scholarly journals Revisiting the Full Spectrum of Helicobacter pylori-Related Gastric Lymphoma

2021 ◽  
Author(s):  
Sung-Hsin Kuo ◽  
Kun-Huei Yeh ◽  
Chung-Wu Lin ◽  
Li-Tzong Chen ◽  
Ming-Shiang Wu ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
B Cells ◽  
B Cell ◽  
Malt Lymphoma ◽  
Early Stage ◽  
Gastric Lymphoma ◽  
Gastric Malt Lymphoma ◽  
Histological Features ◽  
Cytotoxin Associated Gene A ◽  
Src Homology 2 Domain

Early stage gastric diffuse large B-cell lymphomas (DLBCLs) with histological features of mucosa-associated lymphoid tissue (MALT) origin (DLBCL[MALT]) are also closely related to Helicobacter pylori (HP) infection, apart from the classical gastric MALT lymphoma, and are cured by HP eradication therapy (HPE). Whether some gastric “pure” DLBCLs (without histological features of MALT) are also HP-related is clinically very important, since this subtype of gastric lymphoma is relatively common in the population and is still universally treated with intensive systemic chemotherapy. A large proportion of early stage gastric “pure” DLBCL can achieve long-term complete remission after HPE. However, the precise mechanisms of HP-dependent (with complete regression of tumors after HPE) lymphomagenesis of gastric “pure” DLBCL, DLBCL(MALT), and MALT lymphoma remain uncertain. In the classical conception, gastric MALT lymphoma is indirectly caused by HP through T-cell stimulation, with the aid of costimulatory molecules. To explore the direct interactions between HP and lymphoma B-cells of HP-dependent gastric MALT lymphoma, DLBCL(MALT), and “pure” DLBCLs, we assessed the participation of HP-encoded cytotoxin-associated gene A (CagA) in the lymphomagenesis of these tumors. We discovered that CagA oncogenic protein and its regulated signaling molecules including phospho-Src homology-2 domain-containing phosphatase (p-SHP-2) and phospho-extracellular signal-regulated kinase (p-ERK) correlated significantly with HP-dependence of gastric MALT lymphoma. This finding supports previous observations that the CagA protein of HP can be translocated into B-cell lymphoma cells, thereby leading to survival signals. Furthermore, we demonstrated that HP-positive and CagA-expressing gastric “pure” DLBCLs behave in a less biologically aggressive manner, and have better clinical outcomes; this is a distinguishing entity, and its cell origin may include germinal center B cells. In addition, we found that the expression of CagA, p-SHP-2, and p-ERK correlated significantly with the HP-dependence of gastric DLBCL(MALT) and “pure” DLBCL. These findings indicate that the spectrum of HP-related gastric lymphomas including MALT lymphoma, DLBCL(MALT), and “pure” DLBCL, is much wider than was previously thought. Further explorations of the spectrum, lymphomagenesis, and therapeutics of HP-related gastric lymphoma are warranted.

scholarly journals MALT lymphoma: epidemiology, clinical diagnosis and treatment

2018 ◽  
Vol 11 (3) ◽  
pp. 187-193 ◽  
Author(s):  
Petruta Violeta Filip ◽  
◽  
Denisa Cuciureanu ◽  
Laura Sorina Diaconu ◽  
Ana Maria Vladareanu ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
B Cell ◽  
Malt Lymphoma ◽  
Cell Lymphoma ◽  
Gastric Lymphoma ◽  
Eradication Therapy ◽  
B Cell Lymphoma ◽  
Gastric Malt Lymphoma ◽  
H Pylori

Primary gastric lymphoma (PGL) represents a rare pathology, which can be easily misdiagnosed because of unspecific symptoms of the digestive tract. Histologically, PGL can vary from indolent marginal zone B-cell lymphoma of the mucosa-associated lymphoid tissue (MALT) to aggressive diffuse large B-cell lymphoma (DLBCL). During the years, clinical trials revealed the important role of Helicobacter pylori (H. pylori) in the pathogenesis of gastric MALT lymphoma. Infection with Helicobacter pylori is an influential promoter of gastric lymphomagenesis initiation. Long-term studies revealed that eradication therapy could regress gastric lymphomas.

scholarly journals Novel Insights of Lymphomagenesis of Helicobacter pylori-Dependent Gastric Mucosa-Associated Lymphoid Tissue Lymphoma

