Introduction

Mucosa-Associated Lymphoid Tissue (MALT) lymphoma, also known as extranodal marginal zone lymphoma, is a rare form of non-Hodgkin lymphoma. MALT lymphoma is a slow-growing cancer of the B-lymphocytes, or B-cells, a type of white blood cell which works in your immune system. MALT lymphomas comprise 7-8% of B-cell lymphomas.⁸ MALT lymphoma usually develops in the lining of your stomach (gastric MALT), but can also occur in your lungs, skin, thyroid, salivary gland or near your eye (non-gastric MALT). All MALT lymphomas originate in the ‘mucosa’, the mucous membrane that acts as an inner lining of most organs and cavities in your body. Gastric MALT only arises in the stomach, while non-gastric MALT arises in other mucosal areas. The symptoms of MALT lymphomas vary depending on the lymphoma's location in the body. 

Gastric MALT lymphomas are strongly associated with the infectious trigger Helicobacter pylori (H.pylori) infection. H.pylori is the most common infectious agent linked to cancers globally and is responsible for 5.5% of all total cancer cases. While H. pylori is strongly linked to the development of gastric MALT lymphomas, other bacterial infections have also been recognised as potential infectious triggers of MALT lymphomas in other specific sites.⁴ Due to the high association of infectious triggers with the causation of MALT lymphoma, it is important to study and understand the regional variations in these infectious triggers.¹ 

Understanding MALT lymphoma

Gastric MALT lymphoma is the most common form of MALT lymphoma.

The clinical presentation of gastric MALT lymphoma varies and may include: nausea, vomiting, haemorrhage, chronic gastric bleeding with iron-deficiency anaemia, weight loss and abdominal pain.¹ 

Non-gastric MALT lymphoma can develop in the lungs, eyes, skin, thyroid and salivary glands. Symptoms of these MALT lymphomas vary depending on location. 

Role of infections in MALT lymphoma development

Infections have been linked to MALT lymphoma development. The chronic inflammation brought about by infections is thought to be a key factor in MALT lymphoma development. The chronic antigenic stimulation (stimulation of the immune system by the infecting pathogen) in these infections leads to lymphoid (B cell) proliferation and therefore drives lymphoma development. Genetic changes induced by chronic inflammation may also drive lymphoma development. 

Different infectious agents are linked to MALT lymphomas in different sites in the body. These infectious agents and the MALT lymphomas include: 

• Helicobacter pylori (H. pylori) and Gastric MALT lymphoma
• Chlamydia psittaci and Ocular adnexal MALT lymphoma
• Borrelia burgdorferi and Cutaneous MALT lymphoma
• Campylobacter jejuni and small intestine MALT lymphoma
• Achromobacter xylosoxidans and pulmonary MALT lymphoma

Regional infectious triggers

Gastric MALT lymphoma, 

Helicobacter pylori

Helicobacter pylori (H.pylori) is the most common infectious trigger of MALT lymphoma worldwide. Individuals with H. pylori gastritis (H.pylori infection) are at risk of developing gastric MALT lymphomas. The link between chronic H. pylori infection and gastric MALT lymphoma development was first noted in the early 1990s.⁷ Interestingly, around 75% of all gastric MALT lymphomas show regression following eradication of H. pylori.⁷ Though not all strains of H.pylori can trigger MALT lymphoma and cancer development requires specific conditions. A study showed 1 in 13 tested H.pylori strains could induce B-cell proliferation and lead to production of the cytokine IL-2 by T cells. Other bacteria tested, E.coli and Campylobacter jejuni, failed to stimulate B cell proliferation, highlighting that H.pylori has a specific effect linking it to cancer development. Further study highlighted that MALT lymphoma cells express high levels of the ligand APRIL, a cytokine which is important for sustaining B-cell proliferation. H. pylori and H. pylori specific T cells also express high levels of APRIL, which may aid B-cell proliferation and cancer development. Furthermore, H.pylori can translocate (move) a protein called cagA into B-cells, which leads to signalling inhibiting apoptosis (programmed cell death), thus preventing cell death, aiding cell proliferation. CagA-positive strains are more frequently seen in the more aggressive diffuse large B-cell lymphoma (DLBCL) PGL subtype than in low-grade MALT lymphomas.¹

Factors affecting carcinogenesis (the ability to trigger cancer development) of H. pylori infection include diet and obesity. Obesity increases the risk of H. pylori infection, and insulin resistance and high blood sugar are known co-factor risks in H. pylori-induced gastric carcinogenesis. High salt intake may also stimulate CagA expression.¹ 

The prevalence of H.pylori varies globally. The distribution of H.pylori has changed with improvements in sanitation and eradication methods. Africa has the highest prevalence, whilst Oceania has the lowest.² Prevalence ranges from as low as 18.9% in Switzerland to as high as 87.7% in Nigeria. In 2015, an estimated 4.4 billion people had a H.pylori infection globally. Over half the world's population is infected with H.pylori.² H. pylori prevalence is affected by: geographical location, socio-economic status, occupation, education, age and living conditions.¹ HP prevalence tends to be higher in developing countries than in developed countries.²

Ocular adnexal MALT lymphoma

Chlamydia psittaci 

Ocular adnexa MALT-lymphomas represent 5-15% of all extranodal lymphomas.⁴

Chlamydia psittaci is variably associated with ocular adnexal MALT lymphoma in different geographical regions.³ 

Studies from Italy highlighted that 87% of ocular adnexal MALT lymphoma cases had a Chlamydia psittaci infection, and some of these cases showed complete or partial lymphoma regression following C.psittaci eradication. However, C. psittaci infection is not linked with ocular adnexal MALT lymphoma in the USA. A study has highlighted how the prevalence of 

C.psittaci infection in MALT lymphoma shows variation across six different geographical regions.

