KSHV-associated and EBV-associated Germinotropic Lymphoproliferative Disorder: New Findings and Review of the Literature

Abstract

We report 2 cases of Kaposi sarcoma-associated herpesvirus (KSHV)-and Epstein-Barr Virus (EBV) associated germinotropic lymphoproliferative disorder. Both cases arose in patients from regions endemic for KSHV, Cape Verde, and the Democratic Republic of the Congo, presenting as localized lymphadenopathy. The affected lymph nodes showed colonization of the follicles by clusters of large atypical plasmablasts, but also showed regressive changes with vascular proliferation and interfollicular plasmacytosis, both reminiscent of human herpesvirus 8 (HHV-8) positive multicentric Castleman disease. The atypical plasmablasts showed dual positivity for HHV-8 and EBV, being positive for LANA and viral interleukin 6, as well as Epstein-Barr virus-encoded small RNA by in situ hybridization. They showed a latency I phenotype, being negative for LMP1, EBNA2, and BZLF-1. The plasmablasts were negative for immunoglobulin light chains, and in 1 case with successful DNA amplification had a polyclonal immunoglobulin rearrangement pattern. Germinotropic lymphoproliferative disorder is a rare disorder, with only 6 cases reported in the literature. We demonstrate for the first time the expression of HHV-8 viral interleukin 6 and provide evidence for latency I phenotype for EBV. In addition, 1 case progressed to an EBV-positive diffuse large B-cell lymphoma, but interestingly was negative for KSHV/HHV-8, likely indicative of tumor derived from an independent clone.

Figure 1. Morphologic features of KSHV- and EBV-associated GLPD

(A) The atypical cells were largely confined to germinal centers. (B) The cells are large, showing plasmablastic morphology with smooth nuclear contours, vesicular and eccentrically placed nuclei, 1–2 prominent nucleoli and dense amphophilic. (C) Focal Castleman-like areas with regressed germinal centers surrounded by atypical cells are present. (D) Focally the atypical cells infiltrate sinuses, also highlighted with immunohistochemical stains (see Figure 2). (E) There is marked inter-follicular plasmacytosis. Plasma cells are polyclonal for Kappa (F) and lambda (G) light chains by immunohistochemistry, while the plasmablastic cells were negative (not shown).

Figure 2. Localization of EBV and HHV-8 in GLPD

The distribution of tumor cells within colonized follicles is highlighted by EBER in situ hybridization (A) and immunohistochemistry for the latent protein, LANA, of HHV-8 (B). However a sinusoidal distribution was seen focally with EBER (C) and staining for LANA (D). The atypical cells are focally positive for vIL-6 (E). CD23 staining shows an intact FDC meshwork within a partially involved follicle (F).