EBV-positive Diffuse Large B Cell Lymphoma: Understanding Your Pathology Report

by Jason Wasserman MD PhD FRCPC
April 21, 2026

EBV-positive diffuse large B cell lymphoma (EBV-positive DLBCL) is an aggressive blood cancer that starts in B cells — the white blood cells that help the body fight infections by producing antibodies. It is a specific subtype of diffuse large B cell lymphoma defined by the presence of Epstein-Barr virus (EBV) inside the lymphoma cells. EBV is an extremely common virus — most people are infected during childhood or early adulthood, where it typically causes mononucleosis (“mono”) and then persists silently for life without causing problems. In rare circumstances, EBV can escape immune surveillance and directly contribute to the development of lymphoma. EBV-positive DLBCL was previously called “EBV-positive diffuse large B cell lymphoma of the elderly,” but this name was changed because the disease is now understood to occur not only in older people but in anyone whose immune system is unable to adequately control EBV-infected B cells. This article will help you understand the findings in your pathology report, what each term means, and why it matters for your care.

Who develops EBV-positive DLBCL?

EBV-positive DLBCL develops when the immune system loses its ability to control EBV-infected B cells, allowing them to proliferate and accumulate additional genetic changes that lead to lymphoma. This loss of immune control happens in two main settings.

The most common setting is age-related immune senescence, the gradual natural weakening of immune function that occurs with aging. In older adults, the immune system’s ability to recognize and eliminate EBV-infected cells diminishes over time, which is why EBV-positive DLBCL is most frequently diagnosed in people over the age of 50, with a median age at diagnosis of approximately 65–70 years. The risk increases progressively with age.

The second setting is acquired immune deficiency, a weakened immune system caused by a specific condition or treatment rather than aging alone. This includes HIV infection (particularly with low CD4 counts), organ transplantation (where immunosuppressive medications are used to prevent rejection), certain autoimmune diseases treated with immunosuppressive drugs, and other conditions that impair T cell surveillance. In immunocompromised patients, EBV-positive DLBCL can develop at any age. Patients in this setting may be classified as an immunodeficiency-associated lymphoproliferative disorder rather than standard EBV-positive DLBCL, and this distinction has implications for management — including whether reducing immunosuppression may help control the lymphoma.

What are the symptoms of EBV-positive DLBCL?

EBV-positive DLBCL typically presents with rapidly enlarging swollen lymph nodes in the neck, armpits, or groin, or with masses in other organs where the lymphoma has developed. Because EBV-positive DLBCL commonly arises at extranodal sites — organs and tissues outside the lymph nodes — symptoms may reflect involvement of the lungs (cough, shortness of breath), gastrointestinal tract (abdominal pain, bleeding, nausea), skin (nodules or ulcerating masses), or liver.

General constitutional symptoms — called B symptoms — are prominent and common in this disease. These include fever (particularly persistent or recurrent fevers without an obvious infection), drenching night sweats, and significant unintentional weight loss of more than 10% of body weight over six months. Fatigue is also common. The combination of rapidly growing masses with prominent B symptoms often brings patients to medical attention quickly.

In older patients or those with pre-existing medical conditions, the disease may initially be mistaken for an infection or inflammatory condition before biopsy confirms the diagnosis. Because EBV-positive DLBCL is an aggressive lymphoma, symptoms can worsen quickly over weeks, and prompt diagnosis and treatment are important.

What causes EBV-positive DLBCL?

EBV-positive DLBCL is caused by a combination of EBV infection and inadequate immune control of infected B cells. Understanding this two-part mechanism helps explain both who gets this disease and why treating the immune deficiency — when present — can sometimes help.

EBV is one of the most widespread viruses in the world, infecting more than 90% of adults globally. After primary infection, EBV establishes a lifelong latent infection inside B cells — meaning the virus remains in a dormant state inside the cells, producing very few viral proteins. In healthy people, the immune system continuously monitors for EBV-infected cells and keeps them under tight control, preventing any of them from proliferating abnormally. This immune surveillance depends on a specific population of T cells (a different type of immune cell) that recognize and eliminate EBV-infected B cells upon activation.

