Pylori-negative Gastric Mucosa-associated Lymphoid Tissue Lymphoma Research Articles

Role of non-Helicobacter pylori gastric Helicobacters in helicobacter pylori-negative gastric mucosa-associated lymphoid tissue lymphoma.

Marginal zone lymphomas rank as the third most prevalent form of non-Hodgkin B-cell lymphoma, trailing behind diffuse large B-cell lymphoma and follicular lymphoma. Gastric mucosa-associated lymphoid tissue lymphoma (GML) is a low-grade B-cell neoplasia frequently correlated with Helicobacter pylori (H. pylori)-induced chronic gastritis. On the other hand, a specific subset of individuals diagnosed with GML does not exhibit H. pylori infection. In contrast to its H. pylori-positive counterpart, it was previously believed that H. pylori-negative GML was less likely to respond to antimicrobial therapy. Despite this, surprisingly, in-creasing evidence supports that a considerable proportion of patients with H. pylori-negative GML show complete histopathological remission after bacterial eradication therapy. Nonetheless, the precise mechanisms underlying this treatment responsiveness are not yet fully comprehended. In recent years, there has been growing interest in investigating the role of non-H. pylori gastric helicobacters (NHPHs) in the pathogenesis of H. pylori-negative GML. However, additional research is required to establish the causal relationship between NHPHs and GML. In this minireview, we examined the current understanding and proposed prospects on the involvement of NHPHs in H. pylori-negative GML, as well as their potential response to bacterial eradication therapy.

Comprehensive Analysis of Gene Expression Profiling to Explore Predictive Markers for Eradication Therapy Efficacy against Helicobacter pylori-Negative Gastric MALT Lymphoma

Although radiotherapy is the standard treatment for Helicobacter pylori (Hp)-negative gastric mucosa-associated lymphoid tissue (MALT) lymphoma, eradication therapy using antibiotics and an acid secretion suppressor can sometimes induce complete remission. We explored predictive markers for the response to eradication therapy for gastric MALT lymphoma that were negative for both API2-MALT1 and Hp infection using comprehensive RNA sequence analysis. Among 164 gastric MALT lymphoma patients who underwent eradication therapy as primary treatment, 36 were negative for both the API2-MALT1 fusion gene and Hp infection. Based on eradication therapy efficacy, two groups were established: complete response (CR) and no change (NC). The Kyoto Encyclopedia of Genes and Genomes pathway analysis showed that cancer-related genes and infection-related genes were highly expressed in the NC and CR groups, respectively. Based on this finding and transcription factor, gene ontology enrichment, and protein-protein interaction analyses, we selected 16 candidate genes for predicting eradication therapy efficacy. Real-time PCR validation in 36 Hp-negative patients showed significantly higher expression of olfactomedin-4 (OLFM4) and the Nanog homeobox (NANOG) in the CR and NC groups, respectively. OLFM4 and NANOG could be positive and negative predictive markers, respectively, for eradication therapy efficacy against gastric MALT lymphoma that is negative for both API2-MALT1 and Hp infection.

S3738 Agent Orange as a Possible Cause of Helicobacter pylori Negative Gastric Mucosa-Associated Lymphoid Tissue Lymphoma

