Gastric mucosa-associated lymphoid tissue (MALT) lymphoma, a subtype of non-Hodgkin lymphoma, arises from the MALT of the stomach. This indolent lymphoma is often associated with chronic Helicobacter pylori infection, a bacterium implicated in several gastric diseases. The discovery of the association between H. pylori and gastric MALT lymphoma has improved the management of this disease, indicating the importance of microbial factors in its pathogenesis and therapy [1]. Gastric MALT lymphoma is typically indolent and may remain localized in the gastric mucosa for extended periods.

Diagnostic and treatment strategies mainly focus on the identification and eradication of H. pylori, which can lead to complete remission in a significant proportion of cases. However, for H. pylori-negative cases or those unresponsive to eradication therapy, alternative therapeutic strategies such as radiotherapy and chemotherapy can be considered. In general, the prognosis for gastric MALT lymphoma is favorable, particularly when diagnosed early and managed appropriately [2]. This study aimed to provide updated information regarding the pathogenesis, diagnosis, treatment, and prognosis of gastric MALT lymphoma.

Gastric MALT lymphoma is closely associated with chronic H. pylori infection, although a subset of cases are independent of this bacterium. The pathogenesis of gastric MALT lymphoma is a multistep process involving both infectious and genetic factors, leading to the malignant transformation of lymphoid cells.

The pathogenesis of most gastric MALT lymphomas begins with H. pylori infection. Notably, H. pylori induces a local immune response in the gastric mucosa, leading to the recruitment and proliferation of MALT. A chronic inflammatory environment facilitates genetic mutations and acquisition of autonomic growth properties by lymphoid cells, eventually leading to lymphoma. Therefore, H. pylori eradication often leads to lymphoma regression, indicating the pivotal role of this infection in the early stages of lymphoma [3,4].

Other pathogenic mechanisms have been implicated in cases where the disease persists or recurs despite successful H. pylori eradication. Genetic alterations, including trisomies and translocations, such as t(11;18)(q21;q21), play crucial roles in treatment failure. These genetic events can activate oncogenes or deactivate tumor suppressor genes, thereby promoting the survival and proliferation of malignant cells independent of H. pylori infection [5].

The immune response to H. pylori infection can also contribute to the pathogenesis of gastric MALT lymphoma. Chronic antigenic stimulation by bacteria or other stimuli can lead to the unchecked clonal expansion of B cells. In addition, the tumor microenvironment, which is enriched in T cells and other immune cells, may contribute to the survival and proliferation of malignant B cells [6]. The interaction between H. pylori and gastric epithelial cells triggers molecular pathways that contribute to lymphomagenesis. Therefore, the CagA protein injected by H. pylori into the host cells can disrupt normal cellular functions and promote oncogenic activity [7]. Furthermore, the ongoing inflammatory response creates a background rich in cytokines and other growth factors, further supporting the growth of malignant lymphoid cells.

Patients may experience symptoms such as indigestion, nausea, heartburn, and gastrointestinal bleeding; however, some are asymptomatic and symptoms are often accidentally detected during endoscopy [8]. Endoscopic biopsy and immunochemical staining are the most important techniques for diagnosing gastric MALT lymphoma. Gastric MALT lymphoma mainly arises in the distal part of the stomach but can also occur in the proximal part or multiple areas; thus, it is important to perform biopsies in multiple locations [9].

The most important aspect of the treatment of gastric MALT lymphoma is the determination of the presence or absence of H. pylori infection. If the histological or rapid urease test results are negative, a urea breath test or serum antibody test should be conducted to identify false-negative infections [22]. In Lugano clinical stage I or II1 gastric MALT lymphoma, H. pylori eradication therapy is considered the first-line treatment, regardless of the presence of H. pylori infection.

In H. pylori-positive gastric MALT lymphoma, the complete remission rate is reported to be 60%–100% [23,24]. A recent Korean multicenter study reported that the 10-year survival rate of 1,163 patients with gastric MALT lymphoma was 99.1%, particularly in patients with low-stage and those with positive H. pylori infections [2]. In general, endoscopic and histological remission is achieved at an average of 3–6 months after eradication therapy; however, remission is often achieved even after 1 or 2 years; therefore, complete remission after treatment should be carefully decided [24,25]. In cases of failed H. pylori eradication therapy or even successful eradication but incomplete remission, additional treatments, such as radiotherapy or chemotherapy, can be considered.

In high-grade gastric MALT lymphoma, chemotherapy can be considered; however, the evidence for this remains unclear. Therefore, the “watch-and-wait” strategy or radiotherapy is mainly performed as additional treatments for gastric MALT lymphoma that does not respond to H. pylori eradication therapy [16,26]. The entire stomach and perigastric area are irradiated with a total of 30.6 Gy during 17 treatments, with a treatment success rate of 88%–100% and a 5-year progression-free survival rate of 90%–100% [27–29]. Acute side effects associated with radiotherapy include nausea, vomiting, and loss of appetite; however, most symptoms are mild and can be controlled with conservative treatment [28].

Although the mechanism of H. pylori-negative gastric MALT lymphoma remains unclear, some hypotheses such as the infection of Helicobacter strains, including Helicobacter heilmannii, the existence of t(11;18)(q21;q21) gene mutation, or autoimmune mechanism are being proposed [8,30]. The clinical symptoms of H. pylori-negative gastric MALT lymphoma are similar to those of H. pylori-positive MALT lymphoma, with indigestion and epigastric pain being the most common symptoms. Diagnostic evaluation and staging workup through endoscopic examination and biopsy should be performed similar to that in H. pylori-positive gastric MALT lymphoma; however, at least two diagnostic tests for H. pylori are recommended to exclude false-negative H. pylori infections [31].

The treatment success rate of H. pylori eradication therapy in H. pylori-negative gastric MALT lymphoma is 0%–83%; however, the treatment success rate is low when multiple lesions are found, tumor invasion is deeper than the submucosal layer, lymph node involvement is positive, and gene mutation of t(11;18)(q21;q21) is observed [31–33]. If there is no response to H. pylori eradication therapy, chemotherapy or radiotherapy can be considered as an additional treatment [34,35]. A Korean study reported that 57.1% of patients with H. pylori-negative gastric MALT lymphoma showed complete remission only after H. pylori eradication; this can be explained as the possibility of hidden H. pylori infection which was not properly diagnosed or other Helicobacter spp. that can induce gastric MALT lymphoma being removed by eradication therapy [25].

Gastric MALT lymphoma represents a unique model of malignancy in which chronic H. pylori infection plays a pivotal role in pathogenesis. Therefore, successful H. pylori eradication therapy alone can lead to a complete remission in many cases.

Endoscopic examination and biopsy are important for diagnosing gastric MALT lymphoma. However, the symptoms are nonspecific and the endoscopic findings are diverse; thus, careful endoscopic examination and sufficient biopsies are necessary for an accurate diagnosis. Gastric MALT lymphoma is closely associated with H. pylori infection in most cases, and remission can only be achieved with H. pylori eradication therapy. Radiotherapy for gastric invasion may be an effective treatment method for patients who fail to respond to H. pylori eradication therapy. Even after successful treatment, remission can take a long time; thus, follow-up examinations with endoscopy and biopsy should be considered.