Marginal Zone Lymphoma Overview

Marginal zone lymphoma (MZL) is a slow-growing (indolent) form of non-Hodgkin lymphoma that originates in the marginal zone of lymphoid tissue. This area contains specialized white blood cells (B lymphocytes) that recognize and respond to bloodborne and mucosal pathogens, including encapsulated bacteria that are highly resistant to the body’s immune response. Most cases of MZL develop in mucosa-associated lymphoid tissues (MALT), lymph nodes or the spleen.

Although marginal zone B-cell lymphoma can spread over time, it tends to progress slowly and may not require immediate treatment. Management often involves careful monitoring or targeted therapy based on the location and extent of the cancer. On the whole, the condition is considered relatively rare, with an estimated 1,000 to 2,300 new cases diagnosed each year, according to the Leukemia & Lymphoma Society.

The World Health Organization (WHO) recognizes three main subtypes of marginal zone lymphoma:

Mucosa-associated lymphoid tissue B-cell lymphoma

MALT lymphoma is the most common type of marginal zone lymphoma, accounting for approximately 70% of cases. Usually, the cancer arises in tissues outside the lymph nodes, such as the stomach, lungs, thyroid, salivary glands or skin. For this reason, it is sometimes referred to as extranodal marginal zone lymphoma.

What are the causes and risk factors for mucosa-associated lymphoid tissue B-cell lymphoma?

In many cases, MALT lymphoma develops in response to long-term inflammation or infection. For example, one of the most well-established causes of gastric MALT lymphoma is chronic infection with Helicobacter pylori, a bacterium commonly found in the digestive system that can cause persistent inflammation of the stomach lining (mucosa). As the body’s immune system attempts to fight the infection, lymphocytes (particularly B-cells) may accumulate and organize into mucosa-associated lymphoid tissue in the gastrointestinal tract, potentially leading to the development of MALT lymphoma.

Infectious agents linked to non-gastric mucosa-associated lymphoid tissue lymphoma include:

• Borrelia burgdorferi – Typically associated with cutaneous MALT lymphoma, which affects the skin
• Campylobacter jejuni – Sometimes traced to immunoproliferative small intestinal disease, a rare form of intestinal MALT lymphoma
• Chlamydophila psittaci – Commonly attributed to ocular adnexal MALT lymphoma, which infects tissues around the eyes

Additionally, chronic immune system stimulation from an autoimmune condition can trigger abnormal B-cell proliferation, leading to mucosa-associated lymphoid tissue lymphoma. This is most often seen in:

• Sjögren’s syndrome – Sometimes associated with MALT lymphoma of the salivary glands
• Hashimoto’s thyroiditis – Often connected to thyroid MALT lymphoma

In some cases, mucosa-associated lymphoid tissue lymphoma is linked to a genetic mutation or chromosomal translocation involving the MALT1 gene, which disrupts normal B-cell function and growth. This abnormality can promote uncontrolled cell proliferation and survival, driving lymphomagenesis—the transformation of healthy lymphocytes into malignant cells that leads to lymphoma.

Other risk factors for mucosa-associated lymphoid tissue lymphoma include:

• Advanced age – MALT lymphoma typically affects older adults, with most cases diagnosed after age 50.
• Female gender – Some forms of MALT lymphoma, such as those associated with Sjögren’s syndrome, are more common in women than men, possibly due to the higher prevalence of autoimmune conditions in females.

What are the signs and symptoms of mucosa-associated lymphoid tissue B-cell lymphoma?

MALT lymphoma often develops gradually and may not cause noticeable symptoms in its early stages. When symptoms do appear, they are typically related to the specific organ or tissue affected. For example:

Cutaneous MALT lymphoma, which affects the skin, may cause:

• Skin growths that slowly increase in size over time
• Skin lesions that may be itchy or tender
• Visible skin changes, such as reddish or purplish nodules or patches

Gastric MALT lymphoma, which affects the stomach, may cause:

• Abdominal pain or discomfort
• Bloating after eating
• Gastrointestinal bleeding
• Heartburn or indigestion
• Loss of appetite
• Nausea or vomiting
• Unexplained weight loss

Intestinal MALT lymphoma may cause:

• Abdominal pain or cramping
• Changes in bowel habits, such as persistent diarrhea or constipation
• Fatigue or anemia
• Occult gastrointestinal bleeding

Ocular adnexal MALT lymphoma, which affects the eyes, may cause:

