Follicular Lymphoma With a Predominantly Diffuse Growth Pattern: Understanding Your PathologyReport

by Jason Wasserman MD PhD FRCPC
April 14, 2026

Follicular lymphoma with a predominantly diffuse growth pattern is a rare and recently recognized subtype of follicular lymphoma — a group of blood cancers that start in B cells, the white blood cells that help the body fight infection. Unlike the more familiar form of follicular lymphoma, in which the cancer cells grow in round clusters called follicles, this subtype grows mainly in flat, sheet-like areas that spread through the lymph node without forming those round structures. Despite its unusual appearance, it is a slow-growing (indolent) cancer that most commonly presents at an early, localized stage and has a favorable outcome. Because it looks different from classic follicular lymphoma under the microscope and has a distinct genetic profile, it requires additional testing to diagnose accurately and should not be confused with more aggressive lymphomas that also lack a follicular pattern. 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?

Most people with follicular lymphoma with a predominantly diffuse growth pattern notice a painless, slowly enlarging lump in the groin — the area where the thigh meets the lower abdomen. This swelling is caused by enlarged lymph nodes in the inguinal region, which is the most common site for this subtype. The mass may be large at the time of diagnosis, sometimes involving multiple lymph nodes matted together, but it typically grows slowly and remains localized.

Some people also notice swelling in nearby lymph nodes in the pelvis or abdomen, or experience mild discomfort or a feeling of pressure in the groin from the enlarged nodes. General symptoms such as fever, drenching night sweats, and unintentional weight loss — sometimes called B symptoms — are uncommon in this subtype and, when present, should prompt evaluation to ensure the disease has not progressed or transformed to a more aggressive lymphoma. Because the disease is usually localized, many people feel well at diagnosis and the mass is noticed incidentally during a routine examination or imaging study.

What causes follicular lymphoma with a predominantly diffuse growth pattern?

The exact cause is not known. Like all follicular lymphomas, this subtype starts from B cells that have passed through a structure inside lymph nodes called the germinal center — the area where B cells normally mature, learn to recognize specific infections, and undergo intensive genetic remodeling. An error during this process leads to the development of a clonal population of abnormal B cells: a group of cells that are all descended from a single original abnormal cell and all carry the same genetic changes.

The most important genetic change in this subtype is a mutation in a gene called STAT6. STAT6 is part of a signaling pathway — a chain of molecular messages inside the cell — that normally tells B cells how to respond to signals from the immune system. When STAT6 is mutated, this signaling pathway becomes overactive, contributing to abnormal B cell survival and growth. STAT6 mutations are found in more than half of cases of this subtype and are much less common in classic follicular lymphoma, making them a useful distinguishing feature.

Critically, the chromosomal rearrangement that drives most cases of classic follicular lymphoma — a swap of genetic material between chromosomes 14 and 18, known as t(14;18), that causes overproduction of the BCL2 protein — is absent in this subtype. This means the underlying mechanism of lymphoma development is distinct from that of classic follicular lymphoma, even though the cell of origin is similar. The reasons why this subtype preferentially arises in the inguinal region are not fully understood. No established environmental, infectious, or lifestyle risk factors have been identified for this specific subtype.

How is the diagnosis made?

The diagnosis is made by examining lymph node tissue under the microscope. Because the growth pattern in this subtype lacks the round follicular clusters that make many follicular lymphomas recognizable at low magnification, an adequate tissue sample is essential — a core needle biopsy alone is not sufficient, as the full tissue architecture must be assessed to make the diagnosis reliably. An excisional biopsy — removal of an entire lymph node — is strongly preferred and allows the pathologist to evaluate the overall pattern of growth, the cell types present, and the relationship between the lymphoma cells and any residual normal lymph node structures.

