Study of Gastric MALT Lymphoma: From Treatment to Biology

Mucosa-assocaited-lymphoid tissue (MALT) lymphoma of stomach is the most common extranodal lymphomas of humans. Gastric MALT lymphoma, with its relatively high incidence of occurrence and its unique clinicopathologic features, has recently become an important target of cancer research. Gastric MALT lymphoma is classified into high-grade (HG) and low-grade (LG) subtypes by histological criteria. In the past decade, important consensus has been reached in the management of LG gastric MALT lymphoma. This includes eradication of H pylori as a first step of treatment, followed by radiotherapy, surgery, systemic chemotherapy, or immunotherapy for H pylori -independent cases.

However, the management of HG gastric MALT lymphoma is much less clear; controversies exist regarding the role of H pylori eradication and the efficacy of systemic chemotherapy. It was once a central dogma that transformation of LG MALT lymphoma into HG MALT lymphoma is associated with acquisition of H pylori-independence of MALT lymphoma cells. However, we and other investigators have provided evidence that a substantial portion of the early-stage HG gastric MALT lymphomas remain H pylori -dependent, and thus can be rendered long-term remission by H pylori eradication.

Although the tumor response to H pylori eradication is almost as good as its LG counterpart, HG gastric MALT lymphoma has carried a risk of rapid disease progression if the tumors are not responding to antibiotics. Therefore, identification of cellular or molecular markers that help predict the H pylori-independence state of HG gastric MALT lymphoma is mandatory. We hypothesized that the molecular mechanisms of H pylori-independence may be different between LG and HG gastric MALT lymphoma. For example, t(11;18) (q21;q21), one of the most important predictor of H pylori -independence in LG gastric MALT lymphoma, is rarely found in its HG counterpart. This study aims to identify molecular and cellular markers, as well as gene expression profiles, which may help predict H pylori-dependence state of HG gastric MALT lymphoma. Further clarification of the biologic significance and function of novel H pylori-independence-relevant genes will be performed.

In general, the prognosis of patients with HG gastric MALT lymphoma appears adversely correlated with the proportion of large cell component in their tumor tissues. However, how MALT origin will affect the response of the HG lymphoma to chemotherapy is largely unknown. We have reported that HG gastric lymphoma with evidence of MALT (DLBL-M) respond better to systemic chemotherapy than HG gastric lymphoma without any evidence of MALT (DLBL). This finding has strongly supports that DLBL-M and DLBL are distinct entities of lymphoma. However, whether these two types of gastric lymphomas may be of different cellular origins or different tumor biologic characteristics needs to be further clarified. In this study, we will continue our effort in identification novel biomarkers that help us actually predict the chemotherapy response and the prognosis of HG gastric lymphoma and thereby to improve the care of these patients. Further clarification of the difference of molecular mechanisms and biologic significance in the DLBL and DLBL-M of stomach will be done.

Part IA. Identification of molecular, and cellular markers that may help predicts H pylori-independence state of HG gastric MALT lymphoma.

LG gastric MALT lymphoma is characterized by its closely association with H pylori infection; and eradication of H pylori by antibiotics cures 50-70% of this tumor. Recently, we have clearly demonstrated that early-stage HG gastric MALT lymphoma is as H pylori-dependent as LG gastric MALT lymphoma. We had prospectively treated 24 patients with stage IE HG gastric MALT lymphoma. Eradication of H pylori was achieved in 22 patients and was accompanied by rapid and complete tumor regression in 14 patients. After median follow-up of more than 5 years in complete responders, all these 14 patients remained disease free. The response was not affected by the proportion of large cells in the tumor tissues, but was adversely affected by the depth of tumor invasion.

t(1;14)(p22;q32) is another genetic aberration implicated in the development of MALT lymphoma. t(1;14)(p22;q32) juxtaposes BCL10 of chromosome 1 to an immunoglobulin gene locus of chromosome 14, and results in strong expression of a truncated BCL10 protein in the nuclei and cytoplasm, in contrast to the weak cytoplasmic expression of BCL10 in normal germinal center B cells. It is noteworthy that t(1;14)(p22;q32) was detected in less than 5% of low-grade gastric MALT lymphomas, whereas moderate nuclear expression of BCL10 was found in 30% to 40% of these tumors. In contrast, BCL10 nuclear expression was found to be more closely associated with the genetic aberration t(11;18)(q21;q21) and advanced tumor stages, two of the conditions predictive of H pylori–independent status in LG gastric MALT lymphoma.

