Helicobacter pylori-negative gastric mucosa-associated lymphoid tissue lymphomas: A review

Since Isaacson and Wright first reported on the extranodal marginal zone B-cell lymphoma of the stomach in 1983,following studies have clarified many aspects of this disease.We now know that the stomach is the most affected organ by this disease,and approximately90% of gastric mucosa-associated lymphoid tissue(MALT) lymphomas are related to Helicobacter pylori(H.pylori) infection.This implies that approximately 10% of gastric MALT lymphomas occur independent of H.pylori infection.The pathogenesis of these H.pylori-negative gastric MALT lymphomas remains unclear.To date,there have been several speculations.One possibility is that genetic alterations result in nuclear factor-kappa B(NF-κB) activation.Among these alterations,t(11;18)(q21;q21) is more frequently observed in H.pylori-negative gastric MALT lymphomas,and such translocation results in the synthesis of fusion protein API2-MALT1,which causes canonical and noncanonical NF-κB activation.Another possibility is infection with bacteria other than H.pylori.This could explain why H.pylori eradication therapy can cure some proportions of H.pylori-negative gastric MALT lymphoma patients,although the bacteria responsible for MALT lymphomagenesis are yet to be defined.Recent advances in endoscopy suggest magnifying endoscopy with narrow band imaging as a useful tool for both detecting gastric MALT lymphoma lesions and judging the response to treatment.A certain proportion of H.pylori-negative gastric MALT lymphoma patients respond to eradication therapy; hence,H.pylori eradication therapy could be considered as a first-line treatment for gastric MALT lymphomas regardless of their H.pylori infection status.     

Treatment Outcome for Gastric Mucosa-Associated Lymphoid Tissue Lymphoma according to Helicobacter pylori Infection Status: A Single-Center Experience

Background/Aims

Helicobacter pylori eradication therapy has been used as a first-line treatment for H. pylori-positive gastric mucosa-associated lymphoid tissue (MALT) lymphoma. However, the management strategy for H. pylori-negative MALT lymphoma remains controversial. Therefore, the aim of this study was to examine the success rate of each treatment option for H. pylori-positive and H. pylori-negative gastric MALT lymphomas.

Methods

In total, 57 patients with gastric MALT lymphoma diagnosed between December 2000 and June 2012 were enrolled in the study. The treatment responses were compared between H. pylori-positive and H. pylori-negative gastric MALT lymphomas.

Results

Of the 57 patients, 43 (75%) had H. pylori infection. Forty-eight patients received H. pylori eradication as a first-line treatment, and complete remission was achieved in 31 of the 39 patients (80%) with H. pylori-positive MALT lymphoma and in five (56%) of the nine patients with H. pylori-negative MALT lymphoma; no significant difference was observed between the groups (p=0.135). The other treatment modalities, including radiation therapy, chemotherapy, and surgery, were effective irrespective of H. pylori infection status, with no significant difference in the treatment response between H. pylori-positive and H. pylori-negative MALT lymphomas.

Conclusions

H. pylori eradication therapy may be considered as a first-line treatment regardless of H. pylori infection status.     

Successful Treatment of Helicobacter Pylori-Negative Gastric MALT Lymphoma With Rituximab

Helicobacter pylori infection is strongly associated with low-grade gastric lymphoma, commonly known as mucosa-associated lymphoid tissue (MALT) lymphoma. H. pylori eradication leads to complete remission in 80% of early stage MALT lymphomas. The treatment for early stage H. pylori-negative gastric MALT lymphoma is evolving. Rituximab, a chimeric anti-CD20 antibody, has shown response rates of approximately 50% with minimal toxicity in patients with B-cell non-Hodgkin lymphoma. We describe herein the clinical, endoscopic, and histologic features of a patient with H. pylori-negative gastric MALT lymphoma treated successfully with rituximab.     