After examining the tissue under the microscope, the pathologist performs immunohistochemistry — a laboratory test that detects specific proteins in the cells — and often flow cytometry to characterize the lymphoma cells in detail. Genetic testing for the BCL2 rearrangement and STAT6 mutation is also typically performed, both to support the diagnosis and to confirm that this is not classic follicular lymphoma or another lymphoma type. Once the diagnosis is established, imaging — typically a PET/CT scan — is used to determine whether the disease is localized or has spread to other lymph node groups or organs.

What does this lymphoma look like under the microscope?

Under the microscope, follicular lymphoma with a predominantly diffuse growth pattern looks different from most follicular lymphomas, and this difference is central to the diagnosis. The lymphoma cells grow in a predominantly diffuse pattern — meaning they spread in flat, sheet-like areas through the lymph node rather than forming the round, tightly organized clusters called follicles that give follicular lymphoma its name. In some cases, very small residual follicles called microfollicles can still be identified, but these are scattered and inconspicuous rather than forming a dominant pattern.

The lymphoma cells are almost entirely centrocytes — the smaller cell type that normally lives in lymph node germinal centers and has characteristically irregular, folded, or cleaved (notched) nuclei. Unlike classic follicular lymphoma, which contains a mixture of centrocytes and larger cells called centroblasts, this subtype has very few or no centroblasts. This is an important observation because it means the cells appear relatively uniform and small rather than showing the larger, more activated-looking cells that would suggest higher-grade disease.

The absence of follicular dendritic cells — a type of supporting cell that is normally found inside follicles and helps B cells develop — is another key feature. Pathologists use special immunohistochemistry stains for CD21 or CD23 to highlight these supporting cells; their absence throughout the diffuse areas of the lymphoma confirms that the tissue lacks true follicular organization. Small residual follicles, if present, may show faint remnants of these supporting cells, but the dominant areas of lymphoma are devoid of them.

Areas of sclerosis — patches of scar-like fibrous tissue — may be seen within or around the lymphoma. These do not indicate a worse prognosis and are a recognized feature of this subtype.

Immunohistochemistry results

Immunohistochemistry (IHC) is a test that detects specific proteins in the lymphoma cells and is essential for confirming the diagnosis. The protein profile of follicular lymphoma with a predominantly diffuse growth pattern differs from that of classic follicular lymphoma in several important ways.

CD20 — Positive. Confirms the lymphoma cells are B cells. CD20 is also the target of rituximab, the antibody used in treatment.
CD10 — Usually positive, though expression may be variable or absent in some cases. CD10 is a marker of germinal center B cells that is also positive in classic follicular lymphoma.
BCL6 — Positive. A marker of germinal center activity, expressed by the lymphoma cells.
BCL2 — Negative or weakly positive. This is one of the most important differences from classic follicular lymphoma. In classic follicular lymphoma, BCL2 is strongly and uniformly positive because of the t(14;18) rearrangement. In this subtype, BCL2 expression is absent or only faint, reflecting the absence of that rearrangement. The residual small follicles, if present, may also show weak or absent BCL2 staining.
CD23 — Frequently positive. CD23 is usually negative in classic follicular lymphoma but is expressed in the majority of cases of this subtype, particularly those with STAT6 mutations. CD23 positivity in a diffuse-pattern follicular lymphoma is an important clue to this diagnosis.
CD21 and CD35 — Absent or markedly reduced in diffuse areas. These markers highlight follicular dendritic cells, which are absent from the diffuse areas of this lymphoma. Their absence confirms the lack of true follicular architecture.
CD3 — Negative. Confirms the lymphoma cells are not T cells.
CD5 — Negative. Helps exclude small lymphocytic lymphoma and mantle cell lymphoma.
Cyclin D1 — Negative. Helps exclude mantle cell lymphoma.

Molecular and genetic testing

Molecular testing plays a particularly important role in this subtype because the diagnosis depends heavily on the combination of morphologic, immunohistochemical, and genetic findings rather than any single feature alone.

