Nodal Marginal Zone Lymphoma: Understanding Your Pathology Report

by Jason Wasserman MD PhD FRCPC
April 14, 2026

Nodal marginal zone lymphoma is a slow-growing (indolent) blood cancer that starts in B cells — the white blood cells that help the body fight infection — and develops primarily within the lymph nodes. It belongs to a family of cancers called marginal zone lymphomas, all of which originate from a type of mature B cell normally found in a region of the lymph node called the marginal zone, which sits just outside the germinal center where B cells learn to recognize and respond to infections. Nodal marginal zone lymphoma is distinguished from the other marginal zone lymphomas by its origin strictly within the lymph nodes, without involvement of extranodal sites (organs and tissues outside the lymph nodes) or the spleen at the time of diagnosis. 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 nodal marginal zone lymphoma?

Many people with nodal marginal zone lymphoma have no symptoms at the time of diagnosis. The most common finding is painless, non-bulky swelling of one or more lymph nodes. This is most often noticed in the neck, armpits, or groin, though the lymph nodes in the chest or abdomen may also be affected and discovered on imaging performed for another reason. The swelling tends to be modest and slow-growing, and the affected nodes are typically not tender to the touch.

A small number of people present with more widespread disease and may experience symptoms related to enlarged lymph nodes pressing on nearby structures, reduced blood counts from bone marrow involvement, or general constitutional symptoms such as fatigue. Systemic symptoms — fever, drenching night sweats, and unintentional weight loss of more than 10% of body weight (sometimes called B symptoms) — are uncommon at diagnosis in nodal marginal zone lymphoma. When these symptoms appear, especially if associated with rapidly enlarging lymph nodes, they should be evaluated promptly as they can indicate progression or transformation to a more aggressive lymphoma.

Occasionally, a slightly elevated lymphocyte count (lymphocytosis) is found on a routine blood test, prompting further investigation that leads to the diagnosis.

What causes nodal marginal zone lymphoma?

The exact cause is not known. Like all lymphomas, nodal marginal zone lymphoma arises from acquired genetic changes — changes that happen during a person’s lifetime in a single B cell, rather than being inherited. Over time, these changes allow that cell to multiply uncontrollably, producing a population of abnormal lymphoma cells that all descend from the same original cell. This is called a clonal disorder.

Several risk factors have been associated with nodal marginal zone lymphoma. A personal or family history of lymphoma increases risk. Autoimmune conditions — diseases in which the immune system mistakenly attacks the body’s own tissues — are associated with a higher likelihood of developing marginal zone lymphomas, likely because chronic immune stimulation creates an environment in which abnormal B cells can accumulate. Hepatitis C virus (HCV) infection is a recognized risk factor; HCV directly stimulates certain B cells and promotes their survival, and in HCV-positive patients, successful antiviral treatment can sometimes lead to regression of the lymphoma. Certain inherited variations in immune system genes also influence susceptibility.

The lymphoma cells carry rearrangements of their immunoglobulin (antibody) genes — meaning they have the molecular signature of B cells that have previously passed through the germinal center and responded to an antigen (a foreign substance that triggers an immune response). This suggests that chronic immune system stimulation may play a role in driving the initial abnormal B cell expansion. However, the specific trigger varies from person to person and is often not identified.

How is the diagnosis made?

The diagnosis of nodal marginal zone lymphoma is made by examining lymph node tissue under the microscope, combined with a panel of additional laboratory tests. A biopsy — ideally an excisional biopsy removing an entire lymph node — provides the tissue needed for examination. An excisional biopsy is preferred over a core needle biopsy because the full architecture of the lymph node needs to be assessed to identify the growth pattern and to distinguish nodal marginal zone lymphoma from other lymphomas that can look similar.

