Introduction

Marginal Zone Lymphoma (MZL) is a type of slow-growing B-cell non-Hodgkin lymphoma. It is classified into three subtypes based on its location: nodal, splenic, and extranodal (MALT lymphoma). These subtypes share similar characteristics but differ in their clinical presentation and behaviour. MZL arises from B-lymphocytes in the marginal zone of secondary lymphoid follicles and often expresses markers like CD19, CD20, and CD22. MZL typically lacks CD5, CD10, and CD23 markers, unlike other lymphomas. Each subtype has unique features: splenic MZL often involves the spleen and blood, nodal MZL affects lymph nodes, and extranodal MZL can involve various organs, especially the stomach. Generally, MZL has a slow progression and a favourable prognosis compared to more aggressive lymphomas.

Understanding the causes and risk factors of MZL is important for several reasons. Firstly, it helps in early detection and diagnosis, essential for effective management and better patient outcomes. Identifying genetic and environmental factors can lead to targeted therapies that improve treatment efficacy and reduce side effects. Additionally, recognising risk factors can help prevent and monitor high-risk populations. Knowledge about the causes of the MZL disease process also contributes to the broader understanding of lymphoma biology, which can help develop new therapeutic strategies and improve overall patient care.

Understanding lymphoma

Lymphoma is a type of cancer originating in the lymphatic system, part of the body’s immune system. The lymphatic system includes lymph nodes, the spleen, the thymus gland, and bone marrow. Lymphomas are broadly categorised into two main types: Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL). They differ based on the specific characteristics of the cancer cells involved. Non-Hodgkin lymphomas are more diverse and can occur in various body parts, while the presence of Reed-Sternberg cells marks Hodgkin lymphoma.

The nature of lymphoma involves the malignant transformation of lymphocytes, a type of white blood cell. This transformation disrupts normal lymphocyte functions, leading to uncontrolled cell growth and the formation of tumours in lymphoid tissues. The disease can present with symptoms like swollen lymph nodes, fever, night sweats, and weight loss. The progression and treatment of lymphoma vary widely depending on the type, stage, and specific characteristics of the cancer cells.

Lymphocytes, specifically B and T cells, play a crucial role in developing lymphoma. Lymphomas often arise from genetic mutations in these lymphocytes, leading to their uncontrolled proliferation. For instance, marginal zone B-cell lymphomas originate from B lymphocytes located in specific regions of lymphoid tissues, such as the spleen, lymph nodes, and mucosa-associated lymphoid tissue (MALT). These lymphomas are typically associated with chronic antigenic stimulation from infections or autoimmune conditions.^1,2​

Various genetic and environmental factors can drive the malignant transformation. For example, chromosomal translocations, such as the t(11;18)(q21;q21) translocation in MALT lymphomas, lead to the activation of oncogenes that promote cancer growth. In addition, infections like Helicobacter pylori in gastric MALT lymphoma or hepatitis C virus in splenic marginal zone lymphoma can contribute to the oncogenic process by providing continuous antigenic stimulation.^1,2

Overall, the abnormal behaviour of lymphocytes, including their proliferation and evasion of normal regulatory mechanisms, is fundamental to the pathogenesis of lymphoma. Understanding these processes is essential for developing targeted therapies and improving patient outcomes.

Causes of marginal zone lymphoma

General causes

DNA mutations are crucial in cancer development, including marginal zone lymphoma. These mutations can disrupt normal cell functions, leading to uncontrolled cell growth. The development of lymphoma typically requires multiple mutations. A single mutation may initiate the process, but additional mutations accumulate over time, further disrupting cellular controls and promoting malignancy. This multi-step process often involves genes regulating cell growth, apoptosis, and DNA repair, highlighting the complex nature of cancer development.

Specific causes

1. Gastric MALT Lymphoma

Gastric MALT (mucosa-associated lymphoid tissue) lymphoma is closely linked to infection by Helicobacter pylori, a bacterium that causes stomach ulcers and indigestion. When H. pylori infects the stomach lining, it leads to chronic inflammation and triggers lymphoid tissue formation. This constant immune response can cause genetic mutations in B cells, leading to lymphoma. In many cases, treating the H. pylori infection can cause the lymphoma to regress, highlighting the strong connection between the infection and lymphoma development.^2,3

2. Autoimmune Diseases

Sjögren's syndrome is an autoimmune disease that primarily affects the salivary glands, causing dry mouth and eyes. This condition can lead to the development of MALT lymphoma in the salivary glands. Chronic inflammation from the autoimmune response can bring about genetic changes in the B cells within the glands, encouraging the development of lymphoma. Patients with Sjögren's syndrome are at higher risk because the persistent immune activation creates a beneficial environment for lymphoma.^2,3

