EBV‐positive diffuse large B‐cell lymphoma, not otherwise specified: 2022 update on diagnosis, risk‐stratification, and management

Abstract

Disease Overview Epstein Barr virus‐positive (EBV+) diffuse large B‐cell lymphoma (DLBCL), not otherwise specified (NOS) is an entity included in the WHO classification of lymphoid neoplasms since 2016. EBV+ DLBCL, NOS, is an aggressive B‐cell lymphoma associated with EBV infection, and a poor prognosis with standard chemotherapeutic approaches. Diagnosis The diagnosis is made through a careful pathological evaluation. Detection of EBV‐encoded RNA (EBER) is considered standard for diagnosis; however, a clear cutoff for percentage of positive cells has not been defined. The differential diagnosis includes plasmablastic lymphoma (PBL), DLBCL associated with chronic inflammation, primary effusion lymphoma (PEL), among others. Risk‐Stratification The International Prognostic Index (IPI) and the Oyama score can be used for risk‐stratification. The Oyama score includes age >70 years and presence of B symptoms. The expression of CD30 and PD‐1/PD‐L1 are emerging as potential adverse but targetable biomarkers. Management Patients with EBV+ DLBCL, NOS, should be staged and managed following similar guidelines than patients with EBV‐negative DLBCL. EBV+ DLBCL, NOS, however, might have a worse prognosis than EBV‐negative DLBCL in the era of chemoimmunotherapy. Therefore, the inclusion of patients in clinical trials when available is recommended. There is an opportunity to study and develop targeted therapy in the management of patients with EBV+ DLBCL, NOS.

Epstein–Barr Virus History and Pathogenesis

“…EBV-positive diffuse large B-cell lymphoma (DLBCL), which was formerly designated as EBV-positive DLBCL of the elderly, usually occurs in individuals aged >50 years, with an inferior clinical prognosis in comparison to EBV-negative DLBCL [ 146 ]. The incidence of EBV-positive DLBCL is less than 5% in Western countries, but that percentage goes up to 10–15% in Asian and Latin American countries [ 147 ]. Most EBV-positive DLBCL cases have an activated B-cell (ABC) phenotype, expressing MUM1/IRF4, and are negative for CD10 and BCL6 [ 147 ].…”

“…The incidence of EBV-positive DLBCL is less than 5% in Western countries, but that percentage goes up to 10–15% in Asian and Latin American countries [ 147 ]. Most EBV-positive DLBCL cases have an activated B-cell (ABC) phenotype, expressing MUM1/IRF4, and are negative for CD10 and BCL6 [ 147 ]. Expression of NF-κB and phosphorylated STAT3 are more commonly seen in EBV-positive DLBCL compared with EBV-negative DLBCL [ 146 ].…”

Virological Markers in Epstein–Barr Virus-Associated Diseases

“…EBV-positive DLBCL was included in the 2016 World Health Organization (WHO) classification of lymphoid neoplasms. In the era of chemoimmunotherapy, EBV-positive DLBCL is an aggressive B-cell lymphoma with a worse prognosis than EBV-negative DLBCL, even if several studies showed similar outcomes for both forms [ 90 ].…”

Virus de Epstein-Barr: más que una mononucleosis infecciosa

“…Este tipo de linfoma asociado a la infección por VEB es raro, y se caracteriza por una alta tasa de replicación de células grandes con núcleos vesiculares, con un tamaño del doble de los linfocitos normales [29]. Se considera que aproximadamente el 9 % de los linfomas difusos de células B grandes son positivos para VEB [30], pero también se ha asociado con factores de riesgo como la radiación ionizante, la inmunosupresión y algunos químicos como pesticidas, entre otros [1]. En un metaanálisis reciente en 2021, Hwang y colaboradores [31] encontraron una positividad general del 7,9 % de linfoma difuso de células B grandes asociado a VEB, con una frecuencia del 9,2 % en Asia y América del Sur, y de 4,7 % en las poblaciones occidentales.…”