Cancers ◽  
2019 ◽  
Vol 11 (4) ◽  
pp. 547 ◽  
Author(s):  
Sung-Hsin Kuo ◽  
Ming-Shiang Wu ◽  
Kun-Huei Yeh ◽  
Chung-Wu Lin ◽  
Ping-Ning Hsu ◽  
...  
Keyword(s):  
T Cells ◽  
Helicobacter Pylori ◽  
B Cells ◽  
Gastric Mucosa ◽  
B Cell ◽  
Malt Lymphoma ◽  
Lymphoid Tissue ◽  
B Cell Lymphoma ◽  
Gastric Malt Lymphoma ◽  
First Line

Gastric mucosa-associated lymphoid tissue (MALT) lymphoma is the most common subtype of gastric lymphoma. Most gastric MALT lymphomas are characterized by their association with the Helicobacter pylori (HP) infection and are cured by first-line HP eradication therapy (HPE). Several studies have been conducted to investigate why most gastric MALT lymphomas remain localized, are dependent on HP infection, and show HP-specific intratumoral T-cells (e.g., CD40-mediated signaling, T-helper-2 (Th2)-type cytokines, chemokines, costimulatory molecules, and FOXP3+ regulatory T-cells) and their communication with B-cells. Furthermore, the reason why the antigen stimuli of these intratumoral T-cells with tonic B-cell receptor signaling promote lymphomagenesis of gastric MALT lymphoma has also been investigated. In addition to the aforementioned mechanisms, it has been demonstrated that the translocated HP cytotoxin-associated gene A (CagA) can promote B-cell proliferation through the activation of Src homology-2 domain-containing phosphatase (SHP-2) phosphorylation-dependent signaling, extracellular-signal-regulated kinase (ERK), p38 mitogen-activated protein kinase (MAPK), B-cell lymphoma (Bcl)-2, and Bcl-xL. Furthermore, the expression of CagA and these CagA-signaling molecules is closely associated with the HP-dependence of gastric MALT lymphomas (completely respond to first-line HPE). In this article, we summarize evidence of the classical theory of HP-reactive T-cells and the new paradigm of direct interaction between HP and B-cells that contributes to the HP-dependent lymphomagenesis of gastric MALT lymphomas. Although the role of first-line HPE in the treatment of HP-negative gastric MALT lymphoma remains uncertain, several case series suggest that a proportion of HP-negative gastric MALT lymphomas remains antibiotic-responsive and is cured by HPE. Considering the complicated interaction between microbiomes and the genome/epigenome, further studies on the precise mechanisms of HP- and other bacteria-directed lymphomagenesis in antibiotic-responsive gastric MALT lymphomas are warranted.

scholarly journals Tumor-associated macrophages as major source of APRIL in gastric MALT lymphoma

Blood ◽  
2011 ◽  
Vol 117 (24) ◽  
pp. 6612-6616 ◽  
Author(s):  
Fabio Munari ◽  
Silvia Lonardi ◽  
Marco A. Cassatella ◽  
Claudio Doglioni ◽  
Maria Giulia Cangi ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
B Cell ◽  
Malt Lymphoma ◽  
Cell Activation ◽  
Gastric Lymphoma ◽  
B Cell Lymphoma ◽  
Lymphoid Hyperplasia ◽  
Gastric Malt Lymphoma ◽  
Direct Stimulation

Abstract Lymphoid hyperplasia of gastric mucosa associated with Helicobacter pylori (HP) infection represents a preneoplastic condition of the mucosa associated lymphoid tissue (MALT), which may evolve to a B-cell lymphoma. While it is well established that the initial neoplastic proliferation of B cells is antigen-driven and dependent on the helper activity of HP-specific T cells, it needs to be elucidated which cytokine or soluble factor(s) promote B-cell activation and lymphomagenesis. Herein, we originally report that gastric MALT lymphoma express high levels of a proliferation inducing ligand (APRIL), a novel cytokine crucial in sustaining B-cell proliferation. By immunohistochemistry, we demonstrate that APRIL is produced almost exclusively by gastric lymphoma-infiltrating macrophages located in close proximity to neoplastic B cells. We also show that macrophages produce APRIL on direct stimulation with both HP and HP-specific T cells. Collectively, our results represent the first evidence for an involvement of APRIL in gastric MALT lymphoma development in HP-infected patients.

scholarly journals Can we eradicate gastric MALT-lymphoma?

