Epstein–Barr Virus and the Pathogenesis of Diffuse Large B-Cell Lymphoma

Abstract

Epstein–Barr virus (EBV), defined as a group I carcinogen by the World Health Organization (WHO), is present in the tumour cells of patients with different forms of B-cell lymphoma, including Burkitt lymphoma, Hodgkin lymphoma, post-transplant lymphoproliferative disorders, and, most recently, diffuse large B-cell lymphoma (DLBCL). Understanding how EBV contributes to the development of these different types of B-cell lymphoma has not only provided fundamental insights into the underlying mechanisms of viral oncogenesis, but has also highlighted potential new therapeutic opportunities. In this review, we describe the effects of EBV infection in normal B-cells and we address the germinal centre model of infection and how this can lead to lymphoma in some instances. We then explore the recent reclassification of EBV+ DLBCL as an established entity in the WHO fifth edition and ICC 2022 classifications, emphasising the unique nature of this entity. To that end, we also explore the unique genetic background of this entity and briefly discuss the potential role of the tumour microenvironment in lymphomagenesis and disease progression. Despite the recent progress in elucidating the mechanisms of this malignancy, much work remains to be done to improve patient stratification, treatment strategies, and outcomes.

A Mouse Model to Study the Pathogenesis of γ-herpesviral Infections in Germinal Center B Cells

“…An example is the upregulation of CD30 expression, a member of the tumor-necrosis-factor-receptor (TNF-R) superfamily. The majority of EBV-associated lymphomas such as HL [2], PEL [3], and a subgroup of DLBCL [4], express high levels of CD30, whereas in normal lymphoid tissues, CD30 is expressed by only a few activated B lymphocytes found in the GC and the extrafollicular region, characterized by high proliferation and a c-myc expression profile [24]. Our recent findings provide evidence that aberrant CD30 expression promotes B cell expansion thereby contributing to lymphomagenesis [25].…”

“…Many EBV + B cell lymphomas exhibit high levels of CD30 [2][3][4], prompting the hypothesis that CD30 signaling and γ-herpesviral infection cooperatively contribute to B cell lymphomagenesis. To explore this, we induced the expression of a LMP1/CD30 fusion protein, encoding a constitutively active CD30 receptor, through MHV-68 infection.…”

“…Approximately 30% of Hodgkin lymphomas (HL) are EBV-positive, and nearly all Primary Effusion Lymphomas (PEL) are KSHV-positive with some cases being both KSHV-and EBV-positive [1][2][3]. Moreover, CD30 + Diffuse Large B cell Lymphomas (DLBCL) are significantly associated with EBV [4] and in endemic regions more than 90% of Burkitt's lymphomas are associated with EBV infections [5].…”

The biology and treatment of Epstein-Barr virus-positive diffuse large B cell lymphoma, NOS

“…The proportion of EBV positive rate in DLBCL is relatively higher (8.7%–11.4%) in Asia and Latin America than in Western countries (<5%) [ 4 ]. EBV infection was a risk factor for lymphomagenesis, such as Burkitt lymphoma, NK/T cell lymphoma and EBV+DLBCL-NOS [ 18 , 19 ]. The incidence of EBV+DLBCL-NOS in China accounts for 3.8%–19.0% of DLBCL, and is more common in southern China [ 20 , 21 ].…”

The Possible Role of Pathogens and Chronic Immune Stimulation in the Development of Diffuse Large B-Cell Lymphoma

“…The EBV-positive DLBCL is separated from the DLBCL (NOS) category in all cases where the presence of EBV is detected in most of the malignant cells. This is a new category and an evolution from the EBV-positive DLBCL of the elderly [ 32 ]. EBV is a relatively large double-stranded DNA virus with a 172kb-long genome.…”