• Blurred or double vision
• Bulging of the eye (proptosis)
• Eye dryness or irritation
• Redness or discomfort around the eye
• A painless lump or swelling near the eye

Pulmonary MALT lymphoma, which affects the lungs, may cause:

• Chest discomfort or pain
• Chronic coughing
• Fatigue
• Shortness of breath
• Unintended weight loss

Salivary gland MALT lymphoma may cause:

• Difficulty swallowing
• Dry mouth
• Pain or discomfort in the face or jaw
• Persistent swelling in the salivary glands

Thyroid MALT lymphoma may cause:

• Difficulty swallowing
• A neck mass that can be seen or felt
• Thyroid gland enlargement (goiter)
• Trouble breathing

How is mucosa-associated lymphoid tissue B-cell lymphoma diagnosed?

MALT lymphoma is usually diagnosed through a combination of clinical evaluation, imaging studies and tissue analysis. The diagnostic process may include:

Medical history and physical examination

The physician will typically begin by reviewing the patient’s symptoms, medical history and risk factors. Next, the physician will perform a thorough physical exam, checking for visible skin changes and swelling in lymph nodes and organs, such as the salivary glands, stomach and thyroid.

Endoscopy or imaging

If the physician suspects mucosa-associated lymphoid tissue lymphoma in the gastrointestinal tract or another internal site, they may order an imaging procedure, such as a bronchoscopy, colonoscopy or upper endoscopy, to visualize the area and obtain biopsy samples. Imaging studies, such as computed tomography (CT), magnetic resonance imaging (MRI) and positron emission tomography (PET) scans, can help the physician assess the extent of the abnormality and determine if other organs or tissues are involved.

Biopsy and histopathology

A definitive diagnosis of MALT lymphoma requires a biopsy. This procedure involves removing a small sample of suspicious tissue from the site where lymphoma is suspected, such as the skin or stomach lining. The sample will be sent to a laboratory for microscopic examination by a pathologist, who can identify abnormal B-cells and, if lymphoma is found, determine its subtype.

Immunohistochemistry and molecular testing

Additional lab work, such as immunohistochemistry, flow cytometry and genetic testing, may be performed on the biopsy sample. These specialized tests can help the physician confirm the diagnosis by detecting specific markers or genetic changes characteristic of MALT lymphoma.

Staging workup

After confirming a diagnosis of MALT lymphoma, the physician will usually order staging tests to determine whether the cancer is localized or has spread beyond the site of origin. The staging process may include a bone marrow biopsy, blood work or additional imaging studies. The results can help the physician plan treatment and predict the outcome.

How is mucosa-associated lymphoid tissue B-cell lymphoma treated?

Treatment for MALT lymphoma can vary depending on the organs and tissues affected, the patient’s overall health, the stage of the cancer and whether it is associated with an underlying infection. The primary treatment approaches include:

Active surveillance (watchful waiting)

For stable, confined, asymptomatic MALT lymphoma, a watch-and-wait treatment strategy may be considered. This type of cancer tends to progress very slowly, and regular monitoring can help ensure timely intervention if needed.

Antibiotic therapy for infection-associated MALT lymphoma

When MALT lymphoma is linked to a bacterial infection, such as Helicobacter pylori in the stomach, antibiotic therapy is usually the first line of treatment. Often, eradicating H. pylori can lead to complete remission of gastric MALT lymphoma. Similarly, other site-specific bacterial infections, such as Chlamydophila psittaci in ocular adnexal lymphoma, may be treated with appropriate antibiotics.

Radiation therapy

Localized MALT lymphoma that is not infection-related or does not respond to antibiotics may be treated with radiation therapy. This approach can be especially effective for early-stage cancer confined to one area of the body, such as the ocular region, stomach or salivary glands. Radiation treatment is typically well tolerated and may achieve long-term remission.

Systemic therapy

If MALT lymphoma is more advanced or involves multiple sites throughout the body, systemic therapy may be necessary. Options may include:

• Chemotherapy – An agent such as chlorambucil or bendamustine, or a multi-drug regimen, may be used to address widespread or refractory cancer.
• Immunotherapy – Rituximab, a monoclonal antibody that targets CD20-positive B-cells, may be used alone or in combination with chemotherapy.
• Targeted therapy – In select cases, targeted agents such as BTK inhibitors may be considered for persistent or relapsed lymphoma.

Clinical trials

A patient with treatment-resistant or relapsed MALT lymphoma might consider enrolling in a clinical trial. These important research studies allow select patients to benefit from promising new therapies that are not yet widely available in other settings.

