Low-grade Gastric Lymphoma Research Articles

Mutational Analysis of the 5′ Noncoding Region of the Bcl-6 Gene in Primary Gastric Lymphomas

Bcl-6 mRNA and protein are frequently expressed in the transformed counterparts of the germinal center B-cells, diffuse large B-cell lymphoma and follicular lymphoma, irrespective of the gene rearrangements. Most of the primary gastric lymphomas are thought to be of mucosa-associated lymphoid tissue (MALT) origin, and neither bcl-6 gene rearrangement nor protein expression is found in low-grade gastric lymphomas of the MALT type as in normal marginal zone cells. However, bcl-6 protein expression was identified in high-grade gastric lymphomas, suggesting its role in high-grade transformation. In this study, polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analysis for bcl-6 primer was performed in order to ascertain the molecular mechanisms of bcl-6 protein expression in primary gastric lymphomas. A total 31 cases of gastric lymphoma were classified into low-grade gastric lymphomas of MALT type (n = 13), high-grade gastric lymphomas of MALT type (n = 6) and gastric diffuse large B-cell lymphomas (n = 12). Bcl-6 mutations were observed in 11 of 13 (84.6%) low-grade gastric lymphomas of the MALT type and in 8 of 12 (66.7%) diffuse large B-cell gastric lymphomas. In 6 cases of the high-grade gastric lymphomas of the MALT type, both the low- and high-grade components demonstrated the same frequency (3/6, 50%) of mutations. The tissue obtained from the marginal zone of Peyer's patch by microdissection technique revealed no bcl-6 mutations by the PCR-SSCP analysis. These findings suggest that the acquisition process of bcl-6 mutations by the marginal zone cells may be involved in the lymphomagenesis of the stomach, but our data does not explain the reason why bcl-6 protein is expressed only in high-grade gastric lymphomas.

Complete remission of primary high-grade B-cell gastric lymphoma after cure of Helicobacter pylori infection.

Treatment of low-grade gastric mucosa-associated lymphoid tissue lymphoma by eradication of Helicobacter pylori is reported to result in complete lymphoma remission in approximately 75% of cases. The effect that cure of the infection has on the course of a primary high-grade gastric lymphoma is largely uncertain. The aim of this study was to report the effect of cure of H pylori infection exerted in patients with high-grade B-cell gastric lymphoma. Eight patients (4 males and 4 females; age range, 26 to 85 years) with H pylori infection and high-grade lymphoma received eradication therapy before planned treatment. The effect of H pylori eradication on the course of high-grade lymphoma was assessed by analysis of surgical specimens (n = 2) or endoscopic biopsies (n = 6). H pylori eradication was successful in all patients and led to complete remission of the lymphoma in seven patients. One patient has experienced partial remission. Two patients were referred to surgery, one of whom (stage II(1E)) had lymph node involvement, and the histologic work-up of the resected stomach revealed residual infiltrates of a low-grade lymphoma, which prompted consolidation chemotherapy. In one patient (initially stage I(1E)), abdominal lymphoma developed 6 months after eradication therapy, which regressed completely after chemotherapy. In four patients, no further treatment was given. Six patients continue in complete remission (range, 6 to 66 months). Primary high-grade B-cell gastric lymphoma in stages I(E) through II(E1) associated with H pylori may regress completely after successful cure of the infection. Prospective trials are needed to investigate this treatment in larger numbers of patients.

When can complete regression of low-grade gastric lymphoma of mucosa-associated lymphoid tissue be predicted after helicobacter pylori eradication?

