Diffuse Large B Cell Lymphoma (DLBCL): Understanding Your Pathology Report

by Jason Wasserman MD PhD FRCPC
April 15, 2026

Diffuse large B cell lymphoma (DLBCL) is the most common type of lymphoma in adults. It is an aggressive cancer that starts in B cells — the white blood cells that normally help the body fight infections. The word “diffuse” refers to how the cancer cells grow in flat, sheet-like areas that spread through the affected tissue rather than forming the compact, round clusters seen in slower-growing lymphomas. Despite its aggressive behavior, DLBCL is potentially curable in many patients, and the goal of treatment in most cases is long-term remission or cure. This article will help you understand the findings in your pathology report, what each term means, and why it matters for your care.

What are the symptoms of diffuse large B cell lymphoma?

The most common presentation is a rapidly enlarging mass or swelling — most often a painless but quickly growing lump in the neck, armpit, or groin caused by an enlarged lymph node. Because DLBCL can start almost anywhere in the body, the first symptom depends on where the lymphoma develops. A mass in the chest may cause cough, shortness of breath, or pressure behind the breastbone. Lymphoma in the abdomen can cause pain, bloating, or a feeling of fullness. Lymphoma in the brain, bone, skin, or other extranodal sites (organs and tissues outside the lymph nodes) produces symptoms specific to that location.

Many people also experience general symptoms known as B symptoms — unexplained fever, drenching night sweats, and unintentional weight loss of more than 10% of body weight over six months. Fatigue and loss of appetite are common. Because DLBCL grows quickly, symptoms often develop and worsen over weeks rather than months, which is why prompt evaluation and treatment are important once the diagnosis is made.

What causes diffuse large B cell lymphoma?

In most cases, no single identifiable cause is found. DLBCL arises from acquired genetic changes — mutations and chromosomal alterations that occur in a B cell during a person’s lifetime rather than being inherited. These changes disrupt the normal controls on B cell growth and survival, allowing a single abnormal B cell to multiply into a population of malignant large cells.

Several factors increase the risk of developing DLBCL. A weakened immune system — whether from HIV infection, long-term immunosuppressive medication after an organ transplant, or an inherited immune deficiency — substantially increases risk, in part because the immune system normally suppresses abnormal B cell growth and in part because Epstein-Barr virus (EBV) infection, which is more common in immunosuppressed individuals, can drive lymphoma development. Chronic autoimmune conditions and a prior history of a lower-grade lymphoma that transforms into DLBCL (discussed further below) are also recognized risk factors. Older age is associated with higher incidence, though DLBCL can affect people of any age. Men are slightly more commonly affected than women.

How is the diagnosis made?

The diagnosis of DLBCL can only be made by examining tissue from the affected site under the microscope. A biopsy is performed to obtain a tissue sample — either an excisional biopsy removing an entire lymph node, or a core needle biopsy of a mass when surgical excision is not feasible. Fine needle aspiration alone is not sufficient. The pathologist examines the tissue under the microscope and performs a panel of special tests to confirm the diagnosis, determine the cell of origin subtype, and identify additional features that influence prognosis and treatment.

These tests include immunohistochemistry (IHC) to detect specific proteins in the lymphoma cells, flow cytometry to characterize cell surface proteins, and FISH to look for specific chromosomal rearrangements involving MYC, BCL2, and BCL6. Next-generation sequencing may also be performed at some centers to further characterize the molecular subtype. Once the diagnosis is confirmed, PET/CT imaging, blood tests, and sometimes bone marrow biopsy are used to determine the extent of disease.

What does diffuse large B cell lymphoma look like under the microscope?

Under the microscope, DLBCL is made up of large abnormal B cells — cells that are significantly bigger than normal lymphocytes and have prominent nuclei (the compartment inside each cell that holds the DNA) with large, conspicuous nucleoli (dense structures within the nucleus). The cells divide rapidly, and dividing cells (mitotic figures) are typically easy to find. The lymphoma cells grow in a diffuse pattern — spreading in flat sheets through the lymph node or tissue rather than forming compact follicular clusters. This infiltrative growth replaces the normal architecture of the affected tissue and can involve surrounding structures if the mass becomes large enough.

