As mentioned, MALT lymphoma and diffuse large B-cell lymphoma are as both indolent and aggressive features of PLG, respectively. Mucosal and non-mucosal organs in human body normally lack lymphocytes, and infiltration of B-cell lymphocytes occurs as a result of chronic inflammation or autoimmune diseases (particularly Hashimoto’s thyroiditis). Gastric MALT lymphoma is the most common marginal zone lymphoma [20, 46, 47]. Today, the role of H. pylori infection in the development of gastric MALT lymphoma has been well-described, and recent studies have shown that eradication infection in extranodal marginal zone B-cell lymphoma can lead to lymphoma regression in 60–90% of cases . The most likely hypothesis is that persistent infection with H. pylori can lead to inflammation and infiltration of lymphocytes into the stomach with persistent stimulation of the immune response, and active proliferation of B cells leads to the formation of lymph follicles and the onset of gastric MALT lymphoma . To date, several studies have attempted to investigate the association between cagA status and the development of gastric MALT lymphoma, but the results are unclear [34, 36, 37]. In addition, no comprehensive meta-analysis has been performed in this area; therefore, using the available evidence, we conducted the present meta-analysis to evaluate the exact role of the CagA antigen in the development of gastric MALT lymphoma.
Overall, we did not find a meaningful relationship between cagA status and gastric MALT lymphoma in Western countries. Interestingly, the present analysis showed an inverse association between cagA status and gastric MALT lymphoma risk in the Asian population (OR: 0.104; 0.036–0.307 with 95% CIs).
Previous studies indicated that early lymphomagenesis in lymphomas is a process related to CD4 + T cells stimulated by H. pylori antigens, and the proliferation of B-cell gastric lymphoma is dependent on CD40-mediated signaling, Th2 activities, co-stimulatory CD80, and CD86 [27, 50–53]. Hussel et al. (1993) in their studies showed that the reduction of infiltrating T cells can significantly disrupt the effect of H. pylori infection on tumor B-cell proliferation . Umehara et al. found that CagA could inhibit B-lymphoid cell proliferation by IL-3-dependent signaling by targeting the JAK-STAT pathway . Liu et al. (2001) showed that the API2–MALT1 chimeric transcript was observed in all cases of H. pylori-infected gastric MALT lymphoma . However, there is no correlation between H. pylori infection and the presence of API2–MALT1 . In general, the formation of gastric MALT lymphoma is based on the dependent and independent mechanisms of H. pylori infection; in H. pylori-dependent manner (in most cases), phosphorylated CagA inhibits p53 accumulation, whereas, in H. pylori-independent state, genetic aberrations leadto nuclear translocation of API2–MALT1 chimeric transcript and BCL10, and eventually gastric MALT lymphoma [29, 57].
Ohnishi et al. (2008) demonstrated the major role of CagA in the development of gastric and hematologic neoplasms . After transfer to B-cell lymphocytes via the type 4 secretory system (T4SS), CagA, through the formation of phosphorylated CagA-SHP-2 complex by affecting ERK1, ERK2, p38MAPKs, BCL2, and NF-κB, as well suppression of p53 accumulation or inhibition of the JAK-STAT signaling pathway, promotes lymphogenesis and immortalization of B-cell lymphocytes [29, 49, 59]. Evaluation of cagA status in patients with extranodal marginal zone B-cell lymphoma and DLBCL showed that this gene significantly increases the risk of developing DLBCL (OR: 6.43; 2.45–16.84 with 95% CIs). Based on previous studies, the presence of cagA-positive H. pylori strains in patients with DLBCL is significantly higher than that in patients with extranodal marginal zone B-cell lymphoma . Unfortunately, no studies have yet examined the relationship between CagA and VacA in the development of gastric MALT lymphoma, but VacA induces apoptosis by forming a vacuole and release of cytochrome c from mitochondria and appears to inhibit the development of gastric MALT lymphoma [60, 61]. The role of VacA in gastric MALT lymphoma is also controversial, and in one study, Miehlke et al. (1998) showed that the level of the vacA s1m1 genotype in gastric MALT lymphoma patients is high; however, Doorn et al. (1999) rejected this hypothesis [39, 62]. Although we could not assess the correlation between cagA and vacA, we observed an inverse association between the vacA genotype and gastric MALT lymphoma (OR: 0.92; 0.57–1.50 with 95% CIs). Although vacA is a potent immune gene, given the fact that this protein causes apoptosis, it does not appear to play a significant role in the development of gastric MALT lymphoma [63, 64]. In general, the most likely hypothesis to describe the role of H. pylori in the development of gastric MALT lymphoma is that this bacterium (CagA-dependent or independent) causes chronic gastritis, resulting in the production of IL-8 and other molecules associated with neutrophil chemotaxis. Neutrophil activation leads to destruction of the gastric mucosa and close contact of CD4 + T cells with H. pylori, where the activity of DC and CD4 + T cells causes B cells to mature. Continuous stimulation and proliferation of B-cell lymphocytes leads to the formation of lymph follicles, in which case the patient with PGL develops to DLBCL. In other words, no H. pylori eradication, particularly cagA-positive strains, leads to the translocation of CagA into B cells. Intracellular CagA causes DNA and microRNA damage by reactive oxygen and nitrogen species (RONS), inhibition of p53, and chromosomal translocation, and ultimately the development of DLBCL (Fig. 4).
Our study had several limitations including: I) low sample size, II) evaluation of only English studies, III) high heterogeneity in some cases, IV) inaccessibility to the raw data to find out EPIYA motifs CagA, as well as correlation between CagA and VacA, V) the lack of a sensitivity analysis. The results of the study are unstable under the influence of significant heterogeneity, and more research is needed to confirm the current findings.