Helicobacter pylori eradication in gastric diffuse large B cell lymphoma

Diffuse large B cell lymphoma(DLBCL) of the stomach is a heterogenous disease. There are tumors without histological evidence of mucosa-associated lymphoid tissue(MALT) lymphoma, which are classified as pure or de novo DLBCL and those with evidence of MALT, which are classified as DLBCL(MALT). The association between Helicobacter pylori(H. pylori) and gastric MALT lymphoma and remission with H. pylori eradication was shown in the 1990 s. In recent years, scientists from Taiwan and others have shown that high-grade gastric lymphomas may be dependent on H. pylori and eradication of this microorganism is effective in these cases. This entity is biologically distinct from H. pylori(-) cases and has a better clinical outcome. There are sufficient data about the complete remission in some of these cases with brief treatment with antibiotics. With this strategy, it is possible to save some of these cases from the harmful effects of standard chemotherapy. It is time to treat these cases with H. pylori eradication. However, strict histopathological follow-up is crucial and histopathological response must be evaluated according to the scoring system proposed by Groupe d’Etude des Lymphomes de l’Adulte. If there is no sufficient response, chemotherapy must be given immediately. These results suggest that H. pylori dependency and high-grade transformation in gastric MALT lymphomas are distinct events.     

Regression of superficial gastric MALT lymphoma with unsuccessful eradication therapy forHelicobacter pylori infection

A 51-year-old man had a reddish flat granular lesion in the stomach on endoscopic examination. Histology of biopsied specimen confirmed the diagnosis of low-grade B-cell gastric lymphoma of mucosaassociated lymphoid tissue (gastric MALT lymphoma) and simultaneous infection withHelicobacter pylori. He was given antibiotic treatment. Five weeks later, endoscopy and histology of biopsied specimen showed eradication ofH. pylori, and the tumor had regressed. Six months later,H. pylori reemerged, but the tumor had not recurred. After the second antibiotic therapy,H. pylori has been eradicated. The lymphoma has been in remission for 14 months.     

Gastric mucosa-associated lymphoid tissue lymphomas and Helicobacter pylori infection: a Colombian perspective

AIM: To assess the significance of chromosome translocation t(11;18)(q21;q21), B-cell lymphoma 10 (BCL-10) protein and Helicobacter pylori (H. pylori) infection in gastric mucosa-associated lymphoid tissue (MALT) lymphoma in Colombia.METHODS: Fifty cases of gastric MALT lymphoma and their respective post-treatment follow-up biopsies were examined to assess the presence of the translocation t(11;18)(q21;q21) as identified by fluorescence in situ hybridization; to detect protein expression patterns of BCL10 using immunohistochemistry; and for evaluation of tumor histology to determine the correlation of these factors and resistance to H. pylori eradication.RESULTS: Infection with H. pylori was confirmed in all cases of gastric MALT lymphoma in association with chronic gastritis. Bacterial eradication led to tumor regression in 66% of cases. The translocation t(11;18)(q21;q21) was not present in any of these cases, nor was there evidence of tumor transformation to diffuse large B-cell lymphoma. Thirty-four percent of the patients showed resistance to tumor regression, and within this group, 7 cases, representing 14% of all those analyzed, were considered to be t(11;18)(q21;q21)-positive gastric MALT lymphomas. Protein expression of BCL10 in the nucleus was associated with the presence of translocation and treatment resistance. Cases that were considered unresponsive to therapy were histologically characterized by the presence of homogeneous tumor cells and a lack of plasmacytic differentiation. Responder cases exhibited higher cellular heterogeneity and a greater frequency of plasma cells.CONCLUSION: Both t(11;18)(q21;q21)-positive MALT lymphoma cases and those with nuclear BCL10 expression are considered resistant to H. pylori eradication. It is suggested that chronic antigenic stimulation is not a dominant event in resistant cases.     

Role of Helicobacter pylori virulence factor cytotoxin-associated gene A in gastric mucosa-associated lymphoid tissue lymphoma

Helicobacter pylori(H.pylori)infection might initiate and contribute to the progression of lymphoma from gastric mucosa-associated lymphoid tissue(MALT).Increasing evidence shows that eradication of H.pylori with antibiotic therapy can lead to regression of gastric MALT lymphoma and can result in a 10-year sustained remission.The eradication of H.pylori is the standard care for patients with gastric MALT lymphoma.Cytotoxin-associated gene A(CagA)protein,one of the most extensively studied H.pylori virulence factors,is strongly associated with the gastric MALT lymphoma.CagA possesses polymorphisms according to its C-terminal structure and displays different functions among areas and races.After being translocated into B lymphocytes via typeⅣsecretion system,CagA deregulates intracellular signaling pathways in both tyrosine phosphorylation-dependent and-independent manners and/or some other pathways,and thereby promotes lymphomagenesis.A variety of proteins including p53and protein tyrosine phosphatases-2 are involved in the malignant transformation induced by CagA.Mucosal inflammation is the foundational mechanism underlying the occurrence and development of gastric MALT lymphoma.     