The appearance of the cells can vary. Most cases show either a centroblastic morphology — cells with round or oval nuclei and several small nucleoli — or an immunoblastic morphology, in which cells have a single large central nucleolus and more abundant cytoplasm. Rarer variants include anaplastic (very large, irregularly shaped cells) and plasmablastic morphologies. These morphologic variants are noted in the pathology report and can have implications for the specific diagnosis and treatment.

Cell of origin: GCB versus ABC subtype

One of the most important pieces of information in a DLBCL pathology report is the cell of origin classification, which describes which stage of B cell development the lymphoma cells most closely resemble. This classification divides DLBCL into two main molecular subtypes — germinal center B cell-like (GCB) and activated B cell-like (ABC) — and has implications for prognosis and is increasingly important for treatment selection.

B cells normally pass through a structure inside lymph nodes called the germinal center, where they undergo intense genetic remodeling to fine-tune their ability to recognize specific infections. GCB-type DLBCL resembles B cells at this germinal center stage, while ABC-type DLBCL resembles B cells that have left the germinal center and are in an activated, mature state. A third category called unclassified or non-GCB encompasses cases that do not fit neatly into either group by standard immunohistochemistry-based classification.

The cell of origin is determined by immunohistochemistry using a standardized algorithm called the Hans algorithm, which combines the results of three protein markers — CD10, BCL6, and MUM1 — to assign the lymphoma to the GCB or non-GCB category. Gene expression profiling by next-generation sequencing provides a more precise molecular classification but is not yet universally available in routine clinical practice.

GCB-type DLBCL is generally associated with a more favorable prognosis with standard R-CHOP chemotherapy, with approximately 60–70% of patients achieving long-term remission. ABC-type DLBCL tends to respond less well to R-CHOP and has a somewhat less favorable prognosis, with long-term remission rates of approximately 40–50% with standard treatment. This difference has driven ongoing clinical trials testing novel agents — such as ibrutinib (a BTK inhibitor) and lenalidomide — specifically in ABC-type disease, where NF-κB pathway activation is a key driver of lymphoma cell survival. The clinical significance of cell of origin classification and its impact on treatment selection continues to evolve as new therapies are developed.

Immunohistochemistry results

Immunohistochemistry (IHC) identifies specific proteins in the lymphoma cells and is essential for confirming the diagnosis, determining the cell of origin subtype, assessing MYC and BCL2 expression, and excluding other lymphomas that can appear similar. The typical protein profile of DLBCL is described below.

CD20 — Positive. CD20 is expressed on the surface of most B cells and the large majority of DLBCL cases. It is also the target of rituximab, the monoclonal antibody that is a cornerstone of DLBCL treatment. Rare cases are CD20-negative, which has implications for treatment selection.
PAX5 — Positive. A transcription factor (protein that switches genes on or off) that confirms the B cell origin of the lymphoma cells.
BCL6 — Positive in approximately 70–80% of cases. BCL6 is a protein that normally drives germinal center formation. Its expression in DLBCL reflects the lymphoma’s germinal center origin in many cases.
CD10 — Positive or negative, depending on cell of origin subtype. Positive in GCB-type; typically negative in ABC-type. Used as part of the Hans algorithm.
MUM1 (IRF4) — Positive or negative, depending on cell of origin subtype. Negative in GCB-type; typically positive in ABC-type. Used as part of the Hans algorithm.
BCL2 — Positive or negative. BCL2 is a protein that prevents cell death, helping lymphoma cells survive. BCL2 expression by immunohistochemistry is present in approximately 50–60% of DLBCL cases. Its significance depends on the cell of origin subtype and whether BCL2 protein co-expression with MYC protein defines a double-expressor lymphoma (see below).
CD5 — Negative in most cases. A small subset of DLBCL (approximately 5–10%) expresses CD5, which is associated with a more aggressive clinical course and is thought to arise from a specific precursor B cell population.
CD23 — Negative.
Cyclin D1 — Negative. Helps exclude mantle cell lymphoma, which can occasionally present with large cells.
CD3 — Negative in the lymphoma cells, confirming they are not T cells.
Ki-67 — High, typically 60–90% or higher. Ki-67 measures the proportion of cells that are actively dividing; the high value reflects the aggressive, rapidly proliferating nature of DLBCL.