BCL2 rearrangement — t(14;18)

Testing for the t(14;18) chromosomal rearrangement — which drives most cases of classic follicular lymphoma — is an essential part of the workup. This rearrangement is absent in follicular lymphoma with a predominantly diffuse growth pattern, and its absence is one of the features that defines this subtype. Testing is performed by FISH or PCR. A negative result for BCL2 rearrangement in a diffuse B cell lymphoma with centrocytic morphology, combined with other supporting features, helps distinguish this subtype from classic follicular lymphoma and from other B cell lymphomas.

STAT6 mutation

STAT6 is a gene that encodes a protein involved in immune cell signaling. Normally, STAT6 is only activated temporarily in response to specific immune signals such as the cytokines IL-4 and IL-13. In follicular lymphoma with a predominantly diffuse growth pattern, mutations in STAT6 cause this protein to be permanently switched on, continuously sending growth signals to the lymphoma cells. STAT6 mutations are found in more than 50% of cases and, together with CD23 expression, are strongly associated with this subtype — particularly those arising in the inguinal region. STAT6 mutations are uncommon in classic follicular lymphoma and other low-grade B cell lymphomas, making them a useful diagnostic marker. Testing for STAT6 mutation is performed by next-generation sequencing or targeted mutation testing.

TNFRSF14 deletion and mutation

Deletion of chromosome 1p36 — a region containing the TNFRSF14 gene — is frequently found in this subtype and contributes to an environment that supports lymphoma cell survival by altering how the lymphoma interacts with its surrounding immune cells. TNFRSF14 mutations are also common in classic follicular lymphoma, though 1p36 deletions appear to be particularly enriched in this subtype. These findings are typically identified on comprehensive molecular profiling rather than routine testing.

IGH and immunoglobulin clonality testing

Like all follicular lymphomas, this subtype shows monoclonal rearrangement of the immunoglobulin heavy chain (IGH) and light chain genes — meaning all the lymphoma cells carry the same unique rearrangement, confirming they are descended from a single original abnormal cell. This is a standard part of the workup that helps confirm the diagnosis is a clonal (malignant) process rather than a reactive (non-cancerous) immune response.

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

Why can this diagnosis be challenging?

Follicular lymphoma with a predominantly diffuse growth pattern presents a diagnostic challenge because its appearance overlaps with several other lymphomas that can look similar under the microscope. Understanding why the pathologist ordered specific additional tests — and what those tests were looking for — can help make sense of a complex report.

The most important condition to exclude is nodal marginal zone lymphoma, a different indolent B cell lymphoma in which the cancer cells can also grow in a diffuse pattern and sometimes involve the inguinal lymph nodes. The distinction matters because the two diseases have somewhat different clinical behaviors and genetic profiles. Features that favor follicular lymphoma with a predominantly diffuse growth pattern over nodal marginal zone lymphoma include CD10 positivity, BCL6 positivity, a predominantly centrocytic cell population, STAT6 mutation, and 1p36 deletion. Features that favor nodal marginal zone lymphoma include expression of proteins called MNDA and IRTA1, which are usually absent in follicular lymphoma.

Classic follicular lymphoma with extensive diffuse areas must also be excluded. In classic follicular lymphoma, BCL2 is strongly positive and the t(14;18) rearrangement is present — both features that are absent in this subtype. Additionally, classic follicular lymphoma contains a mixture of centrocytes and centroblasts, whereas this subtype is almost entirely centrocytic.

Diffuse large B cell lymphoma must be excluded, particularly when the cells are large or when the Ki-67 proliferation index is elevated. The predominantly small centrocytic cell population and low proliferation rate of this subtype help distinguish it from diffuse large B cell lymphoma.

Because this distinction requires the full tissue architecture, a core needle biopsy is often insufficient for a definitive diagnosis. If your initial report was made on a core biopsy and mentions uncertainty about the diagnosis, an excisional biopsy of an affected lymph node will likely be recommended before final management decisions are made.