Results showed the highest association of C. psittaci infection and MALT lymphoma was in Germany (at 47%), followed by the East Coast of the USA (35%) and the Netherlands (29%). While association was lower in Italy (13%) and the UK (12%).³ This study highlighted that the association of C.psittaci and MALT lymphoma shows variable frequency dependent on geographic area.⁴ This variable frequency of association means therapeutic strategies may vary across different geographical locations.⁴

C.psittaci may lead to Ocular adnexa MALT-lymphomas, as bacterial infection can cause clonal selection on induced MALT with subsequent lymphoma development. C.psittaci may also promote chromosomal aberration. The most common translocation (moving of parts of chromosomes) described in MALT lymphomas affects the NF-kB pathway with a substantial antiapoptotic effect (preventing cell death).⁴ 

Cutaneous MALT lymphoma

Borrelia burgdorferi 

Borrelia burgdorferi (B.burgdorferi) is a bacterial species known as one of the causative agents of Lyme disease. B.burgdorferi infection may play a role in Cutaneous MALT lymphoma development. Cutaneous (skin) MALT lymphoma may arise following B.burgdorferi infection due to constant stimulation of lymphoid tissue in the skin due to infection.⁵ Similar to how H. pylori stimulates gastric MALT lymphoma development, chronic antigen immunostimulation leads to sustained lymphoid proliferation.⁶ Variations in the prevalence of this bacterium in different regions affect the prevalence of this type of lymphoma. As B.burgdorferi infection is associated with Lyme disease, studies have observed a correlation of Lyme disease incidence with cutaneous MALT lymphoma incidence.¹²

Small intestine MALT lymphoma

Campylobacter jejuni (C.jejuni), a common cause of diarrhoea, may play a role in triggering MALT lymphoma in the small intestine as C.jejuni infection may trigger immunoproliferative small intestinal disease, a known prototype of MALT lymphoma. Immunoproliferative small intestinal disease is more common in the Middle East and North Africa. The disease remains endemic to a limited geographical area, specifically the Mediterranean basin, Middle East, and North Africa. The disease is linked to poor sanitation and rarely occurs in more developed countries.¹¹ However, due to the often short infection time observed with C.jejuni, other factors, such as an immunocompromised host, may be required for disease development with C.jejuni, as most individuals will not experience a chronic infection sufficient to induce immunoproliferation.⁷ 

Other associations

The development of the disease in MALT lymphoma may also be linked to infection with other risk factors, including hepatitis B virus, human immunodeficiency virus (HIV), Epstein-Barr virus (EBV), and human T-cell lymphotropic virus type 1.¹ The bacteria, Achromobacter xylosoxidans, are potentially associated with pulmonary (lung) MALT lymphoma. One study highlighted how Achromobacter xylosoxidans prevalence was significantly higher in those with MALT lymphoma than in controls across various European countries. But whether the significant association of A. xylosoxidans with pulmonary MALT lymphoma is linked to a causative effect has yet to be determined.⁸ Some studies have linked Hepatitis C virus infection with MALT lymphoma development, though other studies have contradicted this and found no link between the two.⁹ Therefore, it is currently unknown if a link exists, but a study has implicated Hepatitis C may increase cancer relapse rate and worse progression-free survival in Ocular adnexal MALT lymphoma.¹⁰

Factors driving regional variation

Infectious disease prevalence patterns

Different infectious diseases have varying prevalence across different geographic regions. Other environmental factors that may influence prevalence include socio-economic status, occupation, sanitation, education level, diet, antibiotic use, access to healthcare for diagnosis and treatment, etc. These factors influence exposure risk to a certain pathogen and may impact the pathogens ability to trigger lymphoma development. For example, H.pylori is more common in areas with poor sanitation, and infection may last longer if individuals are unable to access treatment.¹³

Genetic susceptibility of populations

The genetic susceptibility of populations may also account for the variations seen in the association of specific infectious triggers with MALT lymphoma development. Genetic susceptibility to developing lymphoma following infection means you have genes which make an infection more likely to trigger lymphoma. Alterations in genes controlling immune and inflammatory response, and alterations affecting DNA repair or leading to an immunocompromised host, could all help promote lymphoma development following infection.^14,13

Summary 

MALT lymphoma frequently originates from chronic inflammation. An association between MALT lymphoma and several distinct bacteria species has been confirmed. These different bacterial species are linked to several distinct anatomical sites of MALT lymphoma.⁸ Notably, H.pylori infection is linked to gastric MALT lymphoma; other examples include: Chlamydia psittaci with Ocular adnexal MALT lymphoma and Borrelia burgdorferi with Cutaneous MALT lymphoma. These infectious triggers show regional variation linked to variations in disease prevalence across different geographical areas and other environmental and host factors.