Nodal marginal zone B-cell lymphoma

Less common than MALT lymphoma, node marginal zone lymphoma (NMZL) accounts for approximately 20% of MZL cases. The cancer primarily affects the lymph nodes, although it may also involve the bone marrow or blood. Like other marginal zone lymphomas, NMZL is considered an indolent form of non-Hodgkin lymphoma, although it may transform into a more aggressive form over time.

What are the causes and risk factors for nodal marginal zone B-cell lymphoma?

The precise biological mechanisms behind NMZL are not fully understood. However, like other types of marginal zone lymphoma, the condition is thought to arise from the transformation of B-cells in response to a trigger that disrupts normal cell regulation, such as:

• Chronic immune activation – Repeated or long-term stimulation of the immune system may lead to abnormal B-cell proliferation and survival, contributing to the development of lymphoma.
• Genetic alterations – Some NMZL cases are traced to a mutation or chromosomal abnormality in a gene that regulates B-cell growth and function. However, no single genetic change is specific to this type of lymphoma.
• Unknown antigenic stimulation – While extranodal and spleen-related (splenic) marginal zone lymphomas are often linked to a specific infection or autoimmune condition, the causes of NMZL are less defined and may involve an unknown or nonspecific antigen.

Risk factors for nodal marginal zone lymphoma

Although NMZL is relatively rare, several factors may increase the risk. These include:

• Advanced age – Most cases are diagnosed in adults 60 or older.
• Certain autoimmune conditions – Rheumatoid arthritis, Sjögren’s syndrome and systemic lupus erythematosus (SLE) are associated with an elevated risk of MZLs in general, possibly due to ongoing immune system activation.
• Female gender – Nodal marginal zone lymphoma affects slightly more women than men.
• Family history of lymphoma – A family history of certain hematologic cancers may suggest a genetic predisposition to MZLs, although this link is not well defined for NMZL specifically.
• Immunosuppression – A weakened immune system due to immunosuppressive therapy, organ transplantation or human immunodeficiency virus (HIV) infection may increase the risk of developing lymphoma, including NMZL.

What are the signs and symptoms of nodal marginal zone B-cell lymphoma?

NMZL can be asymptomatic for up to several years. In many cases, the condition is discovered incidentally through routine blood work or imaging studies performed for an unrelated reason. If symptoms do occur, they may include:

• Abdominal discomfort – If nodal marginal zone lymphoma affects lymph nodes in the abdomen, it may cause bloating or fullness.
• Enlarged lymph nodes – The most common sign of NMZL is painless lymph node swelling, often in the neck, armpits or groin. The affected nodes may gradually increase in size over time.
• Fatigue – Some patients may feel tired, weak or generally unwell.
• Fever – A low-grade or persistent fever may develop without an obvious infection.
• Night sweats – Episodes of excessive sweating during sleep may occur, often soaking bedclothes and sheets.
• Recurrent infections – As the lymphoma progresses, it may interfere with the body’s immune function, leading to frequent infections.
• Unexplained weight loss – Some people with NMZL lose weight without trying, possibly due to the extra energy being expended to fight the lymphoma.

How is nodal marginal zone B-cell lymphoma diagnosed?

Because NMZL is a rare and often slow-growing lymphoma, a thorough diagnostic process is essential to distinguish it from other lymphoid cancers and determine the most appropriate treatment approach. This may involve:

Clinical assessment

Typically, the physician will begin with a clinical exam to evaluate any swollen lymph nodes and assess other symptoms, such as fatigue, night sweats and unexplained weight loss. Through a detailed medical history review, the physician may identify an underlying infection or autoimmune condition that could be relevant.

Blood work

Next, the physician may order lab work, such as:

• Complete blood count (CBC) – To measure red blood cells, white blood cells and platelets
• Immunoglobulin test – To identify abnormal antibody levels in the bloodstream, which could indicate lymphoma
• Lactate dehydrogenase (LDH) test – To detect elevated levels of the LDH enzyme (common in lymphoma)
• Flow cytometry – To differentiate lymphoma from other conditions with similar symptoms or distinguish between different types of lymphoma (e.g., B-cell vs. T-cell)

Imaging studies

To assess the extent of lymph node involvement and check for signs of lymphoma in other parts of the body, the physician may order imaging tests, such as:

• CT scans of the chest, abdomen, and pelvis
• PET scans to identify metabolically active lymphoid tissue
• Ultrasound for a targeted evaluation of enlarged nodes

Lymph node biopsy

A lymph node biopsy is the definitive step in diagnosing NMZL. This may involve:

• Core needle biopsy – A thin needle will be used to collect a small tissue sample
• Excisional biopsy – An entire lymph node will be surgically removed

The biopsy tissue will be sent to a lab for microscopic examination by a pathologist, who may also perform immunohistochemistry and molecular studies to confirm the diagnosis and rule out other types of lymphoma.