3. Splenic Marginal Zone Lymphoma (SMZL)

Splenic marginal zone lymphoma (SMZL) is related to Hepatitis C Virus (HCV) infection. HCV can cause chronic liver inflammation and systemic immune activation, which may contribute to developing lymphoma in the spleen. The virus stimulates the immune system, leading to genetic mutations and abnormalities in B cells, which can evolve into lymphoma. Patients with HCV-related SMZL often show immunological abnormalities like autoimmune haemolytic anaemia and immune thrombocytopenia, further linking chronic infection to lymphoma development.^2,4

Risk factors of marginal zone lymphoma

General concept of risk factors

Difference between causes and risk factors

• Causes: Directly result in the disease. For MZL, causes include infections like Helicobacter pylori for gastric MALT lymphoma.
• Risk Factors: Increase the likelihood of developing the disease but do not directly cause it. For example, autoimmune conditions like Sjögren's syndrome are risk factors for MZL.

Difference between increased likelihood and direct cause

• Increased Likelihood: Conditions or exposures that heighten the chance of developing MZL without being a direct cause. Chronic inflammation from infections or autoimmune diseases increases the likelihood.
• Direct Cause: Specific actions or agents that lead directly to MZL. Infections by Helicobacter pylori directly cause chronic inflammation, leading to MALT lymphoma.

Example

• Infection with H. pylori can directly cause MALT lymphoma by inducing chronic gastritis. However, autoimmune diseases like Sjögren's syndrome increase the risk of developing MZL due to sustained immune activation but are not direct causes.

Identified risk factors 

1. Extranodal Marginal Zone B-cell Lymphoma (EMZL)

Risk Factors: EMZL is often linked to infections, autoimmune diseases, and chronic inflammation⁵. Notably, specific bacterial infections significantly increase the risk of developing EMZL. H. pylori is a well-known risk factor for gastric MALT lymphoma, while Chlamydia psittaci and Campylobacter jejuni are associated with lymphoma in the ocular adnexa and intestines, respectively. Additionally, autoimmune conditions like Sjögren's syndrome heighten the risk, as does chronic inflammation over time.

Mitigation Strategies: Treating the underlying infections with antibiotics is crucial to limit these risks⁵. For instance, eradicating H. pylori can significantly reduce the incidence and progression of gastric MALT lymphoma. Additionally, managing autoimmune diseases effectively can help lower the risk of lymphoma. Regularly monitoring patients with known risk factors is essential for early detection and treatment.

• Splenic Marginal Zone Lymphoma (SMZL)

Risk Factors: SMZL is associated with immunological abnormalities and chronic infections⁴. Autoimmune conditions such as autoimmune hemolytic anaemia and immune thrombocytopenia are commonly seen in SMZL patients. Furthermore, chronic Hepatitis C Virus (HCV) infection is a significant risk factor⁶. Genetic factors, particularly mutations in the NOTCH2 gene, have also been implicated in SMZL⁷.

Mitigation Strategies: Managing HCV infection with antiviral therapy can significantly reduce the risk of developing SMZL⁶. Genetic counselling and regular screening are recommended for individuals with a family history of SMZL or relevant genetic mutations⁷. Regular blood tests are also crucial for monitoring and managing immunological abnormalities early⁴.

• Nodal Marginal Zone Lymphoma (NMZL)

Risk Factors: NMZL shares several risk factors with EMZL, including autoimmune conditions and chronic immune stimulation⁶. Genetic mutations, such as those in the PTPRD gene and the Jak/Stat signalling pathway, are also associated with NMZL⁷.

Mitigation Strategies: To limit NMZL risks, immunotherapy can help manage underlying autoimmune conditions⁷. Early identification of genetic predispositions through genetic screening can guide personalised monitoring and intervention strategies. Additionally, managing chronic inflammation through medication and lifestyle changes can reduce the risk⁸.

Conclusion

MZL encompasses several subtypes associated with specific causes and risk factors. Key causes include genetic mutations and chronic infections like Helicobacter pylori for gastric MALT lymphoma and Hepatitis C Virus for splenic marginal zone lymphoma. Autoimmune conditions, such as Sjögren's syndrome, also elevate the risk of MZL. Understanding these factors is crucial for early detection and effective management. Awareness and regular monitoring, especially in high-risk individuals, are essential for improving outcomes. Managing infections, autoimmune diseases, and chronic inflammation through targeted therapies and lifestyle changes can significantly limit risks, highlighting the importance of proactive health management.