Recent studies suggest that primary low-grade gastric lymphomas of mucosa-associated lymphoid tissue (MALT) are cured in many cases between 1 and 18 months after H. pylori eradication. The aim of this study is to elucidate when complete regression (CR) of MALT lymphoma can be histologically predicted after H. pylori eradication. Twenty-one patients with low-grade gastric MALT lymphoma were treated with triple therapy (amoxicillin, clarythromycin and proton pump inhibitor) for 14 days. Subsequently, they were followed up by sequential endoscopy and biopsy (number of biopsy specimens for each endoscopy is 3-8, with an average of 4) from 91 to 657 days (average: 309 +/- 165 days). Eradication of H. pylori infection was achieved in all patients. Nine patients were free of lymphoma at 1 to 2 months after eradication and remained in CR at 163-657 days. Twelve patients showed residual lymphoma at 1 to 2 months after eradication. Five out of 12 patients revealed only one or two small foci of lymphoma-cell aggregation and showed a high incidence (80%) of CR at the latest biopsy (135-434 days, average 276 +/- 115 days after eradication), while seven patients showed diffuse remains of lymphoma cells and indicated CR in only one case (14%) at 362 days, partial regression in five cases at 130-431 days (average 227 +/- 114 days), and no change in one case at 91 days after eradication. : These results suggest that CR of low-grade MALT lymphoma can be predicted at 1 to 2 months after eradication therapy by checking histological changes of MALT lymphoma cells.

Protection of BALB/c mice against experimental Helicobacter pylori infection by oral immunisation with H pylori heparan sulphate-binding proteins coupled to cholera toxin beta-subunit.

The presence of Helicobacter pylori in the gastroduodenal mucosae is associated with chronic active gastritis, peptic ulcers and gastric cancers such as adenocarcinoma and low-grade gastric B-cell lymphoma. In response to the presence of antibiotic-resistant strains, the use of vaccines to combat this infection has become an attractive alternative. The present study used a murine model of infection by a mouse-adapted H. pylori strain to determine whether infection in BALB/c mice can be successfully eradicated by intragastric vaccination with H. pylori heparan sulphate-binding proteins (HSBP) covalently coupled to the beta-subunit of cholera toxin (CTB). It was shown that vaccination confers protection against exposure of BALB/c mice to the pathogen, as revealed by microbiological, histopathological and molecular methods.

7235 Endoscopic ultrasonography in gastric malt and gastritis.

A close association between gastric Helicobacter pylori infection and MALT lymphoma of the stomach has been described and H. pylorieradication can result in histological regression of the gastric lymphoma in most cases. Recent studies suggest that EUS may provide informations useful to predict the lymphoma response to antibiotic therapy: deeper the gastric wall infiltration lower the response rate. AIMS:to compare the gastric wall structure in early gastric MALT lymphoma and chronic H. pylori -associated gastritis. METHODS:10 pts. with low grade gastric MALT lymphoma occasionally diagnosed by biopsies taken in the presence of an endoscopic pattern of gastritis and 10 pts. with H. pylori -associated gastritis were evaluated. Both groups have negative endoscopic appearance (no severe lesions except erythema or aspect of mild atrophy). EUS was performed with a radial (Olympus GF-UM 20 7.5-12 MHz) echoendoscope with the water-filled technique. Thickness of the entire gastric wall and of the mucosa and submucosa layers was measured in antrum, corpus and fundus. RESULTS:structure of the wall with respect to echogenicity, layering and thickness is similar in the two groups (i.e. low-grade MALT lymphoma and gastritis). CONCLUSION:Patients with histological diagnosis of lowgrade gastric lymphoma but no evidence of any endoscopic lesions showed an EUS pattern with normal frequencies (7.5-12 MHz) superimposable to the one observed in H. pylori -associated gastritis. This subset of MALT lymphoma patients may have an early disease with the highest chances of prolonged remission with antibiotic therapy.

Is there an obligatory need for an oncological treatment modality if helicobacter pylori eradication is not followed by complete regression of gastric low-grade lymphoma of malt-type?

Is there an obligatory need for an oncological treatment modality if helicobacter pylori eradication is not followed by complete regression of gastric low-grade lymphoma of malt-type?