The pathologist examines the tissue under the microscope to characterize the cells and their arrangement. Immunohistochemistry (IHC) — a test that detects specific proteins in the cells — and flow cytometry are routinely performed to determine the cell type and to exclude other lymphoma subtypes. Genetic testing using FISH, PCR, or next-generation sequencing may be needed to exclude other specific lymphoma types and to support the diagnosis. Blood tests, including hepatitis C serology, are an important part of the workup, given the therapeutic implications of HCV infection in this disease. Once the diagnosis is established, imaging — typically a CT scan or PET/CT — is used to determine the extent of disease, and a bone marrow biopsy is often performed to assess for marrow involvement.

An important step in the workup is confirming that there is no extranodal primary site — that is, ruling out that what appears to be nodal marginal zone lymphoma is actually an extranodal marginal zone lymphoma (MALT lymphoma) that has spread to nearby lymph nodes. This distinction matters because the management and prognosis of those two conditions differ. Careful imaging of the sites that drain to the involved lymph nodes, and sometimes endoscopy or other tests, may be performed to exclude an occult extranodal primary.

What does nodal marginal zone lymphoma look like under the microscope?

Under the microscope, nodal marginal zone lymphoma is made up of small, mature-appearing B cells that disrupt and partially or completely replace the normal architecture of the lymph node. The cells are typically slightly larger than normal resting lymphocytes, with minimally irregular nuclei and a modest amount of pale cytoplasm — the material surrounding the nucleus inside the cell. Cells with more abundant pale cytoplasm are often described as monocytoid B cells because their appearance resembles that of a monocyte.

Some cases show plasmacytic differentiation — meaning a proportion of the lymphoma cells have begun to mature toward plasma cells, the antibody-secreting cells of the immune system. These cells may appear more oval with more cytoplasm and an off-center nucleus, and they produce a single type of immunoglobulin (antibody), which special stains can detect.

The pattern of growth — how the cells are arranged in the lymph node — can vary considerably between cases. The most important patterns include a nodular or follicular arrangement, a parafollicular or interfollicular arrangement (where lymphoma cells surround or infiltrate between normal follicles), and a diffuse arrangement. A characteristic and diagnostically helpful feature is follicular colonization: the lymphoma cells invade and replace the normal germinal centers within the lymph node follicles, while losing the germinal center proteins (CD10 and BCL6) that would normally be expressed there. This creates follicle-like structures that, on first inspection, can appear similar to classic follicular lymphoma but are actually occupied by marginal zone lymphoma cells.

Scattered larger cells with prominent nucleoli — resembling cells called immunoblasts — may be present among the small lymphoma cells. A few reactive immune cells, including normal small lymphocytes, granulocytes (a type of white blood cell), and plasma cells, are typically also present in the background.

Immunohistochemistry results

Immunohistochemistry is essential for confirming the diagnosis of nodal marginal zone lymphoma and for excluding the many other lymphomas that can look similar under the microscope. The typical protein profile is described below.

CD20 — Positive. Confirms the cells are B cells. CD20 is also the target of rituximab, the antibody used in treatment.
BCL2 — Positive. A survival protein is expressed in most cases. Unlike in classic follicular lymphoma, where BCL2 positivity results from a specific chromosomal rearrangement (t(14;18)), BCL2 in nodal marginal zone lymphoma reflects the normal expression pattern of marginal zone B cells.
CD10 — Negative in the lymphoma cells. This is an important distinguishing feature from follicular lymphoma, in which CD10 is typically positive. When follicular colonization occurs, the residual germinal center cells within the colonized follicles may still express CD10, but the lymphoma cells surrounding and replacing them do not.
BCL6 — Negative in the lymphoma cells. As with CD10, BCL6 negativity in the neoplastic population helps exclude follicular lymphoma. Residual germinal center cells in colonized follicles may retain BCL6 expression.
CD5 — Negative in most cases. CD5 positivity in a small B-cell lymphoma would suggest small lymphocytic lymphoma or mantle cell lymphoma instead.
Cyclin D1 — Negative. Excludes mantle cell lymphoma, which is strongly positive for cyclin D1.
CD23 — Negative or variably expressed in a minority of cases.
MNDA — Positive in approximately 75% of cases. MNDA (myeloid cell nuclear differentiation antigen) is a protein expressed by normal marginal zone B cells and by most nodal marginal zone lymphomas. Its presence is a helpful supportive feature, particularly when distinguishing nodal marginal zone lymphoma from follicular lymphoma with a predominantly diffuse growth pattern, which is typically MNDA-negative.
IRTA1 — Positive in approximately 75% of cases. IRTA1 is another marker of marginal zone B cell differentiation, supporting the diagnosis. Like MNDA, it is absent in most follicular lymphomas.
Ki-67 — Low in most cases, reflecting the indolent nature of the disease. A focal area of high Ki-67 may suggest transformation to a more aggressive lymphoma within that part of the tissue.

