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A diffuse large B-cell lymphoma in which Epstein-Barr virus, the virus of glandular fever, is present in the tumour cells. It is diagnosed by a stain on the biopsy, it is commoner in east Asia and Latin America than in Europe, and it is treated in the same way as diffuse large B-cell lymphoma without the virus.
What it is. Epstein-Barr virus infects almost everybody by adulthood and then lives quietly inside B cells for life. In a small proportion of diffuse large B-cell lymphomas the virus is present in the tumour cells themselves, detectable by a stain called EBER in situ hybridisation. WHO-HAEM5 recognises that group as an entity in its own right and, in 2022, dropped the qualifier that had restricted it to older people.
How it differs from its family. Not much, in the clinic. It behaves as a diffuse large B-cell lymphoma and is treated as one. What differs is how it is recognised and how it is counted. The European study that found 3.1 per cent noted that no appearance and no immunohistochemical marker reliably identified the positive cases, and that only in situ hybridisation for the viral RNA found them; necrosis was present in two-thirds of positive cases and CD30 in half, but neither was specific. The practical recommendation that came out of that work was to run the stain on every new diffuse large B-cell lymphoma in a person over 50.
Why it is the hardest entity in the classification to place. WHO-HAEM5 reorganised the lymphomas of immune deficiency and dysregulation in 2022 around a three-part description: the histological diagnosis, the virus, and the immune setting. That created an unresolved boundary, which the classification states as a question rather than hiding: should an older person with a diffuse large B-cell lymphoma carrying Epstein-Barr virus be diagnosed with this entity, or with diffuse large B-cell lymphoma arising in immune deficiency, on the assumption that their immune system has aged? The classification says the answer awaits further data and that some of the terminology is arbitrary. A reader should take from that that a label of EBV-positive diffuse large B-cell lymphoma is a description of a finding, not a different disease requiring different treatment.
The boundary the other way. Lymphomatoid granulomatosis is a separate Epstein-Barr virus-driven B-cell disease that, by definition, involves the lung; a similar lesion confined to the brain or gut in somebody with an immune deficiency is classified as EBV-positive diffuse large B-cell lymphoma rather than as lymphomatoid granulomatosis. The International Consensus Classification also keeps nearly all EBV-positive diffuse large B-cell lymphomas out of the mediastinal grey zone category even when they contain Hodgkin-like cells, because the genomes differ.
How it is treated. As diffuse large B-cell lymphoma, with the same immunochemotherapy. The European series found no relationship between the virus and outcome except in the subgroup with the broadest pattern of viral gene expression. The regimens are on the diffuse large B-cell lymphoma page.
How common it is depends on where the series was collected, which is the most useful thing to know about it. In a European tissue microarray study, 8 of 258 diffuse large B-cell lymphomas met the criteria, about 3.1 per cent. In a direct comparison of two populations, 9 of 136 Mexican cases (7 per cent) were positive against 4 of 169 German cases (2 per cent), with a median age of 66 years in Mexico and 77 in Germany. Series from east Asia, where the entity was first described, report higher proportions.
Leukaemias, myeloma and MDS live in the marrow and blood; lymphomas grow in lymph nodes and spleen. The node stations are the disease map, not a route of spread, and staging counts them.
In lymphoma the node stations are the disease itself; staging (Ann Arbor / Lugano) counts how many regions and sides of the diaphragm are involved.