Helicobacter pylori and gastric mucosa-associated lymphoid tissue lymphoma:Recent progress in pathogenesis and management

Recent progress in the research regarding the molecular pathogenesis and management of gastric mucosaassociated lymphoid tissue(MALT)lymphoma is reviewed.In approximately 90%of cases,Helicobacter pylori(H.pylori)infection plays the causative role in the pathogenesis,and H.pylori eradication is nowadays the first-line treatment for this disease,which leads to complete disease remission in 50%-90%of cases.In H.pylori-dependent cases,microbe-generated immune responses,including interaction between B and T cells involving CD40 and CD40L co-stimulatory molecules,are considered to induce the development of MALT lymphoma.In H.pylori-independent cases,activation of the nuclear factor-κB pathway by oncogenic products of specific chromosomal translocations such as t(11;18)/API2-MALT1,or inactivation of tumor necrosis factor alpha-induced protein 3(A20)are considered to contribute to the lymphomagenesis.Recently,a largescale Japanese multicenter study confirmed that the long-term clinical outcome of gastric MALT lymphoma after H.pylori eradication is excellent.Treatment modalities for patients not responding to H.pylori eradication include a"watch and wait"strategy,radiotherapy,chemotherapy,rituximab immunotherapy,and a combination of these.Because of the indolent behavior of MALT lymphoma,second-line treatment should be tailored in consideration of the clinical stage and extent of the disease in each patient.     

Role of F-FDG PET Scans in Patients with Helicobacter pylori-Infected Gastric Low-Grade MALT Lymphoma

Background/Aims

Endoscopic ultrasound (EUS) plays a crucial role in the assessment and treatment of low-grade gastric mucosa-associated lymphoid tissue (MALT) lymphoma; however, interobserver variation, inadequate accuracy in judging the depth of tumor invasion, and histological heterogeneity of the tumor can limit its role. Thus, we have assessed the role of ¹⁸F-FDG PET scans in the management of Helicobacter pylori-infected gastric MALT lymphoma.

Methods

Eighteen patients with H. pylori-infected low-grade gastric MALT lymphoma underwent an ¹⁸F-FDG PET scan prior to receiving H. pylori eradication therapy. We analyzed these patients'' clinicopathologic data and measured the baseline and change in the metabolic activity of the tumor using standardized uptake values (SUVs).

Results

Two patients failed to achieve complete remission of the low-grade gastric MALT lymphoma after successful H. pylori eradication. The baseline SUVs were significantly higher in these patients compared to successfully treated patients, 13.35±0.07 vs 2.98±0.93, respectively (n=2 vs n=16, p<0.001). The reduction in the SUV was significantly greater in the complete remission patients compared to treatment failure patients (p=0.018).

Conclusions

A high SUV at baseline ¹⁸F-FDG PET and a lower reduction in the SUV within 3 months after eradication therapy are associated with treatment failure in H. pylori-positive low-grade gastric MALT lymphoma patients undergoing eradication treatment.     

A case of Helicobacter heilmannii-associated primary gastric mucosa-associated lymphoid tissue lymphoma achieving complete remission after eradication

A 46-year-old man underwent gastrointestinal endoscopy while visiting the hospital for a general physical check-up. Coarse mucosa in the antrum with superficial erosions was found by endoscopic gastrointestinal examination, but no atrophic changes were seen in the corpus. Histopathological examination of gastric biopsy specimens revealed mucosa-associated lymphoid tissue (MALT) lymphoma. Although Helicobacter pylori was not detected in our patient, H. heilmannii was identified histologically and by polymerase chain reaction analysis, resulting in the diagnosis of H. heilmannii-associated gastric MALT lymphoma. We successfully eradicated H. heilmannii and achieved complete remission of gastric MALT lymphoma by antibiotic therapy. H. heilmannii usually causes milder gastritis than H. pylori, but it has been more closely associated with MALT lymphoma. As such, when H. pylori infection is excluded in patients with gastric MALT lymphoma, physicians should next consider the possibility of H. heilmannii. Furthermore, our research suggests that eradication therapy is effective for treatment of localized H. heilmannii-associated gastric MALT lymphoma.     