When plasmacytic differentiation is present, the plasma cell component can be highlighted with immunoglobulin light-chain stains (kappa and lambda). The presence of light chain restriction — all the plasma cells producing only one type of light chain rather than the normal mixture — confirms that the plasma cells are part of the clonal lymphoma rather than reactive plasma cells.

Why can this diagnosis be challenging?

Nodal marginal zone lymphoma is one of the most diagnostically challenging lymphomas because it lacks a single defining genetic alteration — unlike mantle cell lymphoma (defined by t(11;14) and cyclin D1) or most follicular lymphomas (defined by t(14;18) and BCL2 rearrangement). Instead, the diagnosis is reached by a combination of morphologic features, immunohistochemistry, and exclusion of other specific lymphoma types. Understanding why additional tests were performed and what they were looking for can help make sense of a detailed report.

The conditions most commonly considered in the differential diagnosis are:

Classic follicular lymphoma can look similar when it has areas of marginal zone differentiation or plasmacytic cells. The key distinguishing features are CD10 and BCL6 positivity in follicular lymphoma (both negative in nodal marginal zone lymphoma cells), BCL2 rearrangement detected by FISH in most follicular lymphoma cases, and MNDA/IRTA1 positivity in nodal marginal zone lymphoma (both absent in follicular lymphoma). Follicular colonization by marginal zone lymphoma cells can particularly mimic follicular lymphoma, making careful IHC interpretation essential.

Follicular lymphoma with a predominantly diffuse growth pattern shares the diffuse architecture and centrocytic cell appearance seen in some cases of nodal marginal zone lymphoma. The distinguishing features include CD10 and BCL6 positivity (usually present in diffuse-pattern follicular lymphoma but absent in nodal marginal zone lymphoma cells), the absence of BCL2 rearrangement and presence of STAT6 mutation in diffuse-pattern follicular lymphoma, and MNDA/IRTA1 positivity in nodal marginal zone lymphoma.

Small lymphocytic lymphoma / chronic lymphocytic leukemia (CLL/SLL) is another small B-cell lymphoma that can present with lymph node involvement and an indolent course. CLL/SLL cells are strongly positive for CD5, CD23, and LEF1, and negative for CD10 — a profile that clearly distinguishes them from nodal marginal zone lymphoma. See the Small Lymphocytic Lymphoma and Chronic Lymphocytic Leukemia articles for more information.

Mantle cell lymphoma can occasionally present with small lymphoid cells in the lymph nodes. Cyclin D1 positivity and SOX11 expression, along with t(11;14) detected by FISH, definitively identify mantle cell lymphoma. See the Mantle Cell Lymphoma article for more information.

Lymphoplasmacytic lymphoma can also involve lymph nodes with small lymphoid cells and plasmacytic differentiation. MYD88 L265P mutation — found in more than 90% of lymphoplasmacytic lymphoma cases but rare in nodal marginal zone lymphoma — is the most reliable distinguishing molecular test. See the Lymphoplasmacytic Lymphoma article for more information.

