Expression of human herpesvirus-6 antigens in benign and malignant lymphoproliferative diseases

Abstract

Immunohistochemistry was used to look for the expression of human herpesvirus-6 (HHV-6) antigens in a well characterized series of benign, atypical, and malignant lymphoid lesions, which tested positive for the presence of HHV-6 DNA. A panel of specific antibodies against HHV-6 antigens, characteristic either of the early (p41) or late (p101K, gp106, and gp116) phases of the viral cycle, was applied to the lymphoid tissues from 15 non-Hodgkin's lymphomas, 14 Hodgkin's disease cases, 5 angioimmunoblastic lymphadenopathies with dysproteinemia, 14 reactive lymphadenopathies, and 2 cases of sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease). In lymphomatous tissues, the expression of late antigens was documented only in reactive cells, and mainly in plasma cells. Of interest, the expression of the early p41 antigen was detected in the so-called "mummified" Reed-Sternberg cells, in two Hodgkin's disease cases. In reactive lymphadenopathies, the HHV-6 late antigen-expressing cells were plasma cells, histiocytes, and rare granulocytes distributed in interfollicular areas. In both cases of Rosai-Dorfman disease, the p101K showed an intense staining in follicular dendritic cells of germinal centers, whereas the gp106 exhibited an intense cytoplasmic reaction in the abnormal histiocytes, which represent the histological hallmark of the disease. The expression of HHV-6 antigens is tightly controlled in lymphoid tissues. The lack of HHV-6 antigen expression in neoplastic cells and the limited expression in degenerating Reed-Sternberg cells argue against a major pathogenetic role of the virus in human lymphomagenesis. The detection of a rather unique pattern of viral late antigen expression in Rosai-Dorfman disease suggests a possible pathogenetic involvement of HHV-6 in some cases of this rare lymphoproliferative disorder.

Figure 1.

A: AILD; positive staining with p101K antibody in a focal collection of plasma cells. Immunoperoxidase method; magnification, ×170. B and C: HD, nodular sclerosis type; positive staining with p41 antibody in R-S cells with shrunken cytoplasm and pyknotic nuclei (mummified cells). Immunoperoxidase method; ×330. D: HD, nodular sclerosis type; positive staining with p41 antibody in mummified R-S cells compared with negative staining in a viable R-S cell (right side). Immunoperoxidase method; ×330.

Figure 2.

A: Reactive lymphadenopathy with a predominantly paracortical lesion; positive staining with p101K antibody in scattered interfollicular cells. Immunoperoxidase method; magnification, ×125. B: Sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease); positive staining with p101K antibody in follicular dendritic cells of a reactive germinal center. Immunoperoxidase method; ×170. C: Sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease); intense cytoplasmic reaction with gp106 antibody in large, abnormal histiocytes located within distended sinuses. Isolated plasma cells are also positive. Immunoperoxidase method; ×250. D: Higher magnification of an abnormal histiocyte with emperipolesis in Rosai-Dorfman disease; intense cytoplasmic reaction with gp106 antibody. Immunoperoxidase method; ×400.

Figure 3.

A: AILD; negative staining with an isotype-matched control mouse mAb against human IgG1. Immunoperoxidase method; magnification, ×300. B: Sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease); negative staining with isotype-matched control mouse mAb against human IgG2b. Immunoperoxidase method; ×200.