MYC, BCL2, and the double-expressor concept

Two proteins — MYC and BCL2 — are particularly important in DLBCL because their co-expression by immunohistochemistry identifies a subgroup of patients with a less favorable prognosis. Your pathology report may describe these results and use the term “double-expressor lymphoma.”

MYC is a protein that drives rapid cell proliferation — it pushes cells to divide quickly. BCL2 is a protein that prevents cell death — it keeps cells alive when they should be dying. Normally, the simultaneous activity of both drives in a single cell creates a powerful cancer-sustaining combination: cells multiply fast and cannot be eliminated. When both MYC protein (typically defined as positive in ≥40% of cells) and BCL2 protein (typically defined as positive in ≥50% of cells) are detected by immunohistochemistry in the same DLBCL, the case is classified as a double-expressor lymphoma. This occurs in approximately 20–30% of all DLBCL cases and is associated with a worse prognosis compared to DLBCL without co-expression.

It is important to understand that protein co-expression detected by immunohistochemistry is different from the presence of gene rearrangements detected by FISH. When both the MYC gene and the BCL2 gene (and sometimes BCL6) are rearranged — meaning pieces of DNA have moved to new locations on chromosomes — the lymphoma is classified as a high-grade B cell lymphoma with MYC and BCL2 rearrangements (sometimes called a “double-hit” lymphoma), which is a distinct and more aggressive entity treated differently from standard DLBCL. Double-expressor DLBCL and double-hit lymphoma overlap but are not the same thing — many double-expressors do not have gene rearrangements, and the treatment implications differ.

FISH testing for MYC, BCL2, and BCL6 rearrangements

FISH (fluorescence in situ hybridization) testing is strongly recommended in all cases of DLBCL to determine whether specific gene rearrangements are present. FISH uses fluorescent probes to detect whether genes have moved from their normal positions on chromosomes — a finding called a gene rearrangement or translocation. In DLBCL, FISH is used to look for rearrangements of three genes: MYC, BCL2, and BCL6.

Testing typically follows a sequential approach. MYC is tested first because it is the most critical driver of aggressive behavior. If a MYC rearrangement is detected, BCL2 is then tested, and in many cases BCL6 is tested as well. If MYC is not rearranged, further FISH testing may still be performed depending on clinical context and local practice.

The outcome of FISH testing determines how the lymphoma is classified and reported:

No rearrangements detected — The lymphoma is classified as DLBCL, not otherwise specified (DLBCL-NOS) and treated with standard R-CHOP-based therapy.
Isolated MYC rearrangement (without BCL2 rearrangement) — The lymphoma remains classified as DLBCL-NOS and is reported as “DLBCL with MYC rearrangement.” This finding is associated with more aggressive behavior than DLBCL without any rearrangement, but the diagnosis and treatment approach are not changed in the same way as for double-hit disease.
MYC and BCL6 rearrangements (without BCL2 rearrangement) — The lymphoma also remains classified as DLBCL-NOS and is reported as “DLBCL with MYC and BCL6 rearrangements.” This is distinct from double-hit lymphoma and is managed as DLBCL, though the prognosis may be somewhat less favorable.
MYC and BCL2 rearrangements (with or without BCL6 rearrangement) — The diagnosis changes from DLBCL to high-grade B cell lymphoma with MYC and BCL2 rearrangements — the “double-hit” lymphoma. This is a distinct and more aggressive entity that typically requires more intensive treatment than standard R-CHOP.

There are important technical limitations to be aware of. FISH probes used to detect MYC rearrangements do not cover every possible breakpoint in the MYC gene. Some rearrangements — including small insertions of DNA into MYC or of MYC into other chromosomal locations, and rearrangements at unusual breakpoints — may not be detected by standard break-apart FISH probes. These cryptic rearrangements may require different probe designs (called fusion probe assays) to identify. Similarly, rare BCL2 rearrangements can occasionally be missed by standard FISH. This means that a negative FISH result, while reassuring, does not completely exclude a rearrangement in every case. If the clinical picture is highly suspicious, your care team or pathologist may recommend additional testing.

