Marginal zone lymphoma (MZL) is a rare type of slow-growing non-Hodgkin lymphoma, a type of cancer that develops within the lymphatic system.¹ The interplay between MZL and autoimmune diseases underscores the pathophysiology of this condition. Therefore, an increased understanding of their biological connection may hold the key to future therapeutic development. 

B cells: a double-edged cell? 

B cells are found within the marginal zones of lymphoid tissues and are a key component of the adaptive immune response. Under normal conditions in the body, B cells are a key defensive component of the immune system, regulating antibody production and various downstream inflammatory pathways.

However, in the context of MZL, B cells are the source of malignancy, leading to decreased immune function and the onset of autoimmunity. Marginal zone lymphoma originates from B cells within the marginal zone of secondary lymphoid tissues. Secondary lymphoid tissues include the spleen and lymph nodes, and immune cells are normally activated.

What is marginal zone lymphoma (MZL)?

Origins of MZL 

Primary lymphoid organs include the bone marrow and the thymus where B and T lymphocytes are produced. In contrast, secondary lymphoid organs are where lymphocytes develop and include the lymph nodes, the spleen, and tissue in mucous membrane layers in the body. Secondary lymphoid organs contain two key zones known as the mantle zone and marginal zone, where the marginal zones wrap around mantle zones. MZL is derived from mutations to B-cells in the marginal zone, which consists of the external part of the secondary lymphoid follicles. 

Subtypes of MZL

There are three distinct subtypes of marginal zone lymphomas; nodal, splenic, and extranodal.⁸ These three subtypes all share common deregulated pathways, however, they also have specific alterations which enable differentiation between them. They differ significantly in their primary sites of involvement, clinical presentations, and treatment approaches. 

Nodal MZL 

Nodal MZL is distinguished from other subtypes of MZL by its primary involvement of lymph nodes and usually does not involve extranodal tissues or the spleen. 

Splenic MZL 

Splenic MZL originates from marginal zone B-cells in the spleen, a small organ part of the lymphatic system which is located inside the left rib cage. 

Extranodal MZL 

Extranodal MZL is the most common form of marginal zone lymphoma, also accounting for 5 to 8% of all B-cell lymphomas.³ Extranodal MZL involves the development of lymphomas in the mucosa-associated lymphoid tissue (MALT). MALT lymphoma starts in the mucosa which lines the body’s organs and cavities.² This can be further divided into gastric MALT and non- gastric MALT.

Gastric MALT has a greater prevalence than non-gastric MALT, and involves the development of lymphoma in the lining of the stomach, In contrast, non-gastric MALT consists of the development of the skin, lungs, and glands. 

Symptoms of MZL 

MZL is often asymptomatic and indolent in the early stages, meaning it progresses slowly and is associated with little or no pain. However, as MZL progresses symptoms can present depending on the subtype. For example, nodal MZL is often presented clinically as painless lymphadenopathy (enlarged lymph nodes) which can be accompanied by weight loss, night sweats and fatigue.

Clinically, splenic NZL presents as Splenomegaly (enlarged spleen). As a consequence, patients may experience abdominal discomfort or fullness, cytopenias (low blood cell counts), and symptoms related to anaemia or thrombocytopenia. Extranodal MALT presents symptoms related to mucosa-associated lymphoid tissues such as stomach discomfort. 

Epidemiology and prevalence of MZL 

Marginal zone lymphomas are the second most common lymphoma, comprising 7% of all non-Hodgkin lymphomas with 7,460 people diagnosed in the USA in 2016.³ Worldwide, the incidence of MZL varies between 0.5 and 2.92 cases per 100,000 person-years.⁵

Extranodal MALT MZL is the most commonly presented, at 61%, followed by nodal MZL at 30% and with 9% of MZL being splenic. Incidence rates were slightly higher in persons assigned male at birth for SMZL and NMZL, but similar for EMZL, and increased steeply with age for all MZL subtypes.⁵ 

Autoimmune diseases 

Autoimmune diseases are characterised by proteins called auto-antibodies that target the body’s healthy tissues, signalling for the body’s immune system to attack them.⁴ 

Prevalence of autoimmune diseases in people with MZL

The increased risk of B-cell non-Hodgkin lymphoma in people with autoimmune diseases has been established.⁶ In recent studies, data on the coexistence of autoimmune diseases and MZL has emerged. In one such study, 50% of MZL patients had a coexisting autoimmune condition. In addition, 3 of 24 people presented with more than one autoimmune disease.⁶ 

The link between autoimmune diseases and MZL pathophysiology

Autoimmune diseases can contribute to the development of MZL through various mechanisms including chronic immune stimulation, genetic and epigenetic changes, pro-inflammatory cytokine environments, immune dysregulation, infection-driven lymphomagenesis, and genetic predisposition.

Prolonged and chronic immune stimulation

Persistent B-cell activation and proliferation increases the likelihood of genetic mutations during B-cell replication, which can in turn lead to malignancy and development of MZL. In Sjögren’s syndrome, chronic inflammation of salivary and lacrimal glands leads to continuous activation and proliferation of B cells, raising the risk of developing MZL, particularly in the salivary glands.