Same organ: High-grade B-cell lymphoma with MYC and BCL2 rearrangements (double-hit lymphoma), Mediastinal grey zone lymphoma, Primary effusion lymphoma, Plasmablastic lymphoma, T-cell/histiocyte-rich large B-cell lymphoma, Primary large B-cell lymphoma of the testis, Gastric MALT lymphoma, Ocular adnexal MALT lymphoma, Extranodal NK/T-cell lymphoma, Adult T-cell leukaemia/lymphoma, ALK-positive anaplastic large cell lymphoma, ALK-negative anaplastic large cell lymphoma, Breast implant-associated anaplastic large cell lymphoma, Primary cutaneous anaplastic large cell lymphoma, Lymphomatoid papulosis, Mycosis fungoides, Enteropathy-associated T-cell lymphoma, Monomorphic epitheliotropic intestinal T-cell lymphoma, Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma), Splenic marginal zone lymphoma, Nodal marginal zone lymphoma, Primary cutaneous marginal zone lymphoma, Primary cutaneous follicle centre lymphoma, Sezary syndrome, Nodal T-follicular helper cell lymphoma, angioimmunoblastic type (angioimmunoblastic T-cell lymphoma), Hepatosplenic T-cell lymphoma, Intravascular large B-cell lymphoma, Lymphomatoid granulomatosis, T-cell prolymphocytic leukaemia, Splenic B-cell lymphoma/leukaemia with prominent nucleoli (formerly B-cell prolymphocytic leukaemia and hairy cell leukaemia variant), T-cell large granular lymphocytic leukaemia, Mixed-phenotype acute leukaemia, Myeloid leukaemia of Down syndrome, Burkitt leukaemia, Marginal zone lymphoma, Cutaneous T-cell lymphoma (mycosis fungoides and Sezary syndrome), Primary mediastinal (thymic) large B-cell lymphoma, Leukaemia (all types), Acute myeloid leukaemia, Acute lymphoblastic leukaemia, Chronic lymphocytic leukaemia, Chronic myeloid leukaemia (CML), Diffuse large B-cell lymphoma, Follicular lymphoma, Hodgkin lymphoma, Mantle cell lymphoma, Multiple myeloma, Non-Hodgkin lymphoma (all types), Myelodysplastic syndromes / neoplasms (MDS), Myeloproliferative neoplasms (PV, ET, myelofibrosis), Polycythaemia vera (PV), Essential thrombocythaemia (ET), Waldenström macroglobulinaemia, Hairy cell leukaemia, Peripheral T-cell lymphomas (including cutaneous T-cell lymphoma), Blastic plasmacytoid dendritic cell neoplasm (BPDCN), Burkitt lymphoma, HIV-associated (AIDS-related) lymphomas, Chronic myelomonocytic leukaemia and MDS/MPN overlap neoplasms, Systemic mastocytosis, Erdheim-Chester disease, Rosai-Dorfman disease and other histiocytic neoplasms, Langerhans cell histiocytosis (LCH), Post-transplant lymphoproliferative disorder (PTLD), FLT3-mutated acute myeloid leukaemia, IDH1- and IDH2-mutated acute myeloid leukaemia, NPM1-mutated and KMT2A-rearranged acute myeloid leukaemia, Secondary and therapy-related acute myeloid leukaemia, Acute promyelocytic leukaemia, Acute myeloid leukaemia in older or unfit patients, Smouldering multiple myeloma, Newly diagnosed multiple myeloma, transplant-eligible, Newly diagnosed multiple myeloma, transplant-ineligible, Relapsed or refractory multiple myeloma, Plasma cell leukaemia, Lower-risk myelodysplastic syndromes, Higher-risk myelodysplastic syndromes, Chronic lymphocytic leukaemia, first treatment, Relapsed or refractory chronic lymphocytic leukaemia, Richter transformation of chronic lymphocytic leukaemia, Chronic myeloid leukaemia, chronic phase, Chronic myeloid leukaemia, accelerated and blast phase, Primary myelofibrosis, Standard-risk B-cell acute lymphoblastic leukaemia in children, High-risk acute lymphoblastic leukaemia in children (high-risk B-ALL and T-ALL), Philadelphia chromosome-positive acute lymphoblastic leukaemia in children (Ph-positive ALL), Philadelphia chromosome-like acute lymphoblastic leukaemia (Ph-like or BCR::ABL1-like ALL), Infant acute lymphoblastic leukaemia (KMT2A-rearranged, under one year), Relapsed and refractory acute lymphoblastic leukaemia in children, Acute myeloid leukaemia in children, Erdheim-Chester disease, Rosai-Dorfman-Destombes disease, Single-system Langerhans cell histiocytosis (bone, skin or one other organ), Multisystem Langerhans cell histiocytosis (with or without risk-organ involvement), Indolent and smouldering systemic mastocytosis, Advanced systemic mastocytosis (aggressive SM, SM with an associated haematological neoplasm, mast cell leukaemia), Early-stage classical Hodgkin lymphoma (stage I to II), Advanced-stage classical Hodgkin lymphoma (stage III to IV), Nodular lymphocyte-predominant Hodgkin lymphoma (nodular lymphocyte-predominant B-cell lymphoma), Relapsed and refractory classical Hodgkin lymphoma
In situ hybridisation for Epstein-Barr-encoded RNA on the biopsy. The European series that put the frequency at 3.1 per cent found that no morphological or immunohistochemical feature reliably identified the positive cases, and recommended running the stain on every new diffuse large B-cell lymphoma in a person over 50. Necrosis and CD30 expression are common in positive cases but neither is specific enough to select who to test.