Bone marrow biopsy

In some cases, a bone marrow biopsy may be performed to help the physician determine if the lymphoma has spread beyond the lymph nodes.

How is nodal marginal zone B-cell lymphoma treated?

Overall, NMZL is considered a manageable lymphoma, and many patients respond well to initial treatment. Additionally, long-term monitoring will be important to detect signs of cancer progression or recurrence and guide future treatment decisions. Options may include:

Active surveillance

If the patient is asymptomatic with a low tumor burden, the physician may suggest a watch-and-wait approach, which will involve monitoring the condition through regular medical checkups and imaging scans rather than starting therapy right away. This strategy can help the patient avoid unnecessary treatment (and the associated side effects) if the lymphoma is not causing harm.

Immunotherapy

Rituximab is the standard first-line treatment for NMZL. This monoclonal antibody binds to CD20, a protein primarily found on the surface of B-cells and absent from other immune cells, such as T-cells. CD20 plays a key role in B-cell development, differentiation and signaling, making it an important therapeutic target in certain B-cell lymphomas. Rituximab is generally well tolerated and effective in controlling symptoms and reducing lymph node enlargement. It may be used alone or in combination with chemotherapy, depending on the stage and progression of the lymphoma.

Chemotherapy

For a patient who requires more aggressive treatment, chemoimmunotherapy may be recommended. Common regimens include:

• R-CVP – A combination of rituximab, cyclophosphamide, vincristine and prednisone
• R-CHOP – A combination of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone

Targeted therapy

In a relapsed or refractory case of NMZL, targeted therapies, such as Bruton’s tyrosine kinase (BTK) inhibitors (e.g., ibrutinib), may be considered. These drugs interfere with the signaling pathways that promote B-cell growth and survival.

Radiation therapy

If NMZL is localized to a single lymph node region, radiation therapy may be considered. This treatment approach can be especially effective for early-stage lymphoma.

Clinical trials

The patient may wish to explore promising new therapies available only through clinical trials, such as novel immunotherapies and targeted agents.

Splenic marginal zone B-cell lymphoma

Splenic marginal zone lymphoma (SMZL) mainly involves the spleen, bone marrow and blood. Its hallmark symptoms are spleen enlargement (splenomegaly) and low blood cell counts (cytopenias). Unlike other MZLs, however, it may not cause noticeable lymph node swelling.

What are the causes and risk factors for splenic marginal zone B-cell lymphoma?

The exact mechanisms behind SMZL are not fully understood. Research suggests a combination of immune, infectious and genetic factors may play a role in its development. Like other indolent B-cell lymphomas, splenic marginal zone lymphoma often arises in the context of chronic immune system stimulation. Possible causes include:

Chronic infections

Certain viral and bacterial infections have been linked to splenic marginal zone lymphoma. Hepatitis C virus (HCV), which may stimulate prolonged immune activity in the spleen and lymphatic tissue, is the most well-established infectious association. In some cases, effective treatment of hepatitis C leads to lymphoma regression, suggesting the infection plays a direct role in lymphomagenesis. Though less clear, the roles of Epstein-Barr virus (EBV) and Helicobacter pylori in SMZL development are also under study.

Genetic abnormalities

Through cytogenetic and molecular studies, scientists have identified various chromosomal abnormalities that may contribute to SMZL, including deletions in chromosome 7q and mutations in certain genes, such as NOTCH2, KLF2 and TP53. These genetic changes can disrupt normal B-cell function and lead to lymphoma development.

Risk factors for splenic marginal zone lymphoma include:

• Advanced age – SMZL most commonly affects older adults, typically those in their 60s or 70s.
• Certain autoimmune disorders – Though not as well established as the HCV link, rheumatoid arthritis and systemic lupus erythematosus may contribute to the development of SMZL due to persistent immune stimulation.
• Family history – While splenic marginal zone lymphoma is not considered an inherited condition, a family history of lymphoid cancers may marginally increase the risk, possibly due to shared genetic or environmental factors.
• Male gender – SMZL affects slightly more men than women.