Later, BCL10 was found to express in the cytoplasm of B-lymphocytes to relay the signals from antigen receptors to NF-kB activation. As NF-kB is known to mediate cell survival and anti-apoptotic signals, it has been speculated that its upregulation of BCL10 may contribute to the malignant transformation of H pylori-independent growth of MALT lymphomas.
We hypothesized that upregulation of BCL10 may trigger a constitutive NF-kB activation signal, and therefore contribute to antigen-independent growth and the progression of the gastric MALT lymphoma. Under this condition, expression patterns of NF-kB and BCL10 may be useful markers for predicting H pylori independence of HG gastric MALT lymphoma.

In this study, we compared the expression patterns of BCL10 and NF-kB in 14 H pylori–dependent and eight H pylori–independent HG gastric MALT lymphomas. The expression of BCL10 and NF-kB in pretreatment paraffin- embedded lymphoma tissues was evaluated by immunohistochemistry and confocal immuno-fluorescence microscopy. The presence of t(11;18)(q21;q21) was identified by a multiplex reverse transcriptase polymerase chain reaction of the API2-MALT1 chimeric transcript. In this study, we have demonstrated that aberrant nuclear expression of BCL10 was detected in seven (87.5%) of eight H pylori–independent and in none of 14 H pylori–dependent HG gastric MALT lymphomas (P< .001). All seven patients with nuclear BCL10 expression had nuclear expression of NF-kB, compared with only two of 15 patients without nuclear BCL10 expression (P < .002). As a single variable, the frequency of nuclear expression of NF-kB was also significantly higher in H pylori–independent tumors than in H pylori–dependent tumors (seven of eight [87.5%] v two of 15 [12.3%]; P < .002). The API2-MALT1 fusion transcript was detected in only one (12.5%) of eight H pylori–independent lymphomas.

This study have demonstrated that nuclear expression of BCL10 or NF-kB is highly predictive of H pylori–independent status in HG gastric MALT lymphoma, and coexpression of these two markers in the nuclei is frequent. Although nuclear BCL10 expression is highly correlated with the presence of API2-MALT1 fusion in LG gastric MALT lymphoma, it has been shown that nuclear expression of BCL10 may also be detected in some LG gastric MALT lymphomas without t(11;18)(q21;q21). These findings suggest that the direct interaction between BCL10 and API2-MALT1 fusion protein may not occur in most MALT lymphomas.

Given that t(11;18)(q21;q21) is rarely found in HG gastric MALT lymphoma, the mechanisms and biologic significance of the aberrant nuclear expression of BCL10 in these tumors are intriguing. Furthermore, the nuclear expression of NF-kB was closely associated with the aberrant nuclear expression of BCL10. Interestingly, the nuclear expression of NF-kB was also closely associated with the H pylori–independent status of HG gastric MALT lymphomas. These findings provided evidence that nuclear translocation of BCL10 or NF-kB is the pivotal molecular determinant of H pylori-independence in gastric MALT lymphoma. However, the molecular mechanisms and the biologic significance of nuclear translocation of BCL10 and NF-kB in MALT lymphoma remain obscure. Additional investigation of the molecular interaction and biologic consequences of nuclear translocation of BCL10 and NF-kB in gastric MALT lymphoma is needed.

Part IB. In search other immunologic markers that may help predict H pylori-independence state of HG and LG gastric MALT lymphoma.

In the early phases of this process, the proliferation response of MALT lymphoma is partly dependent on functional interactions between B and T lymphocytes. It has been demonstrated by in-vitro experiments that the growth and differentiation MALT lymphoma cells require CD-40 mediated signaling and Th-2 type cytokines. The dependence on T cells for growth of the malignant B-cell clones may explain the tendency of early-stage LG MALT lymphomoma to remain localized and to regress after H pylori eradication. Expression of co-stimulatory molecules (CD40, CD80, CD86, and their ligands) and relevant cytokines has been demonstrated in gastric MALT lymphoma cells. The presence of co-stimulatory marker CD86 (B7.2) on lymphoma cells may promote T-cell-mediated neoplastic B cell proliferation. It is speculated that loss of co-stimulatory markers might preclude this interaction and thereby facilitate the transition into the antigen-independent status of HG gastric MALT lymphoma.