Large B cell lymphoma with IRF4 rearrangement

One additional molecular finding worth understanding is IRF4 rearrangement. In younger patients whose DLBCL is localized to lymph nodes in the head and neck region, and whose lymphoma cells show strong, uniform expression of a protein called IRF4 (also known as MUM1) by immunohistochemistry, the pathologist will typically perform FISH testing for an IRF4 gene rearrangement. If an IRF4 rearrangement is detected, the diagnosis changes entirely — from DLBCL to a separate entity called large B cell lymphoma with IRF4 rearrangement, which is a distinct disease with different biology and a generally more favorable prognosis. Identifying this entity matters because it may be overtreated if managed as standard DLBCL. Your pathology report will note whether IRF4 testing was performed and what the result was.

MYD88 mutation and extranodal DLBCL

In some cases — particularly when the biopsy is small or the lymphoma arises at an extranodal site such as the brain, testis, or other unusual location — additional molecular testing for specific gene mutations may help confirm the diagnosis. MYD88 mutation (most commonly the L265P variant) is found in the large majority of primary central nervous system DLBCL and primary testicular DLBCL, and its detection in a biopsy from an unusual site can support the diagnosis of lymphoma in cases where the tissue is limited. MYD88 testing is not routinely performed on all DLBCL biopsies but may be ordered when clinically relevant.

Transformation from a lower-grade lymphoma

Not all DLBCL arises de novo (appearing for the first time without a prior lower-grade lymphoma). A proportion of DLBCL cases develop through transformation — a process in which a slow-growing (indolent) lymphoma acquires additional genetic changes and converts into an aggressive disease. Lower-grade lymphomas that can transform into DLBCL include follicular lymphoma, small lymphocytic lymphoma, chronic lymphocytic leukemia, nodal and extranodal marginal zone lymphoma, and lymphoplasmacytic lymphoma.

Transformed DLBCL is important to recognize because it generally behaves more aggressively and can be more difficult to treat than de novo DLBCL. The pathology report will indicate whether the DLBCL appears to have arisen through transformation, based on the finding of a residual lower-grade lymphoma component alongside the large-cell population. If you have a prior history of a low-grade lymphoma, your care team will consider whether your DLBCL represents transformation and how that affects treatment planning.

Staging

DLBCL is staged using the Lugano classification, which describes how widely the lymphoma has spread in the body. Staging is determined by PET/CT imaging and, in some cases, bone marrow biopsy and lumbar puncture (to check for involvement of the fluid around the brain and spinal cord). PET/CT is the preferred imaging modality because it detects metabolically active disease throughout the body and serves as the baseline against which treatment response is measured.

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 are involved, or a single 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, lung, or central nervous system.

The letters A and B are added to indicate the absence (A) or presence (B) of B symptoms. Bulky disease — typically defined as a single mass measuring 10 cm or more — is noted because it influences treatment decisions. Unlike many indolent lymphomas where advanced stage does not necessarily mean urgent treatment, advanced-stage DLBCL requires prompt treatment because the disease grows quickly.

Risk stratification: the International Prognostic Index

The International Prognostic Index (IPI) is a widely used scoring system that estimates the likely outcome of DLBCL and helps guide treatment intensity. It assigns one point for each of five adverse factors present at diagnosis: age over 60, advanced stage (III or IV), more than one extranodal site involved, an elevated LDH blood level (a marker of rapid cell turnover), and reduced performance status (a measure of the person’s ability to carry out daily activities).

Patients are grouped into low risk (0–1 points), low-intermediate risk (2 points), high-intermediate risk (3 points), and high risk (4–5 points). Higher IPI scores are associated with lower response rates and lower overall survival with standard treatment. An updated version called the Revised IPI (R-IPI) simplifies the groups slightly. Your care team will calculate your IPI score and use it alongside other findings to guide treatment recommendations.

What is the prognosis?

DLBCL is an aggressive cancer, but it is potentially curable — this distinguishes it from many indolent lymphomas, which are rarely cured but often controlled for many years. With modern first-line chemoimmunotherapy, approximately 60–70% of patients achieve long-term remission, and many of these are considered cured. Patients who do not respond to initial treatment or who relapse face a more challenging situation, though salvage therapies — including stem cell transplantation and newer immunotherapies — offer additional opportunities for remission.