What are the signs and symptoms of splenic marginal zone B-cell lymphoma?

SMZL typically develops slowly, and many individuals have no symptoms at the time of diagnosis. In many cases, the condition is discovered incidentally during an imaging test or blood work performed for an unrelated reason. If noticeable symptoms do occur, they may result from the effects of spleen enlargement—the most common clinical finding—or a disruption in normal blood cell production.

Splenomegaly may cause:

• Abdominal bloating or pressure
• Early satiety (a feeling of fullness after eating only a small amount of food)
• Pain or discomfort in the upper left abdomen

Additionally, splenic marginal zone lymphoma can affect bone marrow function or lead to spleen-related destruction of blood cells, potentially resulting in:

• Anemia – Causing weakness or shortness of breath
• Leukopenia – Increasing the risk of infections
• Thrombocytopenia – Leading to easy bruising or bleeding

Persistent fatigue is also common with splenic marginal zone lymphoma. This may be related to anemia or the body’s response to the cancer. Some patients may lose weight without trying, especially as the cancer progresses. Though uncommon, some individuals may experience a low-grade fever or night sweats unrelated to an infection.

How is splenic marginal zone B-cell lymphoma diagnosed?

SMZL is typically diagnosed through a combination of clinical evaluation, imaging studies, laboratory tests and sometimes tissue sampling. The diagnostic process may include:

• Physical examination and medical history – The physician may detect an enlarged spleen during a physical exam. A thorough review of the patient’s personal and family medical history can also provide important context.
• Blood tests – Routine bloodwork may reveal low blood cell counts (cytopenias), elevated lymphocyte levels or the presence of monoclonal B-cells. A peripheral blood smear may show atypical lymphocytes characteristic of SMZL.
• Imaging studies – Ultrasound, MRI or CT scans may be used to help the physician assess the size of the spleen and check for other organ involvement.
• Bone marrow biopsy – A bone marrow sample may be taken for microscopic examination by a pathologist, particularly in a patient with abnormal blood cell counts or systemic symptoms.
• Flow cytometry and immunophenotyping – These specialized tests analyze the types and characteristics of lymphocytes in the blood, bone marrow or spleen. SMZL cells typically show a specific pattern of surface markers that can help the physician differentiate the condition from other types of lymphoma.
• Spleen biopsy or splenectomy – In select cases where the diagnosis is uncertain, a biopsy or surgical removal of the spleen may be performed to obtain a definitive tissue diagnosis.

How is splenic marginal zone B-cell lymphoma treated?

SMZL treatment can vary depending on the severity of symptoms, the cancer progression and the patient’s overall health. Because marginal zone lymphomas often progress slowly, some patients may not require immediate treatment and can be closely monitored through a watchful waiting approach. If treatment is needed, options may include:

Rituximab-based therapy

Commonly used as a first-line treatment for splenic marginal zone lymphoma, rituximab may be given alone or in combination with chemotherapy. This monoclonal antibody, which targets CD20-positive B-cells, is generally well tolerated and effective in controlling SMZL.

Splenectomy

Surgical removal of the spleen was once the standard treatment for SMZL and may still be considered in certain cases, especially when the spleen is significantly enlarged or causing discomfort, low blood counts or other complications. Splenectomy can provide rapid symptom relief and help normalize blood cell levels.

Chemotherapy

If the patient does not respond to rituximab alone or has more aggressive disease features, chemotherapy may be recommended. Agents such as bendamustine or fludarabine are sometimes used in combination with rituximab.

Targeted therapy

In select cases, targeted agents, such as BTK inhibitors, may be prescribed, particularly for a patient who experiences relapse or does not respond to standard therapies.

Antiviral therapy

For a patient with an underlying HCV infection, antiviral treatment may lead to significant improvement or resolution of the lymphoma. For this reason, a thorough evaluation for viral infections is an important step of the initial workup.

Benefit from world-class care at Moffitt Cancer Center

Moffitt is a world-recognized leader in the diagnosis and treatment of cancer, including for all types of lymphoma. We welcome patients who are seeking an initial evaluation, a second opinion or individualized treatment for a confirmed diagnosis of marginal zone lymphoma. To request an appointment with a specialist in our Malignant Hematology Program, call 1-888-663-3488 or complete our online new patient registration form. We do not require referrals.

References

Leukemia & Lymphoma Society – Marginal Zone Lymphoma (MZL)
Healthline – Marginal Zone Lymphoma
Lymphoma Research Foundation – Marginal Zone Lymphoma: Treatment Options