CD56 (+) natural killer (NK) cells are important components of the innate immune system, and have the ability to modulate both humoral- and cell-mediated immune responses. These CD56 (+) NK cells are speculated to have the ability to limit the autonomous growth of MALT lymphoma cells, and may contribute to the remission of HG MALT lymphomas after the eradication of H pylori. This study was conducted to examine the expression of CD86 and the infiltration of CD56 (+) NK cells in 16 H pylori-dependent and 10 H pylori-independent HG gastric MALT lymphomas.

We found that CD86 expression was detected in 11 (68.8%) of 16 H pylori-dependent cases but in none of 10 H pylori-independent cases (P = 0.001). H pylori-dependent HG gastric MALT lymphomas contained significantly higher numbers of CD56 (+) NK cells than H pylori-independent cases (2.8±1.4% vs 1.10.8%; P = 0.003). CD86 positive MALT lymphomas also showed significantly increased infiltration of CD56 (+) NK cells compared to CD86-negative cases (2.9±1.1% vs 1.4±1.3%; P = 0.005). These results suggest that the expression of co-stimulatory marker CD86 and the increased infiltration of NK cells are associated with H pylori-dependent state of early-stage HG gastric MALT lymphomas.


Part II. Identification of molecular, cellular markers and immunologic markers that may help predict H pylori-independence state of LG gastric MALT lymphoma without t(11;18)(q21;q21).

Although t(11;18)(q21;q21) is one of the most important predictors of H pylori- independence in LG gastric MALT lymphomas, only 50% to 70% of H pylori- independent LG gastric MALT lymphomas harbor this genetic aberration. In other words, 30-50% of H pylori-independent LG gastric MALT lymphomas have no reliable markers to predict their H pylori-independent status. Therefore, identification of other easily detected molecular markers that can provide high sensitivity in predicting H pylori -independent status of low-grade gastric MALT lymphomas without t(11;18)(q21;q21) is mandatory.

We have clearly clarified that nuclear translocation of BCL10 or NF-kB is the pivotal molecular determinant of H pylori-independence in HG gastric MALT lymphoma and that co-expression of these two markers in the nuclei is frequent. Since t(11;18)(q21;q21) rarely occurs in HG gastric MALT lymphomas, it is reasonable to speculate that nuclear translocation of BCL10 and NF-kB may also be useful for predicting H pylori-independent status of those LG gastric MALT lymphomas which lack t(11;18)(q21;q21). Therefore, this study was aim to examine whether these two markers can also predict H pylori-independent status of LG gastric MALT lymphomas without t(11;18)(q21;q21).

Sixty patients who underwent successful H pylori eradication for LG gastric MALT lymphomas were included. There were 37 patients with H pylori-dependent and 23 patients with H pylori-independent tumors. The median duration between H pylori eradication and complete histologic remission was 2.6 months (range, 0.9 to 17 months), and 34 of 37 (91.9%) patients did so within 12 months of H pylori eradication. At a median follow-up of 69.2 months (range, 12 to 124 months), 35 patients who had achieved complete histologic remission after eradication of H pylori were alive and free of lymphoma. Two patients experienced histologic relapse. Forty-seven (78.3%) patients were negative for t(11;18)(q21;q21); among them, 36 (76.6%) were H pylori-dependent and 11 (23.4%) were H pylori– independent . Nuclear expression of BCL10 was significantly higher in H pylori-independent than in H pylori-dependent tumors (8 of 11 [72.7%] vs 3 of 36 [8.3%]; P < .001). Nuclear expression of NF-kB was also significantly higher in H pylori-independent than in H pylori-dependent tumors (7 of 11 [63.6%] vs 3 of 36 [8.3%]; P < .001). Further, nuclear translocation of BCL10 and NF-kB was observed in 12 of the 13 cases with t(11;18)(q21;q21); and all these 12 cases were H pylori-independent.

This study indicate that nuclear expression of BCL10 or NF-kB is predictive of H pylori-independent status of LG gastric MALT lymphoma with or without t(11;18)(q21;q21). This finding implies that nuclear translocation of BCL10 and NF-kB may even be more specific than t(11;18)(q21;q21) in predicting H pylori-independence for gastric MALT lymphoma. Although this study did not examine other rare genetic aberrations that may relate to nuclear BCL10 expression, several recent studies revealed that t(1;14)(p22;q32) was detected in less than 5% of LG MALT lymphomas, suggesting that the latter genetic aberration is so rare that it may not be useful as a predictor. Since immunohistochemical staining for detection of BCL10 or NF-kB nuclear expression is not only specific and sensitive in predicting H pylori-independent status but also much more feasible for the daily practice of general pathology laboratories, it is an invaluable method to help select the best first-line treatment for patients with LG gastric MALT lymphoma.