Extranodal marginal zone lymphoma (MALT lymphoma) spreading to lymph nodes must always be excluded, as it can be histologically identical to nodal marginal zone lymphoma. Clinical and imaging evaluation for a primary extranodal site is an essential part of the workup. See the Extranodal Marginal Zone Lymphoma article for more information.

Molecular and genetic testing

Unlike some other lymphomas, nodal marginal zone lymphoma does not have a single defining chromosomal translocation or mutation. Molecular testing is therefore used primarily to exclude specific alterations that would warrant a different diagnosis, to detect clonality, and, in selected cases, to characterize the genetic features of the lymphoma.

Clonality testing by PCR for immunoglobulin gene rearrangements (IGH and IGK) confirms that the lymphoid cells are clonal — all derived from a single abnormal B cell — which supports a diagnosis of lymphoma rather than a reactive (non-cancerous) immune response. This is particularly useful when the tissue sample is small or the morphology is ambiguous.

FISH testing for BCL2 rearrangement (t(14;18)) and BCL6 rearrangement is performed to exclude follicular lymphoma. Testing for CCND1 rearrangement (t(11;14)) is performed to exclude mantle cell lymphoma. Testing for MALT1, BIRC3, BCL10, and FOXP1 translocations — which are characteristic of extranodal marginal zone lymphoma — is absent in nodal marginal zone lymphoma and helps confirm its nodal origin.

Next-generation sequencing may identify mutations in genes such as KMT2D, PTPRD, KLF2, CARD11, CREBBP, and TNFAIP3, which are recurrently mutated in nodal marginal zone lymphoma. PTPRD mutation, in particular, is skewed toward nodal marginal zone lymphoma among marginal zone lymphomas, though it is found in only about 20% of cases. MYD88 mutation is rare in nodal marginal zone lymphoma, and its detection strongly favors a diagnosis of lymphoplasmacytic lymphoma. Comprehensive molecular profiling is not routinely required for diagnosis but may be used in ambiguous cases or to better characterize the disease.

For more information about biomarkers and molecular testing in blood cancers, visit the Biomarkers and Genetic Testing section.

Hepatitis C and nodal marginal zone lymphoma

Hepatitis C virus (HCV) infection is an established risk factor for marginal zone lymphomas, including nodal marginal zone lymphoma. HCV directly stimulates specific B cell receptors, promoting the survival and proliferation of certain B cell clones over time. In HCV-positive patients with nodal marginal zone lymphoma, treating the hepatitis C infection with antiviral medications can lead to regression of the lymphoma in a significant proportion of cases, without the need for chemotherapy or immunotherapy. This is one of the few settings in oncology where treating an underlying infection can directly control the cancer.

For this reason, HCV testing is a standard part of the workup for all patients diagnosed with nodal marginal zone lymphoma. If HCV is detected, your care team will coordinate with an infectious disease or hepatology specialist to discuss antiviral treatment before or alongside lymphoma-directed therapy, depending on the urgency of the lymphoma.

Staging

Nodal marginal zone lymphoma is staged using the Lugano classification, which describes how widely the lymphoma has spread in the body. Staging is based on CT or PET/CT imaging, blood count evaluation, and bone marrow biopsy. Bone marrow involvement occurs in a significant proportion of patients and can upstage the disease.

Stage I — A single lymph node region is involved.
Stage II — Two or more lymph node regions on the same side of the diaphragm (the muscle separating the chest from the abdomen) are involved.
Stage III — Lymph node regions on both sides of the diaphragm are involved.
Stage IV — The lymphoma has spread to one or more organs outside the lymphatic system, such as the bone marrow or liver.

The letters A and B are added to indicate the absence (A) or presence (B) of B symptoms — fever, drenching night sweats, and unintentional weight loss of more than 10% of body weight over six months. Most patients with nodal marginal zone lymphoma present at an advanced stage (III or IV), though despite this, the disease tends to follow an indolent course.