Management and long-term results of surgery for localized gastric lymphomas

Background: High- and low-grade gastric lymphomas (GL) differ in their behavior and chemosensitivity. Surgery has to be reevaluated according to the histologic grade of malignancy. We aimed to assess the place of surgery in the management of GL and its results after long-term follow-up. Methods: Among 54 patients with primary GL prospectively enrolled from 1984 to 1990, 45 with localized disease were studied. Primary resection was done whenever safe. All patients received chemotherapy adapted to the grade of malignancy and/or to the completeness of the resection. Results: Among 18 low- and 27 high-grade GL, 35 patients had primary resections; of those, 23 were complete. The complete response rate for all patients with low- and high-grade GL was 67% and 89%, respectively. After a median follow-up of 8 years, the disease-free survival rates for low-grade GL and high-grade GL were 94% and 89%, respectively. It was better after complete resection. Conclusion: Complete resection is a major determinant of prolonged complete remission.

Prevalence of Helicobacter pylori resistant strains in the southern part of Switzerland

Discovered in the last decade, Heliobacter pylori is now known to play a role in the onset of chronic gastritis and peptic ulcer and also to be strongly associated with gastric cancer and MucosaAssociated Lymphoid Tissue (MALT) lymphoma [1,2]. These findings have revolutionized the therapeutical approach to gastric pathology. Moreover, the wide spread of dyspeptic symptoms has contributed to the development of a variety of noninvasive diagnostic assays, such as the urea breath test, serologic and whole blood tests, most of which are available to the primary care physicians for the rapid diagnosis of H. pylori infection. As a consequence, antibiotic eradication therapy has been widely applied, often without endoscopic examination which is essential for the identification of the cause of the gastric pathophysiological disturbances. At present, the most commonly used treatment is the triple therapy: a proton pump inhibitor and two antibiotics (metronidazole plus clarithromycin, or amoxycillin plus clarithromycin, or metronidazole plus amoxycillin) [3]. Because of the abuse of this therapeutic scheme, a consistent increase in metronidazole and clarithromycin resistance among H. pylori strains has been monitored [4,5]. Recently the first case of an amoxycillin-resistant H. pylori strain has also been reported [6]. The appearance of resistant strains is one of the major causes of treatment failure [7]. Thus, monitoring the prevalence of resistant strains and establishing the local susceptibility level to the commonly used drugs is at least as important as the development of new antimicrobial agents. For this reason and because of the high incidence of gastric cancer in our region [8,9] (the southern part of Switzerland together with the northern part of Italy) we collected 142 H. pylori strains from different patients living in the Cantone Ticino (southern part of Switzerland) in 1996 and 1997. These strains were tested for susceptibility to metronidazole, clarithromycin and amoxycillin. Minimum inhibitory concentrations (MICs) of 142 H. pylori strains were determined using the E-test method (AB Biodisk, Solna, Sweden) according to the manufacturer’s instructions. The MIC breakpoint values for H. pylori resistance were chosen according to the available data published in the literature: 8 mg/L for both metronidazole and clarithromycin, and 2 mg/L

Histological and immunological parameters to predict the outcome after Helicobacter pylori eradication in low-grade gastric lymphoma

Departments of Gastroenterology, Immunology and 3Pathology, The Netherlands Cancer Institute/Antonio van Leeuwon hoekhuis, Amsterdam

Low-grade gastric mucosa-associated lymphoid tissue lymphoma: correlation of radiographic and pathologic findings.

To describe upper gastrointestinal (Gl) examination findings of low-grade gastric mucosa-associated lymphoid tissue (MALT) lymphoma and to correlate them with pathologic examination findings. A retrospective review of upper Gl examinations was performed in 25 patients with proved low-grade gastric MALT lymphomas. Upper Gl examinations were reviewed for common findings and most probable diagnosis, and these findings were correlated with pathologic findings in resected specimens in 15 patients. The common findings at upper Gl examination included mucosal nodularity (n = 13), ulcer (n = 12), rugal thickening (n = 6), mass (n = 4), and enlarged areae gastricae (n = 2). The most probable diagnoses were early gastric carcinoma (n = 7), advanced gastric carcinoma (n = 6), gastritis (n = 9), and lymphoma (n = 3). Of 17 lesions found on resected specimens, six ulcers and two masses were not depicted at barium study. Disorganized convergent rugae projecting to multiple points and vague ulcer margins were present in four and seven lesions, respectively. Multiple ulcers were seen in two patients. Although the common radiographic and pathologic findings observed in low-grade gastric MALT lymphomas were similar to those of gastric carcinomas or gastritis, disorganized convergent rugae, vague ulcer margins, and multiplicity of lesions may be helpful in differentiating them from gastric carcinomas or gastritis.