When T cell surveillance fails — because of aging, immune suppression, or disease — EBV-infected B cells can escape this control and begin dividing. Inside these proliferating B cells, EBV activates several genes that prevent the infected cell from dying when it should and that promote continued growth. Over time, proliferating EBV-infected B cells accumulate additional genetic mutations, and a subset of them transform into the large, aggressive lymphoma cells that define EBV-positive DLBCL.

The disease is not contagious — you cannot pass EBV-positive DLBCL to other people, and the EBV itself is already present in most adults. The development of lymphoma reflects the failure of immune control, not a new or unusual infection.

How is the diagnosis made?

The diagnosis of EBV-positive DLBCL requires tissue examination and cannot be made on clinical findings, blood tests, or imaging alone. A biopsy of an enlarged lymph node or other affected site is required. Excisional biopsy — removal of an entire lymph node — is preferred when accessible, because it provides the most tissue and best preserves the architectural patterns that aid diagnosis. Core needle biopsy is commonly used when an excisional biopsy is not practical and is usually sufficient.

The pathologist examines the tissue under the microscope and then performs a panel of laboratory tests — including immunohistochemistry (IHC) and EBER in situ hybridization — to confirm the diagnosis and characterize the lymphoma. The presence of EBV in the lymphoma cells, detected by EBER testing, is the defining feature that distinguishes EBV-positive DLBCL from standard (EBV-negative) DLBCL and is required for this diagnosis. Additional molecular testing — including FISH for gene rearrangements — may be performed in selected cases. Once the diagnosis is confirmed, PET/CT imaging, blood tests including LDH, and a bone marrow biopsy are used to stage the disease.

What does EBV-positive DLBCL look like under the microscope?

Under the microscope, EBV-positive DLBCL shares many features with standard DLBCL but has some distinctive characteristics. The tumor is made up of large, abnormal-looking B cells with prominent nuclei — the DNA-containing compartments of the cell — that are visibly enlarged and irregular. These large cells grow in sheets or diffuse collections that replace and efface (destroy) the normal architecture of the lymph node or other tissue, so that the original structure of the organ is largely or completely lost.

Large areas of geographic necrosis — patches of dead tissue with a geographic, map-like outline — are commonly seen within the tumor. This reflects the rapid, aggressive growth of the lymphoma outpacing its blood supply, as well as the destructive effect of the EBV-driven proliferation on the surrounding tissue.

EBV-positive DLBCL is classified into two morphologic patterns based on what the background tissue looks like:

Polymorphic pattern — The large abnormal B cells are scattered among a rich background of non-cancerous immune cells, including small lymphocytes, plasma cells, histiocytes, and sometimes eosinophils. This background reflects the body’s reactive immune response to the lymphoma. The polymorphic pattern can resemble Hodgkin lymphoma under the microscope.
Monomorphic pattern — The large abnormal B cells grow in dense sheets with few or no reactive immune cells in the background. This pattern is more straightforwardly identified as a large B cell lymphoma under the microscope.

In some cases — particularly in the polymorphic pattern — the abnormal B cells closely resemble the Reed-Sternberg cells and their variants that define classic Hodgkin lymphoma. These are called Hodgkin/Reed-Sternberg-like (HRS-like) cells. Despite this resemblance, EBV-positive DLBCL is not a form of Hodgkin lymphoma — the distinction is confirmed by immunohistochemistry, which shows a B cell protein profile very different from Hodgkin lymphoma. The presence of HRS-like cells in a DLBCL report does not mean Hodgkin lymphoma is present.

Immunohistochemistry results

Immunohistochemistry (IHC) is a laboratory test performed on biopsy tissue that uses specially prepared antibodies to detect specific proteins within cells. Each antibody produces a visible color change at the location of its target protein, which the pathologist can see under the microscope. In EBV-positive DLBCL, IHC serves two main purposes: it confirms that the lymphoma cells are B cells (and not T cells or Hodgkin lymphoma cells), and it characterizes features of the lymphoma — including CD30 expression and cell-of-origin classification — that may have implications for treatment. Each result is reported as positive (the protein is present) or negative (the protein is absent).

