Clinical management of gastric mucosa-associated lymphoid tissue lymphoma

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Korean J Intern Med. 2025;.kjim.2024.143

Publication date (electronic) : 2025 December 23

doi : https://doi.org/10.3904/kjim.2024.143

Ji Yong Ahn

Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea

Correspondence to: Ji Yong Ahn, M.D., Ph.D., Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Korea, Tel: +82-2-3010-5667, Fax: +82-2-476-0824, E-mail: ji110@hanmail.net, https://orcid.org/0000-0002-0030-3744

Received 2024 April 27; Revised 2025 April 26; Accepted 2025 October 18.

Abstract

INTRODUCTION

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.

PATHOGENESIS 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.

DIAGNOSIS OF GASTRIC MALT LYMPHOMA

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].

Endoscopic findings of gastric MALT lymphoma

The endoscopic findings of gastric MALT lymphoma are extremely diverse, making it challenging to distinguish the lymphoma from early gastric cancer or benign gastric lesions such as atrophic gastritis or erosions. In previous studies, endoscopic findings were classified into four main types, of which large ulcer was the most common (42.9%), followed by small ulcer with gastritis (28.5%), polyps (14.3%), and other atypical forms (14.3%) [10]. Japanese studies have reported the ulcer form (33.3%), multiple erosions (23.4%), scar form (12.8%), and early gastric cancer IIc form (10.6%) [11]. In a Korean study, the findings were classified into raised, ulcer infiltration, early gastric cancer IIc, subepithelial tumor, and multiple-erosion types [12]. Consequently, careful observation and multiple biopsies of suspected lesions are necessary; repeated endoscopy and biopsy are also needed in some cases [12,13]. The various endoscopic findings of MALT lymphomas are shown in Figure 1.

Figure 1

Various endoscopic findings of gastric mucosa-associated lymphoid tissue lymphoma. (A) Ulcer-infiltrative type. (B) Early gastric cancer IIc type. (C) Subepithelial tumor type. (D) Multiple erosion type. (E) Scar type. (F) Polyp type. (G) Cobble stone type. (H) Mass type.

Histological analysis of gastric MALT lymphoma

Histological examination of the biopsy specimens is essential for a definitive diagnosis. Lymphoepithelial lesions are characteristic features of gastric MALT lymphoma, and the scoring system proposed by Wotherspoon et al. was used for the pathological diagnosis of the latter (Table 1) [14]. Gastric MALT lymphoma can be diagnosed if the histopathological changes correspond to a score of 5. If the score is 3 or 4, the diagnosis is confirmed based on the monoclonality of B cells using polymerase chain reaction [15]. However, these findings can be observed with inflammatory changes in the gastric mucosa; for an accurate diagnosis, evaluation by an expert pathologist is necessary [16]. Therefore, if gastric MALT lymphoma is endoscopically suspected, repeated biopsy and discussion with a pathologist should be performed, even if the histological results do not indicate MALT lymphoma in the initial examination. In some cases, endoscopic mucosal resection can be performed for a definite diagnosis that cannot be diagnosed using repeated forceps biopsy [17].

Table 1

Wotherspoon histologic scoring system for gastric MALT lymphoma

Staging workup of gastric MALT lymphoma

Gastric MALT lymphoma is often unaccompanied by symptoms and is limited to the primary lesion for a long period even after diagnosis. Furthermore, a long time is required before an improvement can be observed after H. pylori eradication therapy; therefore, neglecting the test for staging is easy. However, approximately 10%–25% of MALT lymphomas are diagnosed at advanced stages [18,19]. Therefore, it is imperative to evaluate the extent of disease to determine the appropriate treatment method. For the staging workup of gastric MALT lymphoma, other diagnostic modalities such as abdominal and pelvic computed tomography (CT), chest CT, and endoscopic ultrasound (EUS) are recommended in addition to endoscopic examination, histological confirmation, and H. pylori evaluation [16,20]. EUS can be used to assess the depth of tumor infiltration into the gastric wall and evaluate regional lymph node involvement. This modality provides valuable information for accurate staging and can guide the development of appropriate treatment strategies. Among the various staging systems for gastric MALT lymphoma, the Lugano system is mainly used in clinical settings (Table 2) [16]. For further workup, positron emission tomography (PET), bone marrow biopsy, or t(11;18) translocation examination can be performed in selected cases. Gastric MALT lymphoma typically presents as a small, slowly progressing primary lesion, which limits the utility of PET. Therefore, routine PET scanning is not recommended for all patients with gastric MALT lymphoma and can be considered when assessing the extent of the disease, particularly when local treatments such as radiotherapy are planned [21]. The frequency of bone marrow involvement in gastric MALT lymphoma is relatively low. Although bone marrow involvement is classified as a stage IV disease according to the clinical staging system, its impact on the clinical course remains unclear. Therefore, there is an ongoing debate regarding the necessity of routine bone marrow examination in all patients, and can be considered in those with advanced-stage disease or those who do not respond to H. pylori eradication therapy [21]. Genetic alterations are observed in a subset of gastric MALT lymphomas, and the presence of the t(11;18)(q21;q21) translocation is associated with more advanced disease stages and poor response to H. pylori eradication. Although testing for genetic alterations can help predict treatment response and prognosis, its utility is limited; therefore, routine testing is not recommended for all patients [21].

Table 2

Various staging systems of gastric MALT lymphoma

TREATMENT AND PROGNOSIS OF GASTRIC MALT LYMPHOMA

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].

CONCLUSIONS

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.

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