Introduction: Gastric mucosa-associated lymphoid tissue (MALT) lymphoma was first described in 1983 as the most common extranodal site of non-Hodgkin lymphoma. Helicobacter pylori (H. pylori) infection is implicated in 90% of all gastric MALT lymphoma cases. Agent Orange (AO), with traces of oncogenic 2,3,7,8-tetrachlorodibenzo-p-dioxin, has also been classified as a causative agent in non-Hodgkin lymphoma, which includes gastric MALT lymphoma. Here we report a case of H. pylori negative gastric MALT lymphoma in a patient with history of significant AO exposure. Case Description/Methods: A 75-year-old Caucasian male veteran who served in the Vietnam War with significant AO exposure, as well as history of chronic gastroesophageal reflux disease, was referred for endoscopy to evaluate a reported history of un-staged Barrett’s esophagus 5-years prior but with two subsequent normal endoscopies at an outside facility. He noted symptoms of burning chest pain and dyspepsia following large meals, all of which were worsened with spicy foods and improved with omeprazole. Family history was negative for a history of gastric cancer, and he had a 25-pack year smoking history but quit 20 years prior to presentation.Initial esophagogastroduodenoscopy (EGD) revealed abnormal folds in the gastric fundus and erythema in the gastric antrum, but otherwise normal exam including normal duodenum and esophagus. Random gastric biopsies and biopsies of the abnormal folds were consistent with gastric MALT lymphoma, negative for H. pylori and t(11;18)(q21;q21). Repeat EGD 1 month later for further sampling demonstrated identical findings (Figure 1A). Stool testing for H. pylori antigen was also negative. The patient was referred to oncology and after staging imaging was found to have stage IE gastric MALT lymphoma. He was treated with involved site radiation therapy and EGD 3 months later showed both endoscopic and pathologic resolution (Figure 1B). Discussion: The 10% of cases of H. pylori negative gastric MALT lymphoma have an unclear etiology, although dysregulation of nuclear factor-kappa B (NF-κB) principally via translocations t(11;18)(q21;q21) is thought to be a potentially causative genetic alteration. In this patient, neither H. pylori nor the common t(11,18) genetic alteration were present. Given AO is implicated in non-Hodgkin lymphoma and the most common site of extranodal non-Hodgkin lymphoma is the gastric mucosa, AO exposure should be considered a risk factor for development of gastric MALT lymphoma.Figure 1.: (A) EGD demonstrating abnormal gastric mucosa with prominent gastric fundus folds seen on retroflexion during EGD prior to ISRT (radiation) therapy. (B) Post-radiation EGD demonstrating resolution of the abnormalities seen with the pre-treatment EGD including disappearance of the prominent gastric fundus folds.

Endoscopic submucosal dissection for protruding Helicobacter pylori-negative mucosa-associated lymphoid tissue lymphoma of the stomach: a case report

Gastric mucosa-associated lymphoid tissue (MALT) lymphomas have various endoscopic appearances. We report a case of Helicobacter pylori-negative gastric MALT lymphoma with a protruding morphology similar to that of submucosal tumors. A 51-year-old man with a protruding tumor in the gastric cardia was referred to our hospital. Biopsy specimens showed no malignant epithelial tumors or lymphoid hyperplasia. Endoscopic submucosal dissection was performed and the patient was diagnosed with gastric MALT lymphoma. Lymphoma cells were present in the lamina propria mucosae and the submucosa under the non-atrophic fundic gland mucosa, with a feature of homogenous and monotonous growths, which was speculated to have resulted in a protruding morphology similar to that of submucosal tumors. Endoscopic submucosal dissection can be an alternative diagnostic option for gastric MALT lymphoma when the initial pathological diagnosis based on biopsy specimens is difficult.

Mucosa-Associated Lymphoid Tissue (MALT) Lymphoma in the Gastrointestinal Tract in the Modern Era.

Simple SummaryExtranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma), which is frequently linked to chronic antigenic stimulation, is clinically an indolent B-cell lymphoma. The most common site is the stomach, accounting for 35% of MALT lymphomas, with a strong association with Helicobacter pylori (H. pylori) infection. Although antibiotic eradication is first-line therapy for gastric MALT lymphoma, a recent trend showing increasing H. pylori-negative cases may require different treatment strategies. Intestinal MALT lymphoma, including immunoproliferative small intestinal disease, is relatively rare, and the pathogenesis and therapeutic approach have not been fully elucidated. In addition, the gastrointestinal tract was recently considered a preferable site of Epstein–Barr-virus-negative marginal zone lymphoma in the post-transplant setting. We review the updated clinicopathological features, treatment, and evolving concepts of MALT lymphoma of the gastrointestinal tract.Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) typically arises from sites such as the stomach, where there is no organized lymphoid tissue. Close associations between Helicobacter pylori and gastric MALT lymphoma or Campylobacter jejuni and immunoproliferative small intestinal disease (IPSID) have been established. A subset of tumors is associated with chromosomal rearrangement and/or genetic alterations. This disease often presents as localized disease, requiring diverse treatment approaches, from antibiotic therapy to radiotherapy and immunochemotherapy. Eradication therapy for H. pylori effectively cures gastric MALT lymphoma in most patients. However, treatment strategies for H. pylori-negative gastric MALT lymphoma are still challenging. In addition, the effectiveness of antibiotic therapy has been controversial in intestinal MALT lymphoma, except for IPSID. Endoscopic treatment has been noted to usually achieve complete remission in endoscopically resectable colorectal MALT lymphoma with localized disease. MALT lymphoma has been excluded from post-transplant lymphoproliferative disorders with the exception of Epstein–Barr virus (EBV)-positive marginal zone lymphoma (MZL). We also describe the expanding spectrum of EBV-negative MZL and a close association of the disease with the gastrointestinal tract.