Frequency of vacA genotypes and cytotoxin activity in Helicobacter pylori associated with low-grade gastric mucosa-associated lymphoid tissue lymphoma.

The vacA genotypes s1,m1 and s1,m2 were detected in 44 and 30% of Helicobacter pylori isolates, respectively, from patients with gastric mucosa-associated lymphoid tissue lymphoma, compared to 26 and 56% of isolates, respectively, from individuals with gastritis. The vacA s1 genotype was significantly associated with, but not predictive of, the presence of vacuolating cytotoxin activity.

Gastric low-grade mucosa-associated lymphoid tissue lymphomas: their histogenesis and high-grade transformation.

Gastric low-grade mucosa-associated lymphoid tissue (MALT) lymphoma is a unique disease. A vast majority of lymphoma cells are centrocyte-like cells or resemble monocytoid B cells, and occasionally show plasmacytic differentiation. Immunophenotypical and immunogenotypical examinations have indicated that they are in the differentiation stage of memory B cells, whose normal counterparts are marginal zone lymphocytes or monocytoid B cells in the lymphoid tissues. It arises from chronic gastritis closely associated with Helicobacter pylori (H. pylori) infection. Mucosa-associated lymphoid tissue lymphomas of other organs are also based on acquired MALT associated with chronic inflammation or autoimmune diseases. Interestingly, the majority of gastric low-grade MALT lymphomas regress by the eradication of H. pylori. The lymphoma cells, however, are not derived from B cells reacting with H. pylori itself but from autoreactive B cells. Although the mechanism of their oncogenesis has not been clarified, previous data suggest that autoreactive B cells proliferate in response to H. pylori-specific T cells, presumably with some cytokines. The genetic instability of such B cells then induces chromosomal abnormalities including trisomy 3 and/or other genetic changes. These B cells have the ability of autonomic proliferation and, even so, they might be sensitive to T cell stimuli. Low-grade gastric lymphomas occasionally progress to high-grade malignancy. The high-grade component of MALT lymphomas are composed of large-sized lymphoma cells that are morphologically indistinguishable from nodal large B cell lymphomas. This high-grade transformation is associated with p53 abnormalities or Bcl-6 overexpression. Gastric MALT lymphoma may provide a useful model in understanding multistep lymphomagenesis.

Treatment of low-grade gastric lymphoma with anti-Helicobacter pylori triple therapy and chemotherapy

Treatment of low-grade gastric lymphoma with anti-Helicobacter pylori triple therapy and chemotherapy

Mutation of the 5′ Noncoding Region of the BCL-6 Gene in Low-Grade Gastric Lymphoma of the Mucosa-Associated Lymphoid Tissue

BCL-6 gene rearrangement and hypermutations were investigated in four Hong Kong Chinese patients with low-grade gastric lymphoma of the mucosa-associated lymphoid tissue (MALToma). The former was studied by Southern analysis and the latter by the technique of polymerase chain reaction and denaturing gradient gel electrophoresis. BCL-6 gene rearrangement was not detectable in any of the four cases. However, mutations at both the E1.11 and E1.12 segments of the 5′ noncoding region of the BCL-6 gene were found in two patients. This preliminary observation suggests that the mutations of the 5′ noncoding region of the BCL-6 gene rather than gene rearrangement may be playing a more important role in the tumorigenesis of low-grade gastric MALToma. Further confirmation of this finding by studying a larger number of patients will be required.