The same immunochemotherapy as diffuse large B-cell lymphoma without the virus; the presence of Epstein-Barr virus does not currently change the regimen. Where there is an identifiable cause of immune suppression, reducing it is part of the treatment, as it is for the post-transplant lymphoproliferative disorders. The regimens are on the diffuse large B-cell lymphoma page and in the treatment layer of this family.
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Query for this cancer: (TITLE:"EBV-positive diffuse large B-cell lymphoma" OR ABSTRACT:"EBV-positive diffuse large B-cell lymphoma" OR TITLE:"EBV-positive DLBCL" OR ABSTRACT:"EBV-positive DLBCL" OR TITLE:"EBV-positive diffuse large B-cell lymphoma, NOS" OR ABSTRACT:"EBV-positive diffuse large B-cell lymphoma, NOS" OR TITLE:"EBV-positive diffuse large B-cell lymphoma of the elderly" OR ABSTRACT:"EBV-positive diffuse large B-cell lymphoma of the elderly" OR TITLE:"Epstein-Barr virus-positive diffuse large B-cell lymphoma" OR ABSTRACT:"Epstein-Barr virus-positive diffuse large B-cell lymphoma" OR TITLE:"EBV+ DLBCL" OR ABSTRACT:"EBV+ DLBCL") AND (treatment OR therapy OR trial OR survival OR diagnosis). Results are unfiltered search hits about EBV-positive diffuse large B-cell lymphoma, not a curated reading list.
The fourth edition of the WHO classification added EBV-positive diffuse large B-cell lymphoma of the elderly, largely on the strength of east Asian series.
A direct comparison found the virus in 7 per cent of 136 Mexican diffuse large B-cell lymphomas against 2 per cent of 169 German ones, with the Mexican patients a decade younger at diagnosis.
WHO-HAEM5 renamed the entity EBV-positive diffuse large B-cell lymphoma and stated that where it ends and lymphoma of immune deficiency and dysregulation begins is not yet settled.
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Anyone who has ever had hepatitis B can have the virus wake up when rituximab strips out their B cells, sometimes months later and sometimes fatally. A blood test before the first dose, and a tablet for those who need it, prevents almost all of it.
A shortage of antibodies because treatment has wiped out the B cells or plasma cells that make them, as CD19 CAR-T, CD20 antibodies and BCMA therapies deliberately do. It leaves patients prone to infections, sometimes for years, and is managed with immunoglobulin infusions.
Treatments that remove B cells also remove the antibodies B cells make, and some people never make them again. When repeated chest and sinus infections follow, donated antibody given monthly by drip or weekly under the skin prevents them.
Reactions around the moment a drug is given: chills, fever or breathlessness from antibodies (infusion reactions), true allergy (hypersensitivity, rarely anaphylaxis), and leakage of a damaging drug into tissue around the vein (extravasation).
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