Gastric microbiota in patients with Helicobacter pylori-negative gastric MALT lymphoma.

To investigate the mucosal microbiota in the stomach of patients with Helicobacter pylori-negative mucosa-associated lymphoid tissue (MALT) lymphoma by means of metagenomic analysis.Although some gastric MALT lymphomas are associated with the presence of H. pylori, other gastric MALT lymphomas occur independently of H. pylori infection. The pathogenesis of H. pylori-negative MALT lymphoma remains unclear.Mucosal biopsy specimens were collected from the gastric body from 33 MALT lymphoma patients with gastric lesions, including both H. pylori-infection naïve patients and posteradication patients, as well as 27 control participants without H. pylori infection or cancer. Subsequently, the samples were subjected to 16S rRNA gene sequencing. Quantitative insights into microbial ecology, linear discriminant analysis effect size, and phylogenetic investigation of communities by reconstruction of unobserved states softwares were used to analyze the participants’ microbiota.H. pylori-negative MALT lymphoma patients had significantly lower alpha diversity (P = .04), compared with control participants. Significant differences were evident in the microbial composition (P = .04), as determined by comparison of beta diversity between the 2 groups. Taxonomic composition analysis indicated that the genera Burkholderia and Sphingomonas were significantly more abundant in MALT lymphoma patients, while the genera Prevotella and Veillonella were less abundant. Functional microbiota prediction showed that the predicted gene pathways “replication and repair,” “translation,” and “nucleotide metabolism” were downregulated in MALT lymphoma patients.H. pylori-negative MALT lymphoma patients exhibited altered gastric mucosal microbial compositions, suggesting that altered microbiota might be involved in the pathogenesis of H. pylori-negative MALT lymphoma.

Genetic Characterization and Clinical Features of Helicobacter pylori Negative Gastric Mucosa-Associated Lymphoid Tissue Lymphoma.

Simple SummaryThe pathogenesis of H. pylori-associated gastric MALT lymphoma has been well characterized, but the genetic basis and clinical features of H. pylori negative gastric cases remain elusive. In the present study, we investigated the genetic profiles of a large series of H. pylori negative gastric MALT lymphoma by targeted sequencing for a panel of genes specifically designed for marginal zone lymphoma, together with assessment of common translocations and comprehensive clinical data. Targeted sequencing confirmed that NF-κB activation is a major driver in the pathogenesis of H. pylori negative MALT lymphoma, as shown by frequent TNFAIP3 inactivating mutations and also by translocations of MALT1/IGH. This study adds new insights into the genetic background of H. pylori negative MALT lymphoma and will potentially allow us to more specifically target the underlying molecular pathways in future therapeutic concepts.Background: In Western countries, the prevalence of gastric mucosa-associated lymphoid tissue (MALT) lymphoma has declined over the last three decades. Contemporaneously, H. pylori negative gastric MALT lymphoma is increasingly encountered, and their genetic basis and clinical features remain elusive. Methods: A total of 57 cases of H. pylori negative gastric MALT lymphoma were reviewed and investigated for chromosome translocation by fluorescence in-situ hybridization and for somatic mutations by the targeted sequencing of 93 genes. Results: MALT1 translocation, most likely t(11;18)(q21;q21)/BIRC3-MALT1, was detected in 39% (22/57) cases, and IGH translocation was further seen in 12 MALT1-negative cases, together accounting for 60% of the cohort. Targeted sequencing was successful in 35 cases, and showed frequent mutations in NF-κB signaling pathways (TNFAIP3 = 23%, CARD11 = 9%, MAP3K14 = 9%), together affecting 14 cases (40%). The NF-κB pathway mutations were mutually exclusive from MALT1, albeit not IGH translocation, altogether occurring in 86% of cases. There was no significant correlation between the genetic changes and clinicopathological parameters. The patients showed a median of progression-free survival (PFS) of 66.3 months, and a significant superior PFS when treated with systemic versus antibiotic therapy (p = 0.004). Conclusion: H. pylori negative gastric MALT lymphoma is characterized by highly frequent genetic changes in the NF-κB signaling pathways.

