EBV-driven B-cell lymphoproliferative disorders: from biology, classification and differential diagnosis to clinical management

Abstract

Epstein-Barr virus (EBV) is a ubiquitous herpesvirus, affecting >90% of the adult population. EBV targets B-lymphocytes and achieves latent infection in a circular episomal form. Different latency patterns are recognized based on latent gene expression pattern. Latent membrane protein-1 (LMP-1) mimics CD40 and, when self-aggregated, provides a proliferation signal via activating the nuclear factor-kappa B, Janus kinase/signal transducer and activator of transcription, phosphoinositide 3-kinase/Akt (PI3K/Akt) and mitogen-activated protein kinase pathways to promote cellular proliferation. LMP-1 also induces BCL-2 to escape from apoptosis and gives a signal for cell cycle progression by enhancing cyclin-dependent kinase 2 and phosphorylation of retinoblastoma (Rb) protein and by inhibiting p16 and p27. LMP-2A blocks the surface immunoglobulin-mediated lytic cycle reactivation. It also activates the Ras/PI3K/Akt pathway and induces Bcl-xL expression to promote B-cell survival. Recent studies have shown that ebv-microRNAs can provide extra signals for cellular proliferation, cell cycle progression and anti-apoptosis. EBV is well known for association with various types of B-lymphocyte, T-lymphocyte, epithelial cell and mesenchymal cell neoplasms. B-cell lymphoproliferative disorders encompass a broad spectrum of diseases, from benign to malignant. Here we review our current understanding of EBV-induced lymphomagenesis and focus on biology, diagnosis and management of EBV-associated B-cell lymphoproliferative disorders.

Figure 1

LMP-1 and LMP-2 and downstream signal transduction.

Figure 2

Infectious mononucleosis. (a) The paracortex of a lymph node is expanded by proliferation of immunoblasts. Hematoxylin and eosin, × 400. (b) In situ hybridization for EBER shows numerous positive cells, × 400.

Figure 3

EBV-positive diffuse large B-cell lymphoma of the elderly. (a) The lymph node is completely effaced by a homogeneous population of large lymphoma cells. Hematoxylin and eosin, × 400. (b) CD20 stain shows numerous positive B-cells, × 400. (c) Ki-67 stain shows a high proliferation index, × 400. (d) In situ hybridization for EBER shows positive lymphoma cells, × 400.

Figure 4

Plasmablastic lymphoma. (a) Sheets of immunoblasts and/or plasmablasts are present with occasional tingible-body macrophages, imparting a ‘starry-sky' pattern. Hematoxylin and eosin, × 400. (b) In situ hybridization for EBER shows numerous positive cells, × 400.

Figure 5

Extracavitary pleural effusion lymphoma. (a) Sheets of immunoblasts and/or plasmablasts are present with frequent mitotic figures. Hematoxylin and eosin, × 400. (b) CD138 stain is positive in most of the lymphoma cells, × 400. (c) In situ hybridization for EBER shows many positive cells, × 400. (d) HHV-8 stain is positive in the lymphoma cells, × 400.

Figure 6

Burkitt lymphoma. (a) Sheets of medium-sized cells with numerous tingible-body macrophages showing the classic starry-sky pattern. Hematoxylin and eosin, × 400. (b) BCL-6 stain is positive in lymphoma cells, × 400. (c) Ki-67 proliferation rate is virtually 100%, × 400. (d) In situ hybridization for EBER shows numerous positive cells, × 400.

Figure 7

Classical Hodgkin lymphoma. (a) A classic binuclear Reed–Sternberg cell (center) and occasional mononuclear Hodgkin cells are intermixed with many mature-appearing lymphocytes, eosinophils, occasional plasma cells and histiocytes. Hematoxylin and eosin, × 400. (b) Hodgkin Reed–Sternberg cells express CD30 with a membranous and Golgi pattern, × 400. (c) A weak nuclear expression of PAX5 is seen in Hodgkin Reed–Sternberg cells. In contrast, B-lymphocytes in the background show strong expression of PAX5, × 400. (d) Occasional Hodgkin Reed–Sternberg cells are positive for EBER, × 400.

Figure 8

Posttransplant lymphoproliferative disorder, polymorphic type. (a) A mixture of immunoblasts, lymphocytes, plasma cells and Hodgkin Reed–Sternberg-like cells (arrow) is present. Hematoxylin and eosin, × 400. (b) CD20 stain shows a B-cell proliferation, × 400. (c) In situ hybridization for EBER shows numerous positive cells, × 400.