PREDICTIVE VALUE OF ENDOSCOPY AND ENDOSCOPIC ULTRASONOGRAPHY FOR REGRESSION OF GASTRIC DIFFUSE LARGE B‐CELL LYMPHOMAS AFTER HELICOBACTER PYLORI ERADICATION

Background: Some gastric diffuse large B‐cell lymphomas have been reported to regress completely after the successful eradication of Helicobacter pylori. The aim of this study was to investigate the clinical characteristics of gastric diffuse large B‐cell lymphomas without any detectable mucosa‐associated lymphoid tissue (MALT) lymphoma that went into complete remission after successful H. pylori eradication. Patients and Methods: We examined the effect of H. pylori eradication in 15 H. pylori‐positive gastric diffuse large B‐cell lymphoma patients without any evidence of an associated MALT lymphoma (clinical stage I by the Lugano classification) by endoscopic examination including biopsies, endoscopic ultrasonography, computed tomography, and bone marrow aspiration. Results: H. pylori eradication was successful in all the patients and complete remission was achieved in four patients whose clinical stage was I. By endoscopic examination, these gastric lesions appeared to be superficial. The depth by endoscopic ultrasonography was restricted to the mucosa in two patients and to the shallow portion of the submucosa in the other two patients. All four patients remained in complete remission for 7–100 months. Conclusion: In gastric diffuse large B‐cell lymphomas without a concomitant MALT lymphoma but associated with H. pylori infection, only superficial cases and lesions limited to the shallow portion of the submucosa regressed completely after successful H. pylori eradication. The endoscopic appearance and the rating of the depth of invasion by endosonography are both valuable for predicting the efficacy of H. pylori eradication in treating gastric diffuse large B‐cell lymphomas.     

Metabolic consequences of Helicobacter pylori infection and eradication

Helicobacter pylori(H.pylori)is still the most prevalent infection of the world.Colonization of the stomach by this agent will invariably induce chronic gastritis which is a low-grade inflammatory state leading to local complications(peptic ulcer,gastric cancer,lymphoma)and remote manifestations.While H.pylori does not enter circulation,these extragastric manifestations are probably mediated by the cytokines and acute phase proteins produced by the inflammed mucosa.The epidemiologic link between the H.pylori infection and metabolic changes is inconstant and controversial.Growth delay was described mainly in low-income regions with high prevalence of the infection,where probably other nutritional and social factors contribute to it.The timely eradication of the infection will lead to a more healthy development of the young population,along with preventing peptic ulcers and gastric cancer An increase of total,low density lipoprotein and high density liporotein cholesterol levels in some infected people creates an atherogenic lipid profile which could promote atherosclerosis with its complications,myocardial infarction,stroke and peripheral vascular disease.Well designed and adequately powered long-term studies are required to see whether eradication of the infection will prevent these conditions.In case of glucose metabolism,the most consistent association was found between H.pylori and insulin resistance:again,proof that eradication prevents this common metabolic disturbance is expected.The results of eradication with standard regimens in diabetics are significantly worse than in non-diabetic patients,thus,more active regimens must be found to obtain better results.Successful eradication itself led to an increase of body mass index and cholesterol levels in some populations,while in others no such changes were encountered.Uncertainities of the metabolic consequences of H.pylori infection must be clarified in the future.     