Clinical Efficacy of Radiotherapy in Helicobacter pylori Negative or Unresponsive to Eradication Therapy Primary Gastric Mucosa-Associated Lymphoid Tissue Lymphoma

The eradication of Helicobacter pylori (H. pylori) is an effective treatment in gastric mucosa-associated lymphoid tissue (MALT) lymphoma associated with H. pylori infection. However, the treatment strategy in gastric MALT lymphoma patients who are H. pylori-negative or unresponsive to H. pylori eradication therapy remains controversial. In this study, we investigated the clinical efficacy of treatments other than H. pylori eradication therapy in these groups of patients. This was a retrospective single-center study based on the medical records of patients diagnosed with gastric MALT lymphoma at Yeungnam University Medical Center between January 2005 and December 2016. Patients were treated with H. pylori eradication therapy, chemotherapy, or radiotherapy according to their H. pylori infection status and stage of gastric MALT lymphoma. Of the 68 eligible patients, 50 were enrolled in the study. Of the 42 patients with H. pylori-positive gastric MALT lymphoma, 36 (81.7%) were treated with H. pylori eradication therapy as primary treatment and 25 (69.4%) achieved a complete response (CR). Patients without a CR after H. pylori eradication therapy (n=11, 30.6%) received radiotherapy as a secondary treatment. Two patients with H. pylori-positive gastric MALT lymphoma and eight with H. pylori-negative gastric MALT lymphoma received radiotherapy as the primary treatment. CR was achieved in all 21 patients treated with radiotherapy as primary or secondary treatment. The 5-year progression-free survival rate after radiotherapy was 92.9%. Radiotherapy may be a worthwhile treatment option in patients with H. pylori-negative MALT lymphoma or H. pylori-positive MALT lymphoma that is not responsive to H. pylori eradication therapy.

Treatment of Helicobacter pylori-Negative MALT Lymphoma with a Triple Therapy Regimen

A 61 year old African American female with history of hypertension presented for evaluation of dyspepsia. She had symptoms for many years, and did not respond to proton pump inhibitors. She denied nausea, vomiting, and hematochezia. Her only medication was amlodipine. She admitted to smoking one pack of cigarettes per day and drinking alcohol occasionally. Her paternal grandfather and uncle had a history of colon cancer. She underwent upper and lower endoscopy. Her upper endoscopy showed antral erythema, a large hiatal hernia, and esophagitis. Colonoscopy showed three subcentimeter polyps. Pathology of the upper endoscopy revealed mucosa associated lymphoid tissue (MALT) lymphoma in the antrum. Biopsies of the antrum and gastric body were negative for Helicobacter pylori. Based on review of the literature the patient was given amoxicillin 1g, clarithromycin 500 mg, and omeprazole 40 mg twice per day for 14 days. Repeat upper endoscopy performed four months later showed persistent erythema in the antrum. Multiple biopsies were obtained of the antrum and body which showed mild chronic gastritis. There was no evidence of lymphoma on any of the biopsy specimens. According to the National Comprehensive Cancer Network 2014 guidelines treatment for H. pylori negative gastric MALT lymphoma is radiation or rituximab (1). However, recent studies show that treatment with antibiotics may lead to complete remission, and that further chemotherapy or radiation may not be needed. In a study by Raderer et al 46% of patients with H. pylori negative MALT lymphoma achieved complete or partial remission with a triple therapy regimen alone (2). The mechanism as to why antibiotics may work in treating H. pylori negative MALT lymphoma is unclear. There may be a role of other bacteria causing chronic inflammation of the stomach, or clarithromycin may have an immunomodulatory effect (3). Our patient demonstrates a successful resolution of H. pylori negative MALT lymphoma with triple therapy alone. Long term follow up is needed to assess for recurrence of her disease. As antibiotics have been shown to be effective in a significant number of patients with H. pylori negative MALT lymphoma, it is reasonable to give a trial of triple therapy regimen before more toxic treatments such as radiation and chemotherapy are offered.