We have clearly demonstrated that nuclear translocation of NF-kB is the pivotal molecular determinant of H pylori-independence in both HG and LG gastric MALT lymphoma. We also showed that the intranuclear BCL10/BCL3 complex appears to affect the transactivating activity of NF-kB. However, whether the NF-kB-down regulated genes (c-Myc, surviving, and BAFF) also contribute to the H pylori-independence of both HG and LG gastric MALT lymphoma, remain unclear. The c-Myc proto-oncogene has a central role in regulation of lymphoma cell growth and differentiation. Recent reports suggest that constitutive c-Myc expression stimulates angiogenesis and lymphangiogenesis, which may contribute to antigen-independent growth and progression of gastric MALT lymphoma. Survivin, which is a member of the inhibitor of apoptosis protein gene family, regulates both programmed cell death and mitosis. It has been shown that survivin expression and its subcellular localization both have prognostic value for patients with malignant disease. Another interesting gene is BAFF, a TNF superfamily members, has been found to be elevated in the survival of malignant B cells. Recent studies indicate that BAFF, producing by tumor cells and microenvironments, can result in unremitting NF-kB activation by forming a positive feed-back loop pathway.

Since NF-kB can induce c-Myc and survivin gene expression and BAFF expression, detection of nuclear expression of survivin, c-Myc, or BAFF can help us clarify the precise mechanisms of H pylori-independence in gastric MALT lymphoma. Our preliminary reports demonstrated that activation of NF-kB in lymphoma cells could result in upregulation of c-Myc, survivin, and TNF superfamily members BAFF. Further, nuclear translocation of survivin, expression of BAFF, and c-Myc expression were significantly associated with the H pylori-independent status of both HG and LG gastric MALT lymphomas.



Part III Further clarification of novel H pylori–independence-relevant genes of gastric MALT Lymphoma and their functions, molecular mechanisms and biologic significance

Recently, we have further clarified that nuclear translocation of BCL10 is the pivotal molecular determinant of H pylori-independence in both HG and LG gastric MALT lymphoma. This observation is revolutional in that it may lead to new directions of research in this field. However, the molecular mechanisms and the biologic significance of nuclear translocation of BCL10 in MALT lymphoma remain obscure, and is the focus of this study.

BCL10 contains a caspase recruitment (CARD) domain, and a C-terminal serine- and threonine-rich domain. Recent evidence indicates that upregulation of B-cell antigen receptor signaling triggers the activation of protein kinase C b and thereby results in phosphorylation of CARMA1 (also known as CARD11 or BIMP1), leading to BCL10 oligomerization. BCL10 then activates NF-kB by MALT1 and ubiquitin- conjugating enzyme-dependent IkB kinase ubiquitination. As NF-kB is activated, it translocates to the nucleus and results in the production of cytokines and growth factors that are important for cellular activation, proliferation and survival of B-cells. Further, there is a theoretical basis to speculate the involvement of NF-kB in mediating the translocation. This study was to test whether activation of NF-kB can result in the nuclear translocation of BCL10.

In this study, we observed that TNF-α upregulates the expression of BCL10 and induces a fraction of BCL10 nuclear translocation in MCF7 cells. Chromatin immunoprecipitation assays and electromobility shift assays identified that a NF-kB binding site resides in BCL10 5’-untranslated region. This study also demonstrates that Akt1, activated by TNF-α, phosphorylates BCL10 on Ser218 and Ser231, and the phosphorylated BCL10 subsequently complexes with BCL3 to enter the nucleus. Either inhibition of Akt1 or depletion of BCL3 blocks BCL10 nuclear translocation. These findings characterize a molecular linkage that directs BCL10 nuclear translocation in response to TNF-αtreatment.

Given that TNF-αitself induced not only increase of BCL10 but a fraction of BCL10 nuclear translocation. However, the mechanism by which the concentration of nuclear BCL10 is controlled remains unclear. Previous studies have demonstrated that the concentration of BCL3 may determine NF-kB transcriptional activity. Therefore, it is reasonable to speculate that an increasing amount of nuclear BCL10 and BCL3 might enhance NF-kB activity. Given that various cytokines, including TNF-α, are the downstream genes of NF-kB, and NF-KB is a mediator linking inflammation and tumor formation, the elevated NF-KB activity may be responsible for inflammation-associated tumor development and extracellular stimuli-independent tumor progression.