CD20, CD19, CD79a, PAX5 — Positive. These are pan-B cell markers that confirm the lymphoma cells are B cells. CD20 is also the target of rituximab, the antibody drug included in most treatment regimens for this disease.
CD30 — Positive in many cases (approximately 40–80%). CD30 is a protein expressed on activated lymphoid cells and is strongly expressed in classic Hodgkin lymphoma. Its expression in EBV-positive DLBCL is one of the features that can make it look like Hodgkin lymphoma morphologically. CD30 positivity is also clinically relevant because it is the target of brentuximab vedotin — a targeted antibody-drug therapy that delivers chemotherapy directly to CD30-positive cells. Whether brentuximab vedotin has a role in EBV-positive DLBCL is an area of ongoing investigation.
CD3, CD5 — Negative. These are T cell markers that are absent in EBV-positive DLBCL, confirming the tumor is not of T cell origin.
LMP1 (Latent Membrane Protein 1) — Positive in some cases. LMP1 is a viral protein produced by EBV inside infected cells and can be detected by IHC. Its presence in the tumor cells provides additional evidence of EBV infection, complementing EBER testing.
MUM1/IRF4 — Positive in most cases. MUM1 is a marker associated with late germinal center and post-germinal center B cells. Its expression, together with the other markers, contributes to classifying EBV-positive DLBCL using the Hans algorithm (see below).
BCL2 and MYC protein — Variable. When overexpressed together, these proteins are generally associated with more aggressive behavior in DLBCL (the double-expressor phenotype). Their expression is assessed and reported in the pathology report.

Cell of origin: the Hans algorithm

In standard DLBCL, the Hans algorithm is used to classify the lymphoma as either germinal center B cell-like (GCB) or activated B cell-like (non-GCB/ABC) subtype, based on the IHC results for CD10, BCL6, and MUM1. Most cases of EBV-positive DLBCL are non-GCB (activated B cell-like) by the Hans algorithm. This classification contributes to understanding the biology of the lymphoma and is reported in the pathology report, but it does not currently change the initial treatment approach for EBV-positive DLBCL the way it might in standard DLBCL.

EBER testing

EBER in situ hybridization is the test used to confirm EBV infection in the lymphoma cells and is what makes this diagnosis “EBV-positive.” EBER stands for Epstein-Barr virus-encoded small RNAs — small genetic molecules that EBV continuously produces inside infected cells throughout its latent state. Because EBER is produced in very high quantities inside EBV-infected cells, it is easily detectable with a sensitive probe-based test applied directly to the biopsy tissue. A positive EBER result indicates that EBV is present within lymphoma cells — this is the defining feature of the diagnosis. A negative EBER result would indicate that EBV is absent, and the diagnosis would be reclassified as standard (EBV-negative) DLBCL.

EBER positivity must be confirmed in the large lymphoma cells themselves — not just in small background lymphocytes, which can be EBV-infected in any tissue as part of normal latent infection. The pathologist specifically evaluates whether the large abnormal B cells (the actual tumor cells) are EBER-positive.

FISH testing

FISH (fluorescence in situ hybridization) is a molecular test that looks for specific chromosomal changes — rearrangements in which a piece of DNA breaks off from its normal location on one chromosome and reattaches elsewhere, placing a gene in an abnormal context that can drive cancer. In EBV-positive DLBCL, FISH is performed to look for rearrangements in the MYC, BCL2, and BCL6 genes. This is important because if both MYC and BCL2 gene rearrangements are detected simultaneously, the diagnosis changes to high-grade B cell lymphoma with MYC and BCL2 rearrangements (double-hit lymphoma) — a distinct and more aggressive disease that requires different treatment. Confirming whether these rearrangements are present or absent is therefore an important part of the complete workup.

Staging

EBV-positive DLBCL is staged using the Lugano classification, based on PET/CT imaging and bone marrow biopsy. Staging determines how widely the lymphoma has spread and is essential for treatment planning.

Stage I — A single lymph node region or a single extranodal site is involved.
Stage II — Two or more lymph node regions on the same side of the diaphragm, or one extranodal site with regional lymph node involvement on the same side.
Stage III — Lymph node regions on both sides of the diaphragm are involved.
Stage IV — The lymphoma has spread to one or more extranodal organs such as the bone marrow, liver, or lung, in addition to lymph nodes.