2013 ◽  
pp. 154-158
Author(s):  
Angelo Zullo ◽  
Cesare Hassan ◽  
Francesca Cristofari ◽  
Claudia Iegri ◽  
Nicoletta Villiva ◽  
...  
Keyword(s):  
Malt Lymphoma ◽  
Early Stage ◽  
Gastric Lymphoma ◽  
Survival Rates ◽  
Antibody Therapy ◽  
Gastric Malt Lymphoma ◽  
Low Grade ◽  
Success Rates ◽  
H Pylori

The incidence of primary gastric lymphoma in Italy is considerably higher than that observed in the rest of Europe. It is widely accepted that gastric B-cell, low-grade mucosalassociated lymphoid tissue (MALT) lymphoma is caused by specific host-bacterial interactions that occur during Helicobacter pylori infection. This review examines recent findings on the origins, diagnosis, treatment, and follow-up of gastric MALT lymphomas. Clinical and endoscopic findings at diagnosis vary widely. In a substantial number of cases, the patient presents only vague dyspeptic symptoms or poorly defined abdominal pain with no macroscopic lesions on the gastric mucosa. Review of data from 32 trials in which a total of 1,387 MALT-lymphoma patients of the stomach were treated solely with H. pylori eradication revealed high remission rates when the disease is treated early (stage I-II1). Neoplasia confined to the submucosa, antral localization of tumors, and negativity for the API2-MALT1 translocation were associated with a high probability of remission following H. pylori eradication. When the latter approach is not sufficient, radiotherapy, chemotherapy and, in selected cases, surgery are associated with high success rates; data on the efficacy of monoclonal antibody therapy (rituximab) are still limited. Five-year survival rates are higher than 90%. Patients whose tumors have been eliminated require close, long-term endoscopic follow-up since recurrence has been reported in some cases. Broader clinical follow-up is also advisable because the incidence of other solid tumors and of cardiovascular events is reportedly increased in these patients.

scholarly journals Preferential Dissemination of B-Cell Gastric Mucosa-Associated Lymphoid Tissue (MALT) Lymphoma to the Splenic Marginal Zone

Blood ◽  
1997 ◽  
Vol 90 (10) ◽  
pp. 4071-4077 ◽  
Author(s):  
Ming-Qing Du ◽  
Huai-Zheng Peng ◽  
Ahmet Dogan ◽  
Tim C. Diss ◽  
Haiqun Liu ◽  
...  
Keyword(s):  
Gastric Mucosa ◽  
B Cell ◽  
Malt Lymphoma ◽  
Lymphoid Tissue ◽  
Marginal Zone ◽  
Gastric Lymphoma ◽  
Gastric Malt Lymphoma ◽  
Lymphoma Cells ◽  
Marginal Zone B Cells ◽  
Clonal Identity

Abstract The tendency for gastric mucosa-associated lymphoid tissue (MALT) lymphoma cells preferentially to localize around reactive B-cell follicles, both in the mucosa and regional lymph nodes, coupled with their immunophenotype, has led to the proposal that the normal cell counterpart of this lymphoma is the marginal zone B cell. In keeping with this proposition, lymphocytes expressing the lymphoma idiotype have been detected in the splenic marginal zone in a single case of gastric MALT lymphoma. To confirm that this truly represented preferential homing of MALT lymphoma to the splenic marginal zone, we have now re-examined this case, together with 17 other cases, using both immunohistochemical and molecular methods in an attempt to establish clonal identity between the gastric lymphoma and cells in the splenic marginal zone. In three cases, the spleen was characterized by marked expansion of marginal zones by cells showing the same pattern of Ig light chain restriction as the gastric lymphoma. None of the remaining 15 cases showed histologic evidence of lymphomatous infiltration. Analysis of the Ig genes by polymerase chain reaction (PCR), cloning, and sequencing confirmed clonal identity between the splenic marginal zone infiltrates and the gastric lymphoma in the histologically involved cases. Amplifiable DNA could be extracted from only 5 of the remaining 15 cases. In 3 of these cases, including the case previously studied using an anti-idiotype, involvement of the splenic marginal zone could be confirmed using microdissection and clone-specific PCR. No involvement could be detected in the remaining 2 cases. In addition, we have shown that mucosal addressin cell adhesion molecule-1 (MAdCAM-1), the primary homing receptor of gut-mucosa for lymphocytes, was strongly expressed by the sinus lining cells of the splenic marginal zone. These results provide strong evidence for preferential involvement of the marginal zone when gastric MALT lymphomas disseminate to the spleen, which is in keeping with the notion that the marginal zone B cells are the normal counterparts of MALT lymphoma cells.

