Abstract
Expression of the latent membrane protein-1 (LMP1) of Epstein-Barr virus (EBV) was investigated in 153 cases of EBV+ classic Hodgkin lymphoma (cHL); 120 cases were pediatric patients (< 14 years of age) from Iraq, and 33 cases were adult patients from Italy. We describe for the first time the presence of LMP1 protein in EBV-encoded RNA (EBER)-negative follicular dendritic cells (FDCs) of reactive germinal centers (GC) associated with EBV+ cHL. Presence of LMP1+ GCs was independent of geographic region and age of patients. Variable numbers of reactive GCs were present in 22.2% of cases (34 of 153), whereas LMP1 staining of FDCs was present in about a third of cases (10 of 34) with reactive GC. Most cases with LMP1+ GC were mixed-cellularity (MC) subtype, but some nodular sclerosis (NS) was also present. GC cells with LMP1+ FDCs were surrounded by numerous EBV-infected cells which were positive for EBER, LMP1, and CD30. Double immunolocalization analysis revealed that LMP1 was associated with CD63, an exosomal marker, and with CD21. The possibility is discussed that peri-follicular EBV-infected cells release LMP1 protein, perhaps through exosomes, and that the protein is then captured by FDCs and is presented to EBER-negative GC B cells.
Highlights
Epstein-Barr virus (EBV) generally establishes different forms of latency, depending upon the phenotype and the transcription factor repertoire of the infected cell [1]
We describe 10 cases of EBV+ classic Hodgkin lymphoma (cHL) in which latent membrane protein-1 (LMP1) protein was present in HRS cells and in CD21+/ EBV-encoded RNA (EBER)-negative follicular dendritic cells (FDC) of reactive germinal centers (GC) as well
LMP1+ GCs were negative for EBER, suggesting that FDCs were not infected by EBV; numerous EBER+/
Summary
EBV generally establishes different forms of latency, depending upon the phenotype and the transcription factor repertoire of the infected cell [1]. Baghdad, Iraq 3 Department of Clinical and Molecular Medicine, Pathology Unit, Sant’Andrea Hospital, Sapienza University, Via di Grottarossa 1035, 00189 Rome, Italy 4 Department of Pathology, Baghdad Medical City Complex, Baghdad, Iraq 5 Tumor Immunology Unit, University of Palermo, Palermo, Italy 6 Tumor and Microenvironment Histopathology Unit, the FIRC Institute of Molecular Oncology, Milan, Italy gene expression observed in nasopharyngeal carcinoma (NPC) and Hodgkin lymphoma (HL) is of intermediate type II latency and is characterized by expression of latent membrane protein-1 (LMP1) in tumor cells. Using immunohistochemistry, it was demonstrated that LMP1 is present in Hodgkin/ReedSternberg (HRS) cells of EBV+ classic Hodgkin lymphoma (cHL) [3, 4]. Localization of LMP1 to peri-nuclear regions of the cell is believed to be necessary to mediate these signaling functions [5]
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