Taken together, these findings have provided evidence to elucidate a TNF-α-induced pathway by which BCL10 is upregulated and translocated into the nucleus. Whether our findings may be applied to other types of cells, such as inflammation-associated tumors, should be further investigated.

Part IV. Comparison of the clones of LG and HG MALT lymphoma on a background of their individual response to H pylori-eradication therapy of the co-existing HG and LG MALT lymphoma.

It is generally believed that HG MALT lymphoma is transformed from its LG counterpart; and that most patients have in their stomach the co-existence of these two conditions. However, recent studies comparing the patterns of clonal IgH rearrangement between HG- and LG-components of the same stomach have demonstrated the lack of a clonal relationship between these two components, suggesting that HG MALT lymphoma may evolve independently from co-existing LG lymphoma.

We have demonstrated that early-stage HG gastric MALT lymphomas, as well as their low-grade counterpart, may respond to antibiotics. We also clarified that nuclear translocation and co-localization of BCL10 and NF-KB are two molecular determinants of H pylori-independence of both HG and LG gastric MALT lymphomas. Further, the differential response of the co-existing HG and LG MALT lymphoma to H pylori–eradication therapy has frequently been observed in these patients. These findings have presented a strong argument that the HG transformation of gastric MALT lymphoma may not necessary lead to H pylori-independence. However, whether these two co-existing subtypes of MALT lymphoma in the same stomach may be of different cell origins, and thus have a different tumor response to H pylori-eradication, needs to be further clarified.

Among 26 patients with HG gastric MALT lymphoma, 18 containing laser capture microdissectable HG and LG MALT lymphoma cells co-existing in the same stomach were studied. The clonality of the LG and HG MALT lymphoma cells was examined by polymerase chain reaction (PCR)-based amplification of the CDR3 region of the IgH gene. Of 4 patients whose LG and HG components responded differentially to H pylori eradication therapy , three showed a different IgH gene rearrangement and a different pattern of BCL10 and NF-KB expression in the two components. In contrast, of the 14 patients whose co-existing HG and LG MALT lymphoma responded similarly to H pylori eradication (4 H pylori–independent, 10 H pylori–dependent), 12 showed single clonality and a similar pattern of BCL10 and NF-KB expression of the two components (P < .01).

Further, an API2-MALT1 fusion transcript was detected in the H pylori-independent LG part of only one patient with a differential response to H pylori eradication. These results imply that an H pylori–independent HG component may evolve independently from co-existing LG MALT lymphoma; and that the differential response of the co-existing HG and LG MALT lymphoma to H pylori eradication is primarily due to the different clonal origin of these two components of tumors.

Part V. Study of Treatment of H pylori-independent low-grade gastric MALT lymphoma: Is Inhibition of Inflammation-reaction TNF-αor NF-KB A Feasibility Strategy for Treatment of H pylori-independent low-grade gastric MALT lymphoma

Our data strongly suggest that activation of NF-KB pathway may be involved in the H pylori -independence transformation of MALT lymphoma. Recently, we demonstrated that oral thalidomide, an NF-KB and TNF-α inhibitor, induced rapid regression of a H pylori-independent, disseminated LG gastric MALT lymphoma, which showed nuclear expression of NF-KB. Therefore, we propose a proof-of-concept pilot study to evaluate the efficacy of oral thalidomide in H pylori-independent LG MALT lymphoma of the stomach with nuclear NF-KB expression.

Six patients with H pylori-independent LG gastric MALT lymphoma, and two patients with extra-nodal MALT lymphoma who had undergone chemotherapy or anti-CD2 were treated with doses of thalidomide (100-200 mg per day) until disease progression or prohibitive toxicity was observed. We have demonstrated that one patient with evidence of LG gastric MALT lymphoma and one patient with orbital LG MALT lymphoma achieved a complete response, and 4 patients (50%) achieved partial remission. This finding suggests that thalidomide has potential single-agent activity in patients with H pylori-independent MALT lymphoma or pretreated patients with MALT lymphoma.

Hopefully, identification of the molecules both upstream and downstream of BCL10, and elucidation of the interaction between BCL10 and NF-KB will be useful in designing novel therapeutics for gastric MALT lymphoma.