Specific factors associated with prognosis include:

IPI score — Low-risk patients (0–1 factors) achieve long-term remission in approximately 70–80% of cases with standard R-CHOP. High-risk patients (4–5 factors) achieve long-term remission in approximately 40–50%.
Cell of origin — GCB-type generally has a better prognosis than ABC-type with standard R-CHOP treatment, though this gap is narrowing as treatment approaches are refined.
Double-expressor status — Co-expression of MYC and BCL2 proteins is associated with approximately 20–30% lower long-term remission rates compared to DLBCL without co-expression, though the impact varies by clinical context.
Double-hit lymphoma — MYC plus BCL2 gene rearrangements predict a substantially worse prognosis with standard R-CHOP; these patients typically receive more intensive treatment.
Stage and bulky disease — Limited-stage disease without bulky features carries an excellent prognosis. Bulky disease or advanced stage is associated with higher relapse risk.
Response to treatment — Achieving a complete metabolic response on PET/CT after treatment is the single strongest predictor of long-term cure. Patients with residual PET-positive disease after treatment have a substantially higher relapse risk.
CNS involvement — Spread of DLBCL to the central nervous system (brain or spinal cord) — which occurs at diagnosis in approximately 5% of cases and as relapse in others — is associated with a poor prognosis and requires specific treatment.

What happens after the diagnosis?

Because DLBCL grows rapidly, treatment typically begins within days to a few weeks of diagnosis. Most patients are referred to a hematologist or lymphoma oncologist for management. The treatment goal in most patients is cure.

The standard first-line treatment for most patients is R-CHOP — a combination of rituximab (anti-CD20 antibody) with four chemotherapy drugs: cyclophosphamide, doxorubicin, vincristine, and prednisone. R-CHOP is given in cycles every three weeks, typically for six cycles for advanced-stage disease or three to four cycles for limited-stage disease often followed by involved-site radiation therapy. Response is assessed by PET/CT after treatment.

Newer first-line regimens have been developed for specific subgroups. Pola-R-CHP (polatuzumab vedotin — an antibody-drug conjugate targeting CD79b — replacing vincristine in the R-CHOP backbone) has shown superior progression-free survival compared to R-CHOP in a large international trial and is increasingly used in eligible patients. For patients with double-hit lymphoma, more intensive regimens such as DA-EPOCH-R are often recommended instead of standard R-CHOP.

Patients at high risk for central nervous system (CNS) relapse — based on specific clinical risk factors and certain sites of disease involvement — typically receive CNS prophylaxis with intrathecal chemotherapy (medication delivered directly into the fluid around the spine) or high-dose methotrexate.

For patients whose disease does not respond to or relapses after first-line treatment, options include salvage chemoimmunotherapy followed by autologous stem cell transplantation (collection and re-infusion of the patient’s own stem cells after intensive chemotherapy) in transplant-eligible patients. CAR T cell therapy — a form of immunotherapy in which a patient’s own T cells are genetically engineered to recognize and kill lymphoma cells — is approved for relapsed or refractory DLBCL after two or more prior lines of therapy, and is increasingly used in second-line treatment for patients who relapse after initial chemotherapy. Approved CAR T cell products for DLBCL include axicabtagene ciloleucel and lisocabtagene maraleucel. Bispecific antibodies such as epcoritamab and glofitamab, which simultaneously engage T cells and lymphoma cells, are additional options for relapsed disease.

Questions to ask your doctor

What is the cell of origin subtype of my DLBCL — GCB or ABC — and how does that affect my treatment?
Does my report show MYC or BCL2 protein co-expression (double-expressor), and what does that mean for my prognosis?
Was FISH testing performed for MYC, BCL2, and BCL6 rearrangements, and were any rearrangements found?
What is my IPI score, and what does it suggest about my prognosis with standard treatment?
What stage is my lymphoma, and is there any involvement of the bone marrow or central nervous system?
What treatment regimen are you recommending — R-CHOP, Pola-R-CHP, or something else — and why?
How many cycles of treatment will I need, and will I also need radiation therapy?
Will I be assessed for risk of CNS involvement, and will I need CNS prophylaxis?
How will we know if treatment is working — when will I have a PET scan?
Did my DLBCL arise through transformation from a lower-grade lymphoma, and does that change my treatment plan?
What happens if my lymphoma does not respond to or comes back after treatment, and is CAR T cell therapy an option for me?
Are there clinical trials I should consider?