Two Cases of Gastric Mucosa-Associated Lymphoid Tissue Lymphoma With Helicobacter heilmannii Infection

Helicobacter heilmannii (H. heilmannii)-associated gastric mucosa-associated lymphoid tissue (MALT) lymphoma have been reported, although rare. We describe here two cases of H. heilmannii-associated gastric MALT lymphoma. Case 1. A 50-year-old man presented with epigastralgia. Gastrointestinal endoscopy disclosed multiple gastric ulcerations in antrum. The endoscopic biopsy specimen suggested MALT lymphoma and bacteria were observed, which were larger and more tightly coiled than H. pylori. H. pylori was undetectable in histology and serum antibody test. He was treated with a 7-day course of triple therapy consisting of lansoprazole, amoxicillin, and clarithromycin. 2 months after eradication, CR was confirmed by endoscopic and histologic examinations. Four-years after eradication, there were no signs of MALT lymphoma recurrence on endoscopic finding and biopsy specimen. Case 2. A 43-year-old man visited our hospital for epigastralgia. Gastrointestinal endoscopy revealed multiple gastric ulcerations in the upper body and angle. The endoscopic biopsy specimen suggested MALT lymphoma. H. pylori was undetectable in a culture, urea breath test, H. pylori stool antigen test, and serum antibody test. H. heilmannii was positive by immunostaining and pseudo-positive by PCR. We performed eradication therapy with esomeprazole, amoxicillin, clarithromycin, and metronidazole for 7 days, and 2 months after the treatment, endoscopic gastrointestinal examination revealed that the multiple ulcer lesions had improved. Biopsy specimens demonstrated that the small lymphocytes had also decreased, but lymphoid nodules were present. Six months after eradication therapy, there were signs of MALT lymphoma recurrence on endoscopic finding and biopsy specimen. We performed radiation therapy, and CR was confirmed by endoscopic and histologic examinations. We presented two rare cases of H. heilmannii associated MALT lymphoma. Several reports described the effectiveness of eradication therapy for H. pylori-negative gastric MALT lymphoma. H. heilmannii infection may be closely associated with etiology of H. pylori-negative gastric MALT lymphoma.

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

Since Isaacson and Wright first reported on the extra-nodal 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 approximately 90% 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.

Eradication Therapy Is Effective for <i>Helicobacter pylori</i>-Negative Gastric Mucosa-Associated Lymphoid Tissue Lymphoma

Mucosa-associated lymphoid tissue (MALT) lymphomas are extra-nodal B-cell lymphomas arising from MALT, and the most commonly affected organ is the stomach. Helicobacter pylori (H. pylori) eradication therapy with proton-pump inhibitors and antibiotics is the first-line therapy for H. pylori-positive gastric MALT lymphomas, but the effectiveness of the therapy for H. pylori-negative gastric MALT lymphomas remains controversial. Hence, we aimed to evaluate the effectiveness of this eradication therapy for H. pylori-negative MALT lymphomas. The H. pylori infection status of 158 gastric MALT lymphoma patients followed in our unit was judged by urea breath test, rapid urease test, histology of the biopsy specimen taken from the stomach during endoscopy, and serum antibody against H. pylori. Seventeen patients that were negative for all four tests and did not have gastric mucosal atrophy were treated with antibiotic eradication therapy. The average age at diagnosis was 56.8 years old (range: 36-73 years), and the median follow-up period after H. pylori eradication in all 17 patients was 5.3 years (range: 0.3-12.7 years). Five patients (29.4%) achieved complete remission (CR) by eradication therapy alone. Comparison between the responding and non-responding patients revealed that the patients endoscopically diagnosed to have a single lesion of gastric MALT lymphoma were seen only in the responding group, whereas all non-responding patients had multiple lesions (P < 0.05). In conclusion, H. pylori eradication therapy achieved a favorable CR rate in H. pylori-negative gastric MALT lymphoma patients and could be considered as a first-line therapy, especially for patients with a single lesion.