Gastrectomy is another choice for treatment of H pylori-independent LG gastric MALT lymphoma. However, the finding of widespread gastric MALT lymphoma cells within the gastric mucosa may result in the local relapse of the disease in cases with histologically tumor-positive resection margins following gastrectomy. Interestingly, we recent have reported that a disseminated H pylori-independent LG gastric MALT lymphomas have enjoyed long-term disease free after total gastrectomy and splenectomy. These findings further
reinforce the suggestion that the role of surgical resection in the treatment of LG gastric MALT lymphoma should be reassessed.

To investigate the role of gastrectomy in curing of LG gastectomy following the eradication of inflammation and immune reaction triggered by stomach environment. We retrospectively analyzed 8 LG gastric MALT lymphoma patients who had undergone the subtotal gastrectomy or total gastrectomy. The clonality of the laser capture microdissectable resection-margin, metastatic organs and primary lesions was evaluated by polymerase chain reaction (PCR)-based amplification of the CDR3 region of the IgH gene. We have demonstrated that three patients with positive resection-margin have enjoyed long-term disease free. Further, the clonality of resection margin was similar to the primary lesion of MALT lymphoma. These findings provided evidence that H pylori-related inflammation and immune reaction may play a role in the determination of H pylori-independent transformation of gastric MALT lymphoma


Part VI. Clarification of the molecular mechanisms and biologic significances in the different chemoresponse and prognosis between high-grade gastric MALT lymphoma and pure gastric diffuse large cell lymphoma without MALT

Diffuse large B-cell lymphoma (DLBCL) of stomach represents the most common extranodal non-Hodgkin’s lymphomas of humans. Gastric DLBCL is classified into diffuse large cell without MALT (DLBL) or with MALT lymphoma (DLBL-M) by histological criteria. Recently, our groups and other
investigators have demonstrated that systemic chemotherapy alone is a highly effective treatment for localized primary gastric DLBCL. Therefore, it is intriguing for us to further identify whether biomarkers may be used for predicting prognosis and chemoresponse of gastric DLBCL.

Recently, we have demonstrated that patients with DLBL-M patients have a significantly better response to chemotherapy and a better prognosis than patients with DLBL. Further, we have demonstrated that expression of cyclin D3 is associated with a poor response to systemic chemotherapy and a poor survival of the DLBL-M patients. In contrast to cyclin D3, the Bcl-2 expression was only independent prognostic factor for patients of DLBL. These findings imply that the some of biologic characteristics of MALT components, apoptosis-related genes, and the cell cycle protein are involved in the drug resistance and affect the clinical outcome gastric DLBCL (manuscript submitted).

Detailed molecular mechanisms and biologic significance needs to be further explored. Recent studies using a cDNA microarray demonstrate that nodal DLBCL can be divided into germinal center B cell-like (CGB) and non-GCB subgroups. This classification scheme has prognostic significance and can be replicated using immunohistochemical detection of CD10, BCL6, and MUM-1 to define germinal center (GC). Since MALT lymphoma arises from a post GC memory B-cell, the critical evaluation of CD10, BCL6, and MUM-1 to see whether this subclassification can be useful for predicting prognosis of gastric DLBCL is needed.

In this study, we will continue our effort in identification novel biomarkers that help us actually predict the chemotherapy response and the prognosis of gastric DLBCL and thereby to improve the care of these patients. We believe these predictive biomarkers can help select patients for specific treatments, and modulation of these genes expression may be a potential therapeutic strategy to improve clinical outcome in the future.



Future Perspectives

Based on the results we have in the past few years, we will focus on future research on the following four areas: (1) Further clarification of the molecular mechanisms and biologic significance of nuclear translocation of BCL10 and NF-KB. (2) Further exploration of the difference in the genetic expression of HG-transformation and H pylori-independence transformation of gastric MALT lymphoma. (3) Further clarification of the role of inflammation and immune reaction in H pylori-independence transformation of gastric MALT lymphoma. (4) Development of a perspective clinical study to test whether H pylori eradication can cure of early-stage gastric diffuse large cell lymphomas without MALT lymphoma. (5) Seek possible molecule targets to treat gastric diffuse large cell lymphomas without MALT lymphomas that are unresponsively to chemotherapy. (6) Basing on our research model of gastric MALT lymphoma, we will further explore the relationship and possible pathogenic mechanism of inflammation and gastric cancer and gastrointestinal lymphoma.

We believe this study will lead to better care of patients with gastric MALT lymphoma and diffuse large cell lymphoma, and the molecular mechanisms it unveils will further clarify the mechanism of tumor progression of malignancies related to H pylori and cure the cancer patient related to inflammation or other infections.