scholarly journals Helicobacter pylori–Negative MALT Lymphoma Presenting as a Massive Recurrent Gastrointestinal Hemorrhage

2020 ◽  
Vol 8 ◽  
pp. 232470962093716
Author(s):  
Prateek S. Harne ◽  
Samiran Mukherjee ◽  
Ted Achufusi ◽  
Dhruv Lowe ◽  
Divey Manocha
Keyword(s):  
Helicobacter Pylori ◽  
Gastric Mucosa ◽  
Malt Lymphoma ◽  
Lymphoid Tissue ◽  
Gastric Lymphoma ◽  
Hypovolemic Shock ◽  
Gastric Neoplasms ◽  
Gastric Malt Lymphoma ◽  
Primary Gastric Lymphoma ◽  
Life Threatening

Primary gastric lymphoma is rare, representing 5% of all primary gastric neoplasms. The presenting complaints of gastric mucosa-associated lymphoid tissue (MALT) lymphoma are usually nonspecific. However, life-threatening gastrointestinal bleeding from the stomach is unusual and sparsely reported. While studies reveal an indolent course, we present a case that presented with massive and recurrent hematemesis leading to hypovolemic shock secondary to endoscopically confirmed MALT lymphoma, which was treated with radiotherapy to achieve remission. She had no autoimmune diseases and tested negative for Helicobacter pylori. Our case emphasizes the importance of early diagnosis and timely intensive radiotherapy of a localized but aggressive gastric MALT lymphoma.

Early stage gastric MALT lymphoma with high-grade component cured by Helicobacter pylori eradication

2001 ◽  
Vol 36 (2) ◽  
pp. 121-124 ◽  
Author(s):  
Hiroshi Miki ◽  
Shoji Kobayashi ◽  
Hideo Harada ◽  
Not Available Not Available ◽  
Toshio Uraoka ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Malt Lymphoma ◽  
Early Stage ◽  
Gastric Malt Lymphoma ◽  
High Grade ◽  
Helicobacter Pylori Eradication

scholarly journals CagA Phosphorylation in Helicobacter pylori-Infected B Cells Is Mediated by the Nonreceptor Tyrosine Kinases of the Src and Abl Families

2016 ◽  
Vol 84 (9) ◽  
pp. 2671-2680 ◽  
Author(s):  
Linda M. Krisch ◽  
Gernot Posselt ◽  
Peter Hammerl ◽  
Silja Wessler
Keyword(s):  
Signal Transduction ◽  
Helicobacter Pylori ◽  
B Cells ◽  
Epithelial Cells ◽  
B Cell ◽  
Malt Lymphoma ◽  
Tyrosine Kinases ◽  
Signal Transduction Pathways ◽  
Content Type ◽  
H Pylori

CagA is one of the most important virulence factors of the human pathogenHelicobacter pylori. CagA expression can be associated with the induction of severe gastric disorders such as gastritis, ulceration, gastric cancer, or mucosa-associated lymphoid tissue (MALT) lymphoma. After translocation through a type IV secretion system into epithelial cells, CagA is tyrosine phosphorylated by kinases of the Src and Abl families, leading to drastic cell elongation and motility. While the functional role of CagA in epithelial cells is well investigated, knowledge about CagA phosphorylation and its associated signal transduction pathways in B cells is only marginal. Here, we established the B cell line MEC1 derived from a B cell chronic lymphocytic leukemia (B-CLL) patient as a new infection model to study the signal transduction in B cells controlled byH. pylori. We observed that CagA was rapidly injected, strongly tyrosine phosphorylated, and cleaved into a 100-kDa N-terminal and a 40-kDa C-terminal fragment. To identify upstream signal transduction pathways of CagA phosphorylation in MEC1 cells, pharmacological inhibitors were employed to specifically target Src and Abl kinases. We observed that CagA phosphorylation was strongly inhibited upon treatment with an Src inhibitor and slightly diminished when the Abl kinase inhibitor imatinib mesylate (Gleevec) was applied. The addition of dasatinib to block c-Abl and Src kinases led to a complete loss of CagA phosphorylation. In conclusion, these results demonstrate an important role for Src and Abl tyrosine kinases in CagA phosphorylation in B cells, which represent druggable targets inH. pylori-mediated gastric MALT lymphoma.

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