Treatment outcome of localizedHelicobacter pylori-negative low-grade gastric MALT lymphoma

To investigate treatment outcome of Helicobacter pylori (H. pylori)-negative low-grade gastric mucosa-associated lymphoid tissue (MALT) lymphoma. In this study, we retrospectively reviewed the clinical outcome and clinicopathologic factors of stage IE H. pylori-negative low-grade gastric MALT lymphoma cases from August 1998 to June 2009. A total of eleven patients with H. pylori-negative low-grade gastric MALT lymphoma were enrolled in the study and received anti-H. pylori eradication treatment and/or radiotherapy or excisional therapy. Complete remission (CR) of gastric MALT lymphoma was achieved in all patients. The time to CR was 1-66 mo (median, 1 mo). Eradication therapy may be offered as an initial treatment option even in cases of localized H. pylori-negative gastric MALT lymphoma.

An Aggressive MALT Lymphoma Despite Negative Helicobacter pylori Testing

Purpose: MALT lymphoma is a form of non-Hodgkin B cell lymphoma (NHL) involving the mucosa-associated lymphoid tissue (MALT); however, the occurrence of Helicobacter pylori-negative lymphoma of the stomach—a primary gastric lymphoma, is not very common. Methods: We report a case of a 49-year-old Hispanic female with complaints of intermittent gastric pain, nausea and occasional vomiting for 2 years. The patient stated her pain was dull and went away with food and admitted to weight loss. She denied any significant past medical history or any familial gastrointestinal issues. Her lab values were within normal limits, except for mild anemia. Her physical exam was notable for epigastric tenderness. Subsequently, the patient was scheduled for upper endoscopy which demonstrated superficial ulceration, limited distensibility and rigidity. Extensive biopsies of the antrum and proximal stomach revealed necrotic debris with acute leucocytic exudation and extranodal marginal zone B cell lymphoma. Giemsa staining and serology for H. pylori was negative. The patient was then empirically started on triple antibiotic therapy (Amox/clav/PPI) for H. pylori eradication, and scheduled for endoscopic ultrasound (EUS). The EUS demonstrated excellent 5 layer echopattern throughout the stomach. The MALT lymphoma appeared to be confined to the superficial antral mucosa without peri gastric lymph node involvement. The patient underwent repeat endoscopy with multiple biopsies 4 weeks later which showed histologic persistence of MALT lymphoma. She was therefore referred to an oncologist for systemic chemotherapy. Results: Presently, 12 clinical studies with almost 400 patients and case reports have shown that a cure of H. pylori infection is associated with complete remission in approximately 80% of patients with low-grade MALT lymphoma in an early clinical stage. However, what can be done if the patient is found to be H. pylori negative? Rates of about 7-15% of H. pylori-negative gastric MALT lymphoma patients have been reported. The reason for the occurrence of a maltoma without the evidence of H. pylori is unknown. Perhaps multiple etiological factors are at fault for the pathogenesis of MALT lymphoma. Conclusion: Eradication strategies may not entirely preclude the risk for neoplastic transformation. H. pylori negative associated MALT may indeed represent a different clinical entity with more aggressive characteristics. Though rates are low, they remain significant. Despite directed HP treatment, our patient demonstrated persistent malignacy and ultimately needed systemic chemotherapy.

Concerns about the Predictive Factors for Tumor Regression, Definition, and Management of Nonresponders, and Relapse of Gastric Mucosa-Associated Lymphoid Tissue Lymphoma Related to Helicobacter pylori

