Marginal Zone Lymphoma (MZL) is a rare, slow-growing type of non-Hodgkin lymphoma that begins in B lymphocytes, the white blood cells responsible for producing antibodies. This cancer develops in the marginal zone of lymphoid tissue, which surrounds the germinal centers in lymph nodes, spleen, and mucosa-associated lymphoid tissue (MALT). MZL makes up 5–10% of all non-Hodgkin lymphomas, making it uncommon but important to recognize. Because it usually progresses slowly, patients often have more treatment options and a better long-term outlook compared to aggressive lymphomas.

This article explains what Marginal Zone Lymphoma is, the causes and risk factors, how it develops, signs and symptoms, methods of diagnosis, treatment options, and what it means to live with this condition.

Marginal Zone Lymphoma (MZL), also called marginal zone B-cell lymphoma, arises from B lymphocytes and is classified into three main subtypes:

• Extranodal Marginal Zone Lymphoma (MALT lymphoma): The most common form, occurring outside of lymph nodes in mucosal tissues such as the stomach, lungs, thyroid, salivary glands, or eyes. Gastric MALT lymphoma, linked to Helicobacter pylori infection, is the most frequent.
• Nodal Marginal Zone Lymphoma: Originates in lymph nodes and behaves like other indolent lymphomas.
• Splenic Marginal Zone Lymphoma (SMZL): Primarily affects the spleen but can spread to the bone marrow and blood.

Although each subtype has unique features, all are considered indolent, meaning they progress more slowly than aggressive lymphomas. MZL usually affects adults over 60 and tends to occur slightly more often in women.

The exact cause of Marginal Zone Lymphoma is unknown, but several risk factors are linked to its development. These factors often involve chronic immune system activation, leading to abnormal B-cell growth.

Chronic infections

Certain infections can increase the risk of extranodal MZL, especially gastric MALT lymphoma. Examples include:

• Helicobacter pylori (linked to gastric MALT lymphoma)
• Chlamydia psittaci (linked to ocular MALT lymphoma)
• Borrelia burgdorferi (linked to cutaneous MALT lymphoma)
• Hepatitis C virus (linked to splenic and nodal MZL)

Autoimmune diseases

Chronic autoimmune conditions can trigger abnormal immune activity, raising the risk of Marginal Zone Lymphoma. Examples include:

• Sjögren’s syndrome (linked to salivary gland MALT lymphoma)
• Hashimoto’s thyroiditis (linked to thyroid MALT lymphoma)
• Systemic lupus erythematosus (SLE)
• Rheumatoid arthritis

Immune system dysregulation

A weakened or dysfunctional immune system increases risk. Causes may include:

• Genetic predisposition
• Immunosuppressive therapy after organ transplant
• Chronic immune disorders
• Prior cancers or cancer treatments

Age and gender

Marginal Zone Lymphoma most often affects adults over 60. Women are slightly more likely to develop MZL, although some subtypes, like SMZL, are more common in men.

Genetic alterations

Acquired chromosomal changes may play a role, including:

• t(11;18)(q21;q21): Linked to gastric MALT lymphoma and resistance to antibiotic therapy
• Trisomy 3 or 18: May promote abnormal cell growth

These genetic changes are not inherited but occur during a person’s lifetime.

Marginal Zone Lymphoma begins when chronic immune stimulation or genetic changes cause B lymphocytes to grow abnormally. Over time, these altered cells accumulate in lymphoid tissue, forming tumors in lymph nodes, spleen, or mucosal sites. Infections such as H. pylori and autoimmune inflammation play a major role in this process. The disease progresses slowly, often without symptoms for years.

Marginal Zone Lymphoma accounts for 5–10% of all non-Hodgkin lymphomas. It is most common in older adults, typically diagnosed around age 60, and slightly more frequent in women. Gastric MALT lymphoma is the most prevalent subtype worldwide, especially in areas with high rates of H. pylori infection. Splenic and nodal forms are less common but still significant in older populations.

Marginal Zone Lymphoma often causes no symptoms early on and may be found incidentally during routine tests. When symptoms appear, they vary by subtype and location.

General symptoms

• Painless swollen lymph nodes
• Fatigue or weakness
• Unexplained weight loss
• Persistent fever
• Night sweats
• Loss of appetite

Symptoms by subtype

• MALT lymphoma:
  • Stomach: indigestion, nausea, abdominal pain, gastrointestinal bleeding
  • Lungs: persistent cough, chest discomfort, shortness of breath
  • Eyes: swelling around eyes, vision changes
  • Thyroid: neck swelling, trouble swallowing or speaking
• Nodal Marginal Zone Lymphoma: painless swollen lymph nodes in the neck, underarms, or groin
• Splenic Marginal Zone Lymphoma:
  • Enlarged spleen causing abdominal fullness or discomfort
  • Low blood counts leading to anemia, infections, or easy bruising
  • Hypersplenism symptoms such as early satiety and frequent infections

Because Marginal Zone Lymphoma develops slowly, many cases are diagnosed during unrelated medical exams or imaging.

