [H&E] and immunoperoxidase staining, ×20 original magnification; inserts: ×60 original magnification).