I read with interest the recent review article by Suzuki et al.1 This paper helps gastroenterologists to understand the link between gastric mucosa-associated lymphoid tissue (MALT) lymphoma and Helicobacter pylori (H. pylori), but several questions remain unanswered: (i) the predictive factors for regression of gastric MALT lymphoma after H. pylori eradication, (ii) the characteristic endoscopic findings, (iii) how to optimize the definition and managemnet of nonresponders, and (iv) how to manage the relapse and recurrence of these tumors. The first report in 19932 has been followed by numerous reports of regression of MALT lymphoma after H. pylori eradication. However, not all gastric MALT lymphomas regress after H. pylori eradication, and thus three factors related to the prediction of tumor regression need to be considered: (i) the characteristics of gastric MALT lymphoma itself, (ii) the presence of H. pylori infection, and (iii) factors related to the host, such as the score on the international prognostic index and blood-test results. For example, even the location of the tumor has been mentioned as a predictive factor, with gastric MALT lymphomas on the proximal side being linked to autoimmunity.3 These proximal-side tumors progress very slowly and often fail to regress because they are linked to autoantigen responsive T cells.3,4 In addition, histological features of MALT lymphoma are known to be unresponsive to eradication therapy.5 An endoscopic apperance mimiking submucosal tumors and cobblestone like elevated lesions have been classified as polypoid gastric MALT lymphoma, and characterized as H. pylori-negative gastric MALT lymphoma.6,7 Although Suzuki et al. described this briefly in their review,1 H. pylori negativity needs to be defined. Since there is no single gold-standard methods for diagnosing H. pylori infection, the combination of several diagnostic methods including H. pylori IgG antibody, histology, culture, immunohistochemistry, PCR, and the urease breath test is considered to be suitable for confirming H. pylori negativity.8 In addition, the characteristics of H. pylori-negative gastric MALT lymphoma should be managed based on previous reports.9 Put simply, the treatment should differ from H. pylori eradication in these H. pylori-negative gastric MALT lymphoma due to the absence of H. pylori. However, these lymphomas also respond to antibiotic treatment in both the stomach and other parts of the gastrointestinal tracts.10 What mechanism underlies this phenomenon? Does this represent a clue for a false-negative diagnosis of H. pylori infection? What would be the possible hypothesis based on previous reports? On the other hand, non-H. pylori helicobacters related to MALT lymphoma should also be considered, such as H. helimannii and H. felis.11 Interestingly, some of these regress merely after the application of first-line H. pylori eradication therapy.12 In addition, these organisms are detected in both gastric and rectal lymphomas.13 Optimizing the definition and management of nonresponders requires consideration of three issues: (i) the minimum observation period needed to define regression, (ii) interpretating discrepancies between the histologic and endoscopic regression, and (iii) choosing between a wait and see and a second-line treatment such as gastrectomy, chemotherapy, and radiotherapy. Although a Japanese study adressed the last issue,14 the optimal strategy remains unclear. In addition to the definition and management, the relapse and recurrence of gastric MALT lymphoma after successful regression on H. pylori eradication also need to be clarified. There are some reports of the development of high-grade tumor (diffuse large B-cell lymphoma) or gastric adenocarcinoma after successful regression of gastric MALT lymphoma. What would be the mechanisms and prognostic factors in such tumors? In summary, answers to the above questions that arose when I read the review by professor Suzuki and colleagues would be of considerable interest to readers of Gut and Liver. There are already several interesting published papers written by Japanese authors that strengthen our knowledge in this field, and I strongly believe that addressing the above issues would greatly increase the interest in their review article.

Long-term Clinical Outcome of Helicobacter pylori-negative Gastric Mucosa-associated Lymphoid Tissue Lymphoma is Comparable to That of H. pylori-positive Lymphoma

Little is still known regarding the clinical features and prognosis of gastric mucosa-associated lymphoid tissue (MALT) lymphoma without Helicobacter pylori (H. pylori) infection. From January 1996 to April 2006, a total of 185 patients with gastric MALT lymphoma were enrolled at Seoul National University Hospital. To assess the differences in clinical characteristics and long-term outcomes between H. pylori-negative (n=29, 15.7%) and H. pylori-positive (n=156, 84.3%) cases, we compared these 2 types of lymphoma. The overall median follow-up period was 39 months. There were no significant differences between the 2 groups in terms of age, macroscopic phenotype, or histologic grade. H. pylori-negative group showed male predominancy (72.4%) and higher percentage of proximal stomach location (62.1%). Although H. pylori-negative lymphomas were more frequently presented as advanced disease (stage IIE or IV, 37.9%), no significant differences in both the overall complete response and overall survival rates were observed between the 2 groups. Our results suggest that H. pylori-negative gastric MALT lymphoma shows a favorable long-term outcome, which is comparable to that of H. pylori-positive lymphoma.

A Case Report of Helicobacter Pylori Negative Gastric MALT Lymphoma with Monoclonal Gammopathy

Lymphomas of mucosa-associated lymphoid tissue (MALT) comprise 7% of all newly diagnosed non-Hodgkin’s lymphomas. Helicobacter pylori (H. pylori) negative gastric MALT lymphomas account for 28 to 45% of gastric MALT lymphomas. H. pylori infection has a close relationship with most gastric low-grade B cell lymphomas of the MALT type. Monoclonal gammopathy can be seen in 36% of the patients and negatively associated with responses to eradication of H. pylori in gastric MALT lymphoma. Here, we describe a case of H. pylori negative MALT lymphoma that arose from the stomach with massive plasmacytic differentiation mimicking an extramedullary plasmacytoma with monoclonal gammopathy, and that was cured by total gastrectomy, chemotherapy and radiotherapy.