Cytokine environment 

Autoimmune conditions cause elevated levels of pro-inflammatory cytokines such as TNF-alpha, IL-6, and IL-1. These cytokines promote B-cell survival, and proliferation, and enhance resistance to apoptosis which in turn promotes malignancy. In rheumatoid arthritis, high levels of TNF-alpha and IL-6 not only perpetuate joint inflammation but also contribute to a microenvironment that supports lymphoma development.

Dysregulated immune surveillance

Dysregulated immune surveillance, allows abnormal B cells to escape detection and proliferate unchecked. Systemic lupus erythematosus (SLE) is characterised by immune dysregulation that can impair the immune system's ability to detect and destroy malignant cells, increasing the risk of lymphoma.

Infection-driven lymphomagenesis

Autoimmune diseases can be associated with chronic infections that contribute to continuous immune stimulation and inflammation. Chronic Hepatitis C virus (HCV) infection is linked to both Splenic MZL and Autoimmune conditions, with the virus providing a persistent antigenic stimulus that drives B-cell proliferation and increases the risk of lymphoma.

Autoimmune-associated gene mutations

Genetic mutations affecting genes involved in immune regulation and B-cell function can cause a predisposition to both autoimmunity and MZL. Mutations leading to the abnormal proliferation and survival of B-cells within the marginal zones of lymphoid tissues cause B-cells to become malignant and are associated with the onset of MZL. NOTCH2 is frequently mutated in Splenic MZL, affecting the downstream NOTCH signalling pathway to increase B cell survival and proliferation.

BIRC3 mutations are also commonly associated with splenic MZL, affecting the NF-κB signalling pathway, which is crucial for B cell survival. Similarly, the NF-κB pathway is also involved in nodal and extranodal MALT MZL, following a loss of function mutation in TNFAIP3. These mutations are seen in both autoimmune diseases and MZL, highlighting a clear genetic link.

Diagnosing MZL

Diagnosis involves a multistep process including clinical evaluation, imaging studies, laboratory tests, and pathological examination.¹¹ A physical examination is often conducted first to check for enlarged lymph nodes and spleen, which is characteristic of MZL. Following physical examination, various imaging studies are conducted to aid in characterising and staging the disease.

Computed Tomography (CT) Scan is commonly used to assess the extent of lymphadenopathy. Positron Emission Tomography (PET) scan helps in staging the disease by detecting metabolically active lymphoma cells. Ultrasound is used to evaluate splenomegaly.

Magnetic Resonance Imaging (MRI) is used for detailed imaging following initial imaging. Blood tests are used to identify cytopenias and other disease markers such as elevated lactate dehydrogenase. In addition, Bone marrow biopsies are conducted to determine bone marrow involvement and to provide prognostic information.

Lymph Node Biopsy, followed by histopathology and immunohistochemistry to characterise MZL cells by appearance and specific markers. Molecular and Genetic testing can be used to differentiate MZL from other types of lymphomas as well as identify the mutations in genes attributed to the MZL. Screening for associated conditions including infectious diseases such as Helicobacter pylori, and Hepatitis C virus. In addition to screening for autoimmune conditions commonly associated with MZL, such as Sjögren’s syndrome and rheumatoid arthritis.¹¹

Clinical implications of autoimmunity on MZL

Impact of autoimmune diseases on diagnosis

Due to the link between MZL and autoimmune diseases, there is an increased requirement for screening for people with MZL with autoimmune diseases. In addition, people with MZL are also continuously monitored for autoimmune activity. 

Treatment approaches 

Treatment approaches include separate treatment of MZL and autoimmune conditions using conventional therapies. Conventional treatments for MZL include localised therapies which include radiation of affected areas, or surgery such as splenectomy for splenic MZL.

 Systemic approaches involve chemotherapy and immunotherapy, which are often paired together. The conventional ‘treatment’ of autoimmune diseases involves the management of symptoms by various strategies including immunosuppressant therapies such as corticosteroids to reduce inflammation.

Alternatively, a more personalised approach using an integrated treatment strategy can simultaneously address the pathophysiology of both conditions.³ Targeted therapy such as Rituximab, an anti-CD20 monoclonal antibody, is effective in treating both B-cell lymphomas like MZL and autoimmune diseases such as rheumatoid arthritis and Sjögren’s syndrome.⁹

Ibrutinib is an effective targeted therapy for refractory MZL and may also offer benefits in autoimmune conditions by modulating B-cell receptor signalling.¹⁰ Upcoming advances in medical research will continue to enhance the ability to manage these interrelated conditions effectively to improve the prognosis for people affected by MZL and autoimmune diseases. 

Summary 

• Marginal Zone Lymphoma (MZL) is a type of B-cell non-Hodgkin lymphoma that often arises in the context of chronic inflammation and autoimmune diseases 
• MZL can be divided into 3 subgroups; nodal, splenic and extranodal marginal zone lymphoma 
• Autoimmune diseases contribute to the development of MZL by creating a persistent inflammatory environment that stimulates B-cell proliferation and increases the risk of genetic mutations 
• Managing MZL amongst people with autoimmune diseases requires a comprehensive approach to integrated treatment strategies that address both the malignancy and the autoimmune condition
• Targeted therapies including rituximab and Ibrutinib are at the forefront of an integrated treatment approach which offers improved patient outcomes