What Is Marginal Zone Lymphoma?

Lymphoma is a common type of cancer affecting our lymph nodes and other organs of our lymphatic system.¹ However, with so many types of lymphoma, it can be difficult to know what a diagnosis means for you or someone you love. 

According to Cancer Research UK, non-Hodgkin lymphoma (NHL) is the sixth most common cancer in the UK. Marginal zone lymphoma is one of over 90 subtypes of NHL.² Read on to find out all you need to know about this rare form of NHL. 

Introduction

Marginal zone lymphoma is a rare type of non-Hodgkin’s lymphoma.²

Lymphomas are a group of cancers in which white blood cells (lymphocytes) grow rapidly. Lymphomas can be divided into Hodgkin's and non-Hodgkin’s lymphoma, and these categories are further subdivided into over 90 different subtypes of the disease.¹

Hodgkin’s lymphoma often occurs in younger adults and is characterised by abnormal cells called Reed-Sternberg cells.³

Non-Hodgkin’s lymphoma (NHL) can affect B cells or T cells. B cells are white blood cells that mature in the bone marrow, and T cells are white blood cells that mature in the thymus. Both types of cells are important in fighting off infection.⁴ The incidence of NHL increases with age, with the median age at diagnosis being 67 years old.⁵ The symptoms and prognosis of NHL varies widely, in keeping with the diverse range of subtypes.⁵ 

This article will focus on marginal zone lymphoma, a slow-growing variant that is the third most common subtype of B-cell NHL.² The marginal zone is a region found within lymphoid tissues, such as the spleen, lymph nodes, and mucosa-associated lymphoid tissue (MALT). Immune responses are initiated here, and so the marginal zone contains various cells that help fight infection, including marginal zone B cells. Marginal cell lymphoma results when these marginal zone B cells grow in an uncontrolled manner.⁶ 

There are three subtypes of marginal zone lymphoma: extranodal (EMZL), nodal (NMZL), and splenic (SMZL).² Each subtype is unique, with different biological and clinical features.⁶ However, non-specific symptoms like fever, unexplained weight loss and night sweats may be present in all types. These non-specific symptoms are often referred to as B symptoms.⁵

Now, let’s consider each subtype in turn. 

Subtypes of marginal zone lymphoma

Extranodal marginal zone lymphoma (EMZL)

EMZL is the most common subtype, accounting for around 60% of cases in the US.⁷ Its full name is extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue, and so it is often referred to as MALT lymphoma.⁷ MALT lymphoma affects a range of sites around the body. Gastric MALT is the most common form, accounting for 30% of cases of MALT.⁷ Other sites that can be affected are:⁷

• The periocular adnexa (tissues and structures supporting the eyeballs)
• The breasts
• The thyroid gland
• The salivary glands
• The skin

Risk factors for MALT

Some chronic infections and autoimmune conditions have been linked to MALT lymphoma. H. Pylori (a bacterial stomach infection) has been linked with gastric MALT. Achromobacter xylosoxidans infection in the lungs has been associated with MALT lymphoma in the same organ.⁷ The autoimmune condition Sjögren syndrome has been linked with MALT lymphoma of the salivary glands and Hashimoto thyroiditis has been linked with MALT lymphoma of the thyroid.⁷ Various genetic changes also drive the development of MALT lymphoma.⁷

Specific signs and symptoms of MALT

The symptoms of MALT lymphoma depend on the affected site.⁷ For example, gastric MALT symptoms can include stomach pain, vomiting and loss of appetite.⁵ You can find out about the symptoms of MALT lymphoma here.

Diagnosis and treatment of MALT

Clinical work-up for any NHL, including MALT lymphoma, will typically involve the following:^5,8

1. History and physical examination: Your healthcare provider will request a detailed account of your symptoms. They will also consider any other health conditions that you have, whether you are taking any medication, and ask about your current lifestyle. A physical examination will allow your provider to gather physical evidence that could help explain the symptoms you are experiencing. The examination will likely include an assessment of your lymphatic system (including your lymph nodes and spleen), abdomen, head, and neck.
2. Blood tests: Blood tests can show a variety of abnormalities, such as anaemia, or a reduction in the levels of other components of the blood.
3. Imaging: A CT or PET scan may be carried out to look for evidence of disease.
4. Biopsies: The nature of biopsy samples will depend on which type of lymphoma is suspected. In gastric MALT, biopsy samples from the stomach can be examined in a laboratory to look for evidence of lymphoma.
5. Immunophenotyping: Immunophenotyping of biopsy or blood samples uses antibodies to detect markers on the surface of cells that could support a diagnosis of lymphoma or another condition.
6. Bone marrow biopsy: Lymphoma may spread to the bone marrow. If this is suspected, a biopsy may be taken, however, this is required less often as imaging technology improves.
7. Genetic analysis: If cancer cells are detected, it may be appropriate to look for specific genetic changes that can help identify which subtype of NHL you have.

If you are diagnosed with MZL, or another form of NHL, your healthcare provider can use the information they gather from the above tests (particularly imaging tests) to determine what stage of disease you have. Staging indicates how advanced your lymphoma is and can help to determine treatment choices.⁷

MALT lymphomas tend to be slow-growing and usually remain localised. However, in around a quarter of patients, it can spread throughout an organ or to further afield sites.⁷ The latter is less common in gastric MALT.⁹

Patients with localised gastric MALT who have an H. Pylori infection should be treated initially with antibiotics and medication to reduce stomach acid.⁷ This will be sufficient to cause improvement in gastric MALT in three-quarters of patients which can be determined via subsequent endoscopy.⁹ Those without demonstrable H. Pylori infection may still benefit from the same treatment, or treatment with clarithromycin, an alternative antibiotic.⁷ If this approach is ineffective, other treatment options include radiotherapy, chemotherapy, or treatment with rituximab.⁷ Rituximab is a type of medication called a monoclonal antibody. It binds to and destroys B cells.¹⁰

For those with localised non-gastric MALT, antibiotic therapy can be effective in cases where infection is thought to be contributing.⁷ Alternatively, radiotherapy may be offered.⁷ Speak to your healthcare provider to find out what treatment options are most appropriate for your specific case. 

Patients with advanced MALT lymphoma can usually be observed due to the slow-growing nature of the condition. If treatment is necessary, radiotherapy, chemotherapy, and/or rituximab may be used.⁷

Nodal marginal zone lymphoma

Nodal MZL occurs within lymph nodes and accounts for 30% of cases.⁷ 

Risk factors for nodal marginal zone lymphoma

Hepatitis C infection have been linked with the development of nodal MZL.⁷ 20% of patients have changes in the PTPRD gene at diagnosis.⁷

Specific signs and symptoms of nodal MZL

Peripheral lymphadenopathy (swollen lymph nodes around the body), particularly of the head and neck, may be observed.¹¹

Diagnosis and treatment of nodal MZL

The diagnostic principles are similar to those of MALT lymphoma (and NHLs more generally), as discussed above. A biopsy of affected nodes will be taken and examined in the laboratory.⁵

Partially due to the rarity of the disease, there is no standard treatment protocol for nodal MZL. Some healthcare providers may treat the condition in the same way as other NHLs, such as follicular lymphoma.⁷ Any contributing infection, like hepatitis C, should be treated.⁷ Those with localised disease may receive radiotherapy, whereas those with advanced disease are often monitored due to the slow-progressing course of the condition. In advanced cases that are progressing, a combination of chemotherapy and rituximab is the preferred treatment option.⁷

Splenic marginal zone lymphoma (SMZL)

SMZL accounts for roughly 10% of cases of marginal zone lymphoma.⁷ 

Risk factors for SMZL

Complex genetic factors have been linked to the development of SMZL, including mutations in NOTCH pathway genes.⁷ Hepatitis C infection has also been linked with SMZL.⁷ 

Specific signs and symptoms of SMZL

Approximately a third of patients do not have any symptoms.⁷ Others may have an enlarged spleen.⁷ Peripheral lymphadenopathy, often seen in nodal SMZL, is rare.⁷ 

Diagnosis and treatment of SMZL

Diagnosing SMZL follows the same principles as MALT lymphoma (and NHLs more generally), as discussed above. A biopsy of the spleen is not usually required.⁷ 

If hepatitis C infection is present, treatment should be initiated which can lead to regression of the lymphoma.⁷ 

Those without symptoms may not require treatment, and observation is often sufficient.⁷ For symptomatic or progressing disease, radiotherapy, chemotherapy, rituximab treatment and splenectomy (surgical removal of the spleen) will be considered.⁷ However, splenectomy has become less common with the advent of more effective systemic treatments.⁷ 

FAQs

Who gets marginal zone lymphoma?

Marginal zone lymphoma is most common in older people of non-Hispanic white ethnicity. Those assigned male at birth have a slightly higher risk than those assigned female at birth.¹²

What is the outlook for people with marginal zone lymphoma?

The five-year survival rate for MZL is 89.8%. This means that of 100 people diagnosed with MZL, almost 90 can expect to be alive five years later. The rate is highest in MALT (93.8%) and lowest in NMZL (82.8%).¹²

How can I prevent marginal zone lymphoma?

Most risk factors for MZL like age, ethnicity and genetics, are outwith our control. The main way to reduce risk is by preventing or providing early treatment for infections that predispose to MZL, such as H. Pylori and Hepatitis C.¹²

Summary

Marginal zone lymphoma (MZL) is a rare subtype of B-cell Non-Hodgkin’s lymphoma. Marginal zone lymphoma can affect lymph nodes (nodal MZL), the spleen (splenic MZL) and other sites where lymphatic tissue is found, such as the stomach and breast (extranodal MZL or MALT lymphoma). 

MZL can be associated with certain infections and autoimmune conditions. Genetic factors also play a role. 

Diagnosis usually involves a combination of blood tests, imaging and biopsies. Treatment options depend on the stage of the disease and the specific subtype of MZL. However, as MZL is often a slow-growing condition, some patients may not require treatment when they are diagnosed, and a “watch and wait” approach may be employed. If treatment is necessary, this can involve a combination of radiotherapy, chemotherapy and immunological drugs like rituximab. Sometimes, surgery is indicated in the management of splenic MZL. 

Fortunately, five-year survival rates are higher than amongst many other cancers. Around 9 out of 10 people with MZL will be alive five years later.