Helicobacter pylori‐negative gastric mucosa‐associated lymphoid tissue lymphoma

The majority of gastric mucosa-associated lymphoid tissue (MALT) lymphoma develops in Helicobacter pylori-associated chronic gastritis. Little is still known regarding the clinicopathologic features of gastric MALT lymphoma not associated with H. pylori infection. One hundred thirty-seven patients with gastric MALT lymphoma, in whom H. pylori status was evaluated using at least both serology and histology, were enrolled. Clinical, histopathologic, and molecular findings were compared between H. pylori-negative group (n = 12; 9%) and H. pylori-positive group (n = 125; 91%). t(11;18)(q21;q21) was investigated by reverse-transcription polymerase chain reaction and interphase fluorescence in situ hybridization. In cases without diffuse large B-cell lymphoma (DLBCL) component, H. pylori-negative lymphomas located more frequently in the proximal stomach (70%), less frequently appeared as superficial type (40%), and frequently invaded the submucosa or beyond (70%). Histologically, lymphoepithelial lesions (57%), lymphoid follicles (43%), and background mucosal atrophy (50%) in the H. pylori-negative group were less frequent than in the H. pylori-positive group (91%, 93%, and 100%, respectively). The frequencies of t(11;18)(q21;q21) (100%) and BCL10 nuclear expression (100%) in the H. pylori-negative group were significantly higher than in the H. pylori-positive group (2% and 27%, respectively). Response to antibiotic treatment was observed not only in the H. pylori-positive group (75%), but also in the H. pylori-negative group (2 of 7 patients, 29%). In cases with a DLBCL component, such differences were not observed between the 2 groups. H. pylori-negative gastric MALT lymphoma is characterized by frequent t(11;18)(q21;q21). Antibiotic treatment should be considered also for this disease, although cases with t(11;18)(q21;q21) may need additional strategies.

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.

Comparison of Localized Gastric Mucosa‐Associated Lymphoid Tissue (MALT) Lymphoma with and without Helicobacter pylori Infection

The clinical features and clinical course of Helicobacter pylori-negative gastric mucosa-associated lymphoid tissue (MALT) lymphoma are unclear and a treatment strategy has not yet been established. To clarify the clinical differences between H. pylori-positive and H. pylori-negative gastric MALT lymphoma, we compared these two types of gastric MALT lymphoma. Fifty-seven patients with localized gastric MALT lymphoma were studied. H. pylori infection was present in 41 and absent in 16. Treatment consisted of antibiotic therapy and/or 30 Gy radiation therapy. Response assessment was performed every 3-6 months by esophagogastroduodenoscopy including gathering biopsy samples, endoscopic ultrasonography, clinical examination, and various imaging procedures. The median follow-up period was 37 months. There were no significant differences between H. pylori-positive and H. pylori-negative gastric MALT lymphoma patients in terms of sex, age, stage, gross phenotype, affected area of the stomach, or the presence of monoclonality. Complete regression was achieved with antibiotic therapy against H. pylori-negative gastric MALT lymphoma in one of nine patients (11.1%), compared to 28 of 38 patients (73.7%) with H. pylori-positive gastric MALT lymphoma (p < .001). Radiation therapy showed high effectiveness for the local control of H. pylori-negative or antibiotic-resistant gastric MALT lymphoma (92.9%), although distant recurrence was recognized in three of 14 patients (21.4%). Two of 16 patients (12.5%) with H. pylori-negative gastric MALT lymphoma died because of the transformation of the disease into diffuse large B-cell lymphoma. There was a significant difference in both the overall and cause-specific survival rate between the two groups (p = .038). Radiation therapy is the effective treatment for H. pylori-negative or antibiotic-resistant localized gastric MALT lymphoma. However, careful systemic follow-up for distant involvement should be required. Transformation into diffuse large B-cell lymphoma is thought to be the important cause of death in patients with gastric MALT lymphoma.