Management of Helicobacter pylori infection after gastric surgery

The Maastricht IV/Florence Consensus Report and the Second Asia-Pacific Consensus Guidelines strongly recommend eradication of Helicobacter pylori(H.pylori)in patients with previous gastric neoplasia who have undergone gastric surgery.However,the guidelines do not mention optimal timing,eradication regimens,diagnostic tools,and follow-up strategies for patients undergoing gastrectomy and do not indicate if eradication of H.pylori reduces the risk of marginal ulcer or stump cancer in the residual stomach after gastrectomy.The purpose of this review is to provide an update which may help physicians to properly manage H.pylori infection in patients who have undergone gastric surgery.This review focuses on(1)the microenvironment change in the stomach after gastrectomy;(2)the phenomenon of spontaneous clearance of H.pylori after gastrectomy;(3)the effects of H.pylori on gastric atrophy and intestinal metaplasia after gastrectomy;(4)incidence and clinical features of ulcers developing after gastrectomy;(5)does eradication of H.pylori reduce the risk of gastric stump cancer in the residual stomach?(6)does eradication of H.pylori reduce the risk of secondary metachronous gastric cancer in the residual stomach?and(7)optimal timing and regimens for H.pylori eradication,diagnostic tools and follow-up strategies for patients undergoing gastrectomy.     

Efficacy of Helicobacter pylori eradication for the prevention of metachronous gastric cancer after endoscopic resection for early gastric cancer

Helicobacter pylori(H.pylori)plays an important role in gastric carcinogenesis,as the majority of gastric cancers develop from H.pylori-infected gastric mucosa.The rate of early gastric cancer diagnosis has increased in Japan and Korea,where H.pylori infection and gastric cancer are highly prevalent.Early intestinal-type gastric cancer without concomitant lymph node metastasis is usually treated by endoscopic resection.Secondary metachronous gastric cancers often develop because atrophic mucosa left untreated after endoscopic treatment confers a high risk of gastric cancer.The efficacy of H.pylori eradication for the prevention of metachronous gastric cancer remains controversial.However,in patients who undergo endoscopic resection of early gastric cancer,H.pylori eradication is recommended to suppress or delay metachronous gastric cancer.Careful and regularly scheduled endoscopy should be performed to detect minute metachronous gastric cancer after endoscopic resection.     

Enfermedades relacionadas con la infección por Helicobacter pylori

This article summarizes the main conclusions drawn from the presentations on Helicobacter pylori at Digestive Disease Week 2013. Knowledge of this infection among the general population continues to be extremely limited. H. pylori is the main cause of “aging” of the human stomach. In developed countries, the prevalence of H. pylori infection has decreased but continues to be considerable. In most countries, clarithromycin and metronidazole resistance rates are markedly high. H. pylori eradication improves the symptoms of functional dyspepsia, but only in a minority of patients. The frequency of idiopathic peptic ulcers seems to be rising and their prognosis is worse. Most patients with gastric cancer have, or have had, prior H. pylori infection. The risk of developing preneoplastic lesions depends on the type (strain) of the microorganism. To prevent the development of gastric cancer, eradication therapy should be administered early (before the development of intestinal metaplasia). Among H. pylori-infected patients, those who receive long-term treatment with proton pump inhibitors more frequently develop preneoplastic lesions. In patients who undergo endoscopic resection of early gastric cancer, H. pylori eradication reduces the incidence of metachronous tumors. Eradication therapy induces regression of MALT lymphoma in most patients and tumoral recurrence in the long term is exceptional; eradication is a reasonable option even when H. pylori infection has not been identified in patients with MALT lymphoma. Several diagnostic innovations were presented, such as some polymerase chain reaction techniques for use in gastric biopsy specimens or gastric juice. The efficacy of triple standard therapy is clearly inadequate. The superiority of “sequential” therapy over standard triple therapy has not been definitively established. “Concomitant” therapy is more effective and is simpler than “sequential” therapy. After failure of standard triple therapy, second-line levofloxacin–based schemes for 10 days are effective and are also simpler and better tolerated than bismuth-based quadruple therapy. Levofloxacin-based triple therapy is also a promising alternative after failure of “sequential” and “concomitant” therapies. New-generation quinolones, such as moxifloxacin, could be useful as eradication therapy, especially as rescue therapy. After failure of clarithromycin-based triple therapy, followed by that of levofloxacin-based triple therapy, a bismuth-based quadruple scheme is an acceptable alternative. Even after the failure of 3 eradication therapies, a fourth empirical rescue therapy (with rifabutin) can be effective.     