Diagnosing Marginal Zone Lymphoma involves a combination of medical history, physical exam, lab tests, imaging, and biopsy.

• Medical history and physical exam: Includes review of symptoms, history of infections or autoimmune disease, and exam for enlarged lymph nodes or spleen.
• Laboratory tests:
  • Complete blood count (CBC)
  • Liver and kidney function tests
  • Lactate dehydrogenase (LDH)
  • Beta-2 microglobulin
  • Hepatitis B and C screening
  • H. pylori testing in suspected gastric MALT lymphoma
• Imaging: CT, PET-CT, ultrasound, or endoscopy depending on location
• Biopsy: Tissue or lymph node biopsy confirms diagnosis under the microscope
• Bone marrow biopsy: Often done in splenic MZL to check marrow involvement
• Cytogenetics and molecular testing: Identify alterations like t(11;18) or trisomy 3/18
• Serum protein immunofixation: Detects abnormal proteins linked to lymphoma

Accurate diagnosis and subtype classification are essential for treatment planning.

Differential diagnosis for Marginal Zone Lymphoma

Because symptoms are nonspecific, Marginal Zone Lymphoma may be mistaken for other conditions, including:

• Other indolent lymphomas (follicular lymphoma, small lymphocytic lymphoma)
• Chronic lymphocytic leukemia (CLL)
• Reactive lymph node enlargement from infections or autoimmune disease
• Other cancers involving the spleen, lymph nodes, or mucosal tissues

Careful pathology review and molecular testing help confirm the diagnosis.

Treatment depends on subtype, stage, symptoms, and overall health. Some patients with early, asymptomatic disease may be monitored with watchful waiting until treatment is necessary.

Antibiotic therapy

For gastric MALT lymphoma linked to H. pylori, eradication therapy with antibiotics and acid-reducing drugs can cure many patients.

Radiation therapy

Targeted radiotherapy is effective for localized MALT lymphoma, especially in the stomach, salivary glands, or orbit.

Chemotherapy

Used in more advanced or nodal/splenic cases. Options include:

• Chlorambucil
• Bendamustine plus rituximab (BR regimen)

Immunotherapy

• Rituximab: A monoclonal antibody targeting CD20 on B cells
• Given alone in older patients or combined with chemotherapy
• Especially effective in splenic MZL with bone marrow or blood involvement

Surgery

Rarely used today, but splenectomy may be considered for symptomatic splenic MZL.

Targeted therapy and clinical trials

For relapsed or refractory Marginal Zone Lymphoma, options include:

• Ibrutinib (BTK inhibitor)
• Lenalidomide (immune modulator)
• Ongoing clinical trials exploring novel therapies

Management of HCV-related MZL

In cases linked to hepatitis C, antiviral therapy can sometimes induce remission.

Stem cell transplant

Reserved for relapsed or aggressive cases, usually in younger patients.

Complications vary by subtype and disease extent. They may include:

1. Enlarged spleen causing pain or anemia
2. Increased infection risk due to low blood counts
3. Transformation into a more aggressive lymphoma
4. Side effects from treatment such as fatigue, nausea, or immune suppression

Marginal Zone Lymphoma is usually highly treatable. Many patients live for years with good quality of life, even without immediate therapy. Prognosis depends on age, subtype, genetic changes, and response to treatment. Gastric MALT lymphoma often responds well to antibiotics, while other subtypes may require long-term therapy.

While Marginal Zone Lymphoma cannot always be prevented, risk may be reduced by:

• Treating chronic infections such as H. pylori or hepatitis C
• Managing autoimmune conditions effectively
• Avoiding unnecessary immunosuppressive therapy when possible

Living with Marginal Zone Lymphoma often means managing a chronic but treatable cancer. Many patients require long-term monitoring, and treatment may be needed at different points. Practical steps include:

• Keeping regular follow-up appointments
• Reporting new or worsening symptoms promptly
• Staying up to date with vaccines and infection prevention strategies
• Seeking emotional support through counseling or support groups

With appropriate medical care, many patients can achieve long periods of remission and maintain a fulfilling quality of life.

Marginal Zone Lymphoma is a rare but generally treatable form of non-Hodgkin lymphoma. While it develops slowly and often affects older adults, treatments ranging from antibiotics to immunotherapy and targeted drugs offer many effective options. Early diagnosis, regular monitoring, and individualized care are key to achieving the best outcomes. Ongoing research continues to bring new hope for improved therapies and long-term survival.

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