Transformation to a more aggressive lymphoma

Like other indolent lymphomas, nodal marginal zone lymphoma can occasionally transform into a more aggressive lymphoma, most commonly diffuse large B-cell lymphoma. This occurs in approximately 5% of patients. Transformation typically heralds a significant change in the disease’s behavior and requires a more intensive treatment approach.

Signs that may suggest transformation include a sudden, rapid increase in the size of one or more lymph nodes, new B symptoms (fever, night sweats, weight loss), a sharp rise in LDH (a blood marker of cell turnover), or involvement of new sites. A new biopsy of the most rapidly enlarging or metabolically active site — identified by PET/CT — is needed to confirm transformation. All lymphoma tissue is examined at diagnosis for any evidence of transformation, and if present, it will be described in your pathology report.

What is the prognosis?

Nodal marginal zone lymphoma is an indolent disease with a median overall survival exceeding 10 years. However, it does affect long-term life expectancy, and most patients experience a pattern of disease progression and response to treatment over time rather than a single curative episode.

The strongest adverse prognostic factor is early progression — disease that progresses or relapses within 24 months of starting first-line treatment. This occurs in approximately 20% of patients and is associated with a substantially shorter median survival of 3–5 years. Younger patients generally have a better prognosis than older patients. Transformation to an aggressive lymphoma, which occurs in approximately 5% of patients, is associated with a poor prognosis. In HCV-positive patients, achieving virological clearance through antiviral therapy is associated with improved overall survival.

What happens after the diagnosis?

Management of nodal marginal zone lymphoma depends on the stage, symptom status, disease progression, HCV status, and individual patient factors. Because the disease is indolent and treatment is not curative in most advanced-stage cases, the general approach mirrors that used for other indolent lymphomas.

For HCV-positive patients, antiviral therapy is prioritized and may result in lymphoma regression without additional treatment. For patients with limited-stage (stage I–II) disease and no HCV association, involved-site radiation therapy can achieve durable disease control and is used with curative intent in some patients. For advanced-stage patients without symptoms, active surveillance (watch-and-wait) is an acceptable initial strategy — treatment is deferred until the lymphoma causes symptoms, grows rapidly, affects blood counts, or meets criteria that warrant intervention.

When treatment is needed, the most common approach is immunotherapy with rituximab (anti-CD20 antibody) alone or combined with chemotherapy (chemoimmunotherapy). Rituximab-based regimens, including R-CHOP, R-CVP, or bendamustine-rituximab, are used depending on the clinical situation. Maintenance rituximab after chemoimmunotherapy may be recommended in some patients to prolong remission. For relapsed disease, options include alternative chemoimmunotherapy combinations, PI3K inhibitors, or other regimens used in indolent B-cell lymphomas.

All patients require ongoing monitoring with periodic blood tests and imaging, and prompt re-evaluation if symptoms change or new lymph node enlargement develops.

Questions to ask your doctor

Is the diagnosis definitely nodal marginal zone lymphoma, or are there features that still need clarification?
Has testing been done to confirm there is no extranodal primary site — for example, a stomach or salivary gland lymphoma that has spread to my lymph nodes?
Was I tested for hepatitis C, and if positive, what does that mean for my treatment?
What stage is my lymphoma, and is my bone marrow involved?
Is watch-and-wait an option for me, and if so, what signs or symptoms should prompt me to contact you?
If treatment is recommended, what regimen are you proposing and why?
What does the MNDA or IRTA1 result in my report mean, and how did it help confirm the diagnosis?
What is the Ki-67 score in my biopsy, and does it suggest the lymphoma is growing at a typical pace?
What are the signs that my lymphoma might be transforming to a more aggressive type, and what would happen then?
How will you monitor me over time, and how often will I need imaging or blood tests?
What happens if the lymphoma progresses within the first two years of treatment?
Are there clinical trials I should consider?