Staging

Follicular lymphoma with a predominantly diffuse growth pattern is staged using the Lugano classification, which describes how widely the lymphoma has spread throughout the body. Staging is determined primarily by PET/CT imaging, and a bone marrow biopsy is sometimes performed to look for involvement beyond the lymph nodes. A defining clinical feature of this subtype is that it most commonly presents at a limited stage — stage I or II — meaning the disease is largely confined to the inguinal and, in some cases, adjacent pelvic lymph nodes. This limited-stage presentation is substantially more common than in classic follicular lymphoma, where the majority of patients present with advanced-stage (stage III–IV) disease.

Stage I — A single lymph node region is involved. For most patients with this subtype, this means inguinal lymph nodes on one side.
Stage II — Two or more lymph node regions on the same side of the diaphragm are involved. This may include inguinal and pelvic lymph nodes.
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. This is uncommon at diagnosis in this subtype.

What is the prognosis?

Follicular lymphoma with a predominantly diffuse growth pattern has a favorable prognosis, particularly because most patients present with limited-stage disease. Long-term outcomes for limited-stage disease treated with involved-site radiation therapy or rituximab are generally excellent, with many patients achieving durable remission and some achieving what may be long-term disease control equivalent to cure.

Even in the minority of patients who present with more widespread disease, the lymphoma tends to behave in an indolent manner. The risk of transformation to a more aggressive lymphoma such as diffuse large B cell lymphoma appears to be low, although long-term data specific to this subtype remain limited because it has only recently been formally recognized as a distinct entity in the WHO 2022 classification. Published studies to date report favorable progression-free and overall survival outcomes, though comprehensive long-term follow-up data from large patient cohorts are still being gathered.

Because this subtype has a distinct biology from classic follicular lymphoma — lacking the BCL2 rearrangement and having a frequent STAT6 mutation — it is not yet clear whether all prognostic tools developed for classic follicular lymphoma (such as the FLIPI score) apply equally to this subtype. Your care team will discuss your individual prognosis based on your specific findings, stage, and overall health.

What happens after the diagnosis?

Management depends on the stage at diagnosis. For most patients, who present with limited-stage (stage I–II) disease, involved-site radiation therapy — radiation directed at the affected lymph node region — is the standard treatment and can achieve durable disease control in a high proportion of patients. Rituximab (an anti-CD20 antibody) alone or in combination with limited chemotherapy is an alternative for patients unsuitable for radiation. For patients with very limited disease (a single small mass), careful observation after diagnosis may occasionally be considered, though treatment is generally recommended.

For the minority of patients with more advanced-stage disease, management follows principles similar to those used for advanced-stage classic follicular lymphoma. Active surveillance (watch and wait) may be appropriate in the absence of symptoms or rapid progression. When treatment is needed, chemoimmunotherapy with rituximab is typically used, often followed by rituximab maintenance. Given that the BCL2 rearrangement is absent in this subtype, the clinical relevance of drugs that specifically target BCL2 (such as venetoclax) in this setting is uncertain and would typically not be selected as therapy outside a clinical trial context.

All patients require ongoing monitoring with periodic blood tests and imaging to assess for progression, new disease sites, or the rare event of transformation to a more aggressive lymphoma. The frequency and type of monitoring will be determined by your care team based on your stage and response to treatment.

Questions to ask your doctor

Is my diagnosis definitely follicular lymphoma with a predominantly diffuse growth pattern, or are there still features that need further clarification?
Was an excisional biopsy performed, and if not, will one be needed to confirm the diagnosis?
Was testing for BCL2 rearrangement performed, and was the result negative as expected for this subtype?
Was a STAT6 mutation found, and what does that mean for my diagnosis and prognosis?
What stage is my lymphoma — is it limited to the groin, or has it spread to other lymph node regions?
Is radiation therapy being recommended, and what area would be treated?
Is watch and wait an option for me, and if so, what signs should prompt me to contact you?
How does this subtype differ from the more common classic follicular lymphoma in terms of prognosis and treatment?
How will you monitor me for disease recurrence or transformation to a more aggressive lymphoma over time?
Are there clinical trials relevant to this subtype that I should consider?