Marginal zone B-cell lymphoma (MALT lymphoma)

Opinion statement The preferred terminology for mucosa-associated lymphoid tissue (MALT) lymphoma of the stomach (variously referred to as MALT lymphoma, MALToma, low-grade MALToma, or pseudolymphoma) is marginal zone B-cell lymphoma (MZBL). MZBL, the hallmark of which is the lymphoepithelial lesion, develops as a consequence of Helicobacter pylori infection in susceptible individuals. In general, MZBL is slow growing, can remain localized for years, and has an excellent prognosis. Staging involves endoscopy with biopsy, computed tomography scanning, and endoscopic ultrasound. In patients with limited disease, eradication of H. pylori leads to remission. In patients who fail eradication therapy or have more extensive disease, surgery, chemotherapy, and radiation alone and in various combinations have been used successfully.     

Regression of atypical lymphoid hyperplasia after eradication ofHelicobacter pylori

A rare case of endescopic and histological regression of a gastric lymphoid mucosal lesion after eradication ofHelicobacter pylori is reported. A 72-year-old man was suspected of having a low-grade B-cell gastric mucosa-associated lymphoid tissue (MALT) lymphoma by endoscopic and histological findings. Histology of biopsy specimens showed massive infiltration of atypical lymphocytes and lymphoepithelial lesions. Immunohistochemical staining revealed kappa light chain expression in the infiltrated atypical lymphocytes to be twofold that of lambda light chain. The above diagnosis was thus highly suspected but not confirmed. Antibiotic therapy was given on the basis of evidence ofH. pylori infection. Successful eradication ofH. pylori resulted in remarkable improvement of endoscopic and histological findings. Follow-up studies were carried out 8 months after eradication, with no evidence of relapse. The eradication ofH. pylori appears to be an effective alternative therapy for B-cell lymphoproliferative disease, although longer follow-up and further studies are needed before this treatment can be establisted.     

Extragastric manifestations of Helicobacter pylori infection: Possible role of bacterium in liver and pancreas diseases

Helicobacter pylori (H. pylori) is an ancient microorganism that has co-evolved with humans for over 60000 years. This bacterium typically colonizes the human stomach and it is currently recognized as the most common infectious pathogen of the gastroduodenal tract. Although its chronic infection is associated with gastritis, peptic ulcer, dysplasia, neoplasia, MALT lymphoma and gastric adenocarcinoma, it has been suggested the possible association of H. pylori infection with several extragastric effects including hepatobiliary and pancreatic diseases. Since a microorganism resembling H. pylori was detected in samples from patients with hepatobiliary disorders, several reports have been discussed the possible role of bacteria in hepatic diseases as hepatocellular carcinoma, cirrhosis and hepatic encephalopathy, nonalcoholic fatty liver disease and fibrosis. Additionally, studies have reported the possible association between H. pylori infection and pancreatic diseases, especially because it has been suggested that this infection could change the pancreatic physiology. Some of them have related a possible association between the microorganism and pancreatic cancer. H. pylori infection has also been suggested to play a role in the acute and chronic pancreatitis pathogenesis, autoimmune pancreatitis, diabetes mellitus and metabolic syndrome. Considering that association of H. pylori to liver and pancreas diseases needs further clarification, our work offers a review about the results of some investigations related to the potential pathogenicity of H. pylori in these extragastric diseases.     

A review of Helicobacter pylori diagnosis,treatment, and methods to detect eradication

Helicobacter pylori(H. pylori) affects nearly half of the world’s population and, thus, is one of the most frequent and persistent bacterial infections worldwide. H. pylori is associated with peptic ulcer disease, gastric ulcers, mucosa-associated lymphoid tissue lymphoma, and gastric cancer. Various diagnostic methods exist to detect infection, and the choice of one method or another depends on several factors, such as accessibility, advantages and disadvantages of each method, cost, and the age of patients. Once H. pylori infection is diagnosed, the clinician decides whether treatment is necessity, according to the patient’s clinical condition. Typically, eradication of H. pylori is recommended for treatment and prevention of the infection. Cure rates with the standard triple therapy are acceptable, and effective quadruple therapies, sequential therapies, and concomitant therapies have been introduced as key alternatives to treat H. pylori infection. In this work, we review the main diagnostic methods used to identify H. pylori infection and to confirm eradication of infection. In addition, key factors related to treatment are reviewed.