Classification of Primary Gastric Lymphomas According to Histologic Features

Histologic features of low-grade gastric lymphomas of mucosa-associated lymphoid tissue (MALT) have been extensively described, and transformation to a large cell (high-grade) lymphoma can occur. We characterize high-grade gastric lymphoma histologically in an attempt to distinguish between MALT-type and non-MALT-type lesions. We studied a series of 60 gastric lymphomas and characterized them clinically, histopathologically, and immunophenotypically. Low-grade gastric lymphomas were classified according to established criteria. High-grade lymphomas were classified in three groups based on the presence or absence of a low-grade component and lymphoepithelial lesions (LELs): 1) high-grade MALT lymphomas appearing in low-grade MALT lymphomas (LG/HG MALT lymphoma); 2) large cell lymphoma with LELs composed of large cells (high-grade LELs) but without a low-grade component (HG MALT lymphoma); and 3) diffuse large cell lymphoma without a low-grade MALT lymphoma component or LELs (DLCL). Twenty-two lymphomas were classified as low-grade MALT lymphomas, 16 as LG/HG MALT lymphomas, 10 as HG MALT lymphomas, and 12 as DLCL. B-cell immunophenotype was confirmed in all 55 cases in which immunophenotyping was performed. Low-grade LELs were seen in all low-grade MALT lymphomas, and CD20(L26) expression confirmed B-cell phenotype in the LELs in 20 of 20 cases. Clinical follow-up was available for 56 patients (range, 1-264 months; mean, 57 months). Actuarial analysis of disease-specific survival and relapse-free survival showed that clinical stage was highly statistically significant (P < 0.0001), whereas histologic type and grade approached statistical significance. Multivariate analysis showed that clinical stage was the only significant factor in relapse-free and disease-specific survival.

Therapeutic intragastric vaccination against Helicobacter pylori in mice eradicates an otherwise chronic infection and confers protection against reinfection.

Chronic infection of the gastroduodenal mucosae by the gram-negative spiral bacterium Helicobacter pylori is responsible for chronic active gastritis, peptic ulcers, and gastric cancers such as adenocarcinoma and low-grade gastric B-cell lymphoma. The success of eradication by antibiotic therapy is being rapidly hampered by the increasing occurrence of antibiotic-resistant strains. An attractive alternative approach to combat this infection is represented by the therapeutic use of vaccines. In the present work, we have exploited the mouse model of persistent infection by mouse-adapted H. pylori strains that we have developed to assess the feasibility of the therapeutic use of vaccines against infection. We report that an otherwise chronic H. pylori infection in mice can be successfully eradicated by intragastric vaccination with H. pylori antigens such as recombinant VacA and CagA, which were administered together with a genetically detoxified mutant of the heat-labile enterotoxin of Escherichia coli (referred to as LTK63), in which the serine in position 63 was replaced by a lysine. Moreover, we show that therapeutic vaccination confers efficacious protection against reinfection. These results represent strong evidence of the feasibility of therapeutic use of VacA- or CagA-based vaccine formulations against H. pylori infection in an animal model and give substantial preclinical support to the application of this kind of approach in human clinical trials.

Editorial: The Role of Endoscopy in the Diagnosis and Follow-up of Low-Grade Gastric Mucosa-Associated Lymphoid Tissue Lymphoma

Low-grade gastric mucosa-associated lymphoid tissue (MALT) lymphoma is a rare gastric neoplasia that arises from mucosa-associated lymphoid tissue. Histologic criteria for diagnosing this neoplasia have been defined, as has the key role of Helicobacter pylori in its origin. Endoscopic aspects of low-grade MALT-lymphoma vary considerably in diagnosis and follow-up, ranging from normal-appearing mucosa to obviously malignant lesions, and thus they have a low diagnostic value. Because an earlier diagnosis of low-grade MALT-lymphoma is now possible through such sophisticated techniques as the polymerase chain reaction, low-grade MALT-lymphoma will be diagnosed in the future more frequently with minimal macroscopic lesions or even without them.

Endoscopic ultrasonography for the initial staging and follow-up in patients with low-grade gastric lymphoma of mucosa-associated lymphoid tissue treated medically

Background: Endