Lymphoma is a hematologic malignancy (blood cancer) that arises when lymphocytes, a type of white blood cell integral to the immune system, proliferate (mutate and divide) uncontrollably. These lymphocytes circulate through the lymphatic system, combating infections. There are two primary types of lymphocytes: B lymphocytes (B cells) and T lymphocytes (T cells). Lymphomas are classified into Hodgkin lymphomas (arises in the upper body) and non-Hodgkin lymphomas (arising in lymph nodes anywhere in the body) based on specific cellular characteristics.¹

Marginal zone lymphoma (MZL), a subtype of non-Hodgkin lymphoma, is a low-grade malignancy originating from B cells. It falls under the broader category of marginal zone lymphomas, which develop in the marginal zone—a specific area at the periphery of lymphoid tissues. MZL is classified into three main subtypes: extranodal marginal zone lymphoma (MALT lymphoma), nodal marginal zone lymphoma (NMZL), and splenic marginal zone lymphoma (SMZL). Although MZL is relatively rare, it presents unique challenges and treatment options. Among these, radiation therapy plays a crucial role. This article delves into the mechanisms, efficacy, and considerations of radiation therapy for MZL.

Understanding marginal zone lymphoma

Types of marginal zone lymphoma

• Extranodal marginal zone lymphoma (MALT Lymphoma): Often associated with chronic inflammation and infections, such as Helicobacter pylori in gastric MALT lymphoma
• Nodal marginal zone lymphoma (NMZL): Occurs within lymph nodes and has no known association with specific infections
• Splenic marginal zone lymphoma (SMZL): Primarily affects the spleen and blood, sometimes linked to hepatitis C virus (HCV) infection

Symptoms and diagnosis

Symptoms of MZL vary based on the affected area but can include:²

• Fatigue
• Inexplicable weight loss
• Night sweats
• Fever
• Indigestion or heartburn
• Nausea or being sick
• Tummy pain

Diagnosis typically involves imaging studies, blood tests, and biopsy of the affected tissue. Immunophenotyping and genetic tests help to confirm the diagnosis and subtype of MZL

Radiation therapy for marginal zone lymphoma

Mechanism of radiation therapy

Radiation therapy uses high-energy particles or waves, such as X-rays, gamma rays, electron beams, or protons, to destroy or damage cancerous cells. The primary mechanism involves damaging the DNA within cancer cells,³ which impairs their ability to reproduce, leading to cell death. Radiation therapy can be delivered externally or internally:

• External beam radiation therapy (EBRT): The most common form, where radiation is directed from a machine outside the body
• Internal radiation therapy (Brachytherapy): Involves placing radioactive material inside or near the tumour

Radiation therapy is particularly effective in localised MZL , especially MALT lymphoma.⁴ The localised nature of many MZLs makes them ideal candidates for radiation therapy, which can precisely target affected areas while sparing surrounding healthy tissue.

Efficacy of radiation therapy for marginal zone lymphoma

Extranodal marginal zone lymphoma (MALT Lymphoma)

MALT lymphoma is often localised at diagnosis, making it highly amenable to radiation therapy. Studies have shown high response rates and durable remissions with radiation therapy:

• Gastric MALT lymphoma: Radiation therapy achieves complete remission rates of up to 85% in patients younger than 60 and 60% in patients aged 60 or older.⁵ This is especially significant in cases resistant to antibiotic therapy aimed at eradicating H. pylori
• Ocular adnexal MALT lymphoma: Radiation therapy provides excellent local control with minimal side effects, preserving vision and eye function⁶
• Other sites: MALT lymphoma at sites such as the lung, thyroid, and salivary glands also responds well to radiation therapy, with cure rates almost at 100%⁷ 

Nodal marginal zone lymphoma (NMZL)

For NMZL, radiation therapy can be effective for localised disease. Although less common than MALT lymphoma, localised NMZL treated with radiation therapy shows good outcomes, with long-term remission and minimal toxicity.

Splenic marginal zone lymphoma (SMZL)

SMZL typically presents as a systemic disease involving the spleen and bone marrow, making localised radiation therapy less applicable. However, radiation therapy can be used palliatively to manage splenic symptoms or as part of a combined modality approach.

Treatment protocols and considerations

Combination therapies

Radiation therapy for marginal zone lymphoma is typically the primary treatment for certain types of non-Hodgkin lymphoma when detected early (stage I or II). For more advanced or aggressive lymphomas, radiation is often combined with chemotherapy. In cases where patients undergo stem cell transplants, whole-body radiation may be administered alongside high-dose chemotherapy to eliminate lymphoma cells throughout the body.

Additionally, radiation therapy can be utilised to alleviate symptoms (palliation) caused by lymphoma that has metastasized to organs like the brain or spinal cord or when a tumour exerts pressure on nerves, resulting in pain.

Radiation therapy can be combined with other treatments for enhanced efficacy:

• Antibiotic therapy: For gastric MALT lymphoma associated with H. pylori, antibiotics are the first line of treatment. Radiation therapy is used for antibiotic-refractory cases
• Chemotherapy and immunotherapy: For more advanced MZL, combination regimens with chemotherapy (e.g., rituximab-based therapies) can be used alongside or following radiation therapy

The radiation dose and fractionation schedule for MZL depend on the disease location and extent. Standard doses range from 24 to 30 Gy,⁸ delivered in daily fractions over several weeks. For highly localised MALT lymphoma, lower doses are sufficient.

Possible side effects

Side effects of radiation therapy are generally localised to the treatment area and may include:⁹

• Acute effects: Skin redness, fatigue, nausea, and localised pain, depending on the treated site
• Chronic effects: Long-term risks include fibrosis, secondary malignancies, and organ-specific damage (e.g., lung fibrosis in pulmonary MALT lymphoma)

Advances and research in radiation therapy for marginal zone lymphoma

Precision radiation techniques

Advancements in radiation technology have improved the precision and effectiveness of radiation therapy for MZL:

• Intensity-modulated radiation therapy (IMRT): Allows for precise dose distribution, minimising exposure to surrounding healthy tissues
• Proton therapy: Uses protons instead of X-rays, delivering maximum energy directly to the tumour with less impact on adjacent tissues
• Stereotactic body radiation therapy (SBRT): Delivers high doses of radiation to small, well-defined tumours in fewer sessions, increasing convenience and potentially improving outcomes

Personalised treatment approaches

Ongoing research is focused on personalising radiation therapy based on the genetic and molecular characteristics of the tumour. Biomarkers and genetic profiling can help predict response to radiation therapy and tailor treatment protocols for individual patients, enhancing efficacy and minimising toxicity.

Clinical trials and future directions

Numerous clinical trials are underway to evaluate novel radiation techniques and combination therapies for MZL. These studies aim to optimise treatment protocols, reduce side effects and improve long-term outcomes. One of which aims to understand if response-adapted, ultra-low dose radiation therapy can control MZL.¹⁰ This clinical trial aims to evaluate efficacy of response as well as recurrence rates and relapse at 24 months.

Additionally, another clinical trial led by MD Anderson has been investigating BTK inhibitors for the treatment of MZL. Patients with MZL are encouraged to consider participation in clinical trials, which provide access to cutting-edge treatments and contribute to advancing the field. 

FAQs

When should I see a doctor?

MZL are slow-growing and it usually takes patients years before experiencing symptoms. So, typically MZL is diagnosed as a secondary underlying disease when a patient is referred or tested for another medical diagnosis. Health check-ups are therefore an important part of the best way to diagnose MZL and you should always seek advice from your healthcare provider.

How common is MZL?

MZL accounts for fewer than 2% in every 100 non-Hodgkin lymphoma cases.³ While nodal MZL can occur at any age, it is most commonly diagnosed in individuals over 50.

The exact cause of nodal MZL is often unknown. It is more frequently observed in people who have been infected with the hepatitis C virus and those with certain autoimmune conditions. However, the majority of people with these conditions do not develop MZL. MZL remains a rare disease.

Summary

Radiation therapy remains a cornerstone in the treatment of marginal zone lymphoma, particularly for localised MALT lymphoma. With high response rates and durable remissions, radiation therapy offers a vital option for patients and often with minimal side effects. Advances in precision radiation techniques and personalised treatment approaches continue to enhance the efficacy and safety of radiation therapy for MZL. Ongoing research and clinical trials promise to further improve outcomes, offering hope and improved quality of life for patients with this indolent but challenging lymphoma.

As our understanding of MZL evolves, so too will the strategies for its management. Radiation therapy, with its ability to precisely target malignant cells while preserving healthy tissue, will undoubtedly remain a pivotal component of treatment regimens for marginal zone lymphoma.