Because EBV-positive DLBCL commonly involves extranodal sites and tends to present with widespread disease, many patients are diagnosed at stage III or IV. The International Prognostic Index (IPI) — which combines age, performance status (ability to carry out daily activities), LDH level, stage, and the number of extranodal sites involved — is used alongside stage to estimate prognosis and guide treatment intensity.

What is the prognosis?

EBV-positive DLBCL is an aggressive lymphoma, and overall outcomes are somewhat less favorable than for EBV-negative DLBCL when treated with standard R-CHOP chemotherapy. Five-year overall survival rates range from approximately 40–60% in most published series, compared to 60–70% for standard DLBCL, though outcomes vary considerably by clinical context. Patients with high IPI scores, advanced stage, significant B symptoms, or very high LDH at diagnosis tend to have less favorable outcomes.

In patients whose EBV-positive DLBCL develops in the setting of iatrogenic immunosuppression — for example, following organ transplantation or immunosuppressive therapy for an autoimmune condition — reducing the immunosuppression (when medically safe to do so) may cause the lymphoma to partially or completely regress without chemotherapy in some cases. This immunosuppression-reduction strategy is unique to this clinical setting and does not apply to age-related EBV-positive DLBCL. Your care team will assess whether this approach is appropriate in your situation.

Response to initial treatment is the most important predictor of long-term outcome. Patients who achieve a complete metabolic response (no detectable lymphoma activity on PET/CT) after treatment have a significantly better prognosis than those with residual disease.

What happens after the diagnosis?

Because EBV-positive DLBCL is aggressive, treatment typically begins within one to two weeks of diagnosis. Most patients are referred to a hematologist or lymphoma oncologist.

The standard first-line treatment for EBV-positive DLBCL is R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) — the same chemoimmunotherapy backbone used for standard DLBCL. Treatment is typically given in cycles (usually six cycles) every 21 days, administered intravenously in a hospital or as a day procedure. Rituximab targets CD20, which is expressed on the lymphoma cells, while the chemotherapy agents work together to kill rapidly dividing cells.

Whether EBV-positivity should prompt a modification of the standard R-CHOP approach — for example, using a more intensive regimen such as DA-EPOCH-R — remains an area of ongoing investigation, and practices vary across centers. Patients with adverse features, such as very high Ki-67, high IPI score, MYC overexpression, or double-expressor status, may be offered more intensive regimens or participation in clinical trials. CNS (central nervous system) prophylaxis — treatment to prevent lymphoma from spreading to the brain and spinal fluid — may be recommended for patients with specific high-risk features, including high IPI score and certain extranodal sites of involvement.

For patients whose disease arises in the setting of organ transplant immunosuppression, reduction of immunosuppression is attempted as an initial step, where medically safe, sometimes in combination with rituximab, before proceeding to full chemotherapy if response is inadequate.

Response to treatment is assessed with PET/CT imaging after several cycles of chemotherapy and at the completion of treatment. Patients who achieve complete metabolic remission are monitored with regular clinical assessments and imaging. For patients who relapse or have refractory disease, salvage chemotherapy regimens, autologous stem cell transplantation, and CAR T cell therapy are potential options depending on age, fitness, and the extent of disease.

Questions to ask your doctor

Was EBER testing confirmed as positive in the large tumor cells, not just in background lymphocytes?
Do I have the polymorphic or monomorphic pattern, and are there HRS-like cells in my biopsy?
Is my EBV-positive DLBCL related to my age and immune system, or is it associated with an immunosuppressive medication or condition?
If I am on immunosuppressive therapy, is it safe to reduce or stop it, and might that help the lymphoma?
Was FISH testing for MYC, BCL2, and BCL6 rearrangements performed, and were any detected?
Is my lymphoma CD30-positive, and does that affect my treatment options?
What is my IPI score, and what does it tell you about my expected outcome?
What stage is my lymphoma, and has it spread to my bone marrow or other organs?
Is R-CHOP the recommended treatment, or are you considering a more intensive regimen?
Do I need CNS prophylaxis, and in what form?
How will you assess whether my treatment is working — and at what point will I have a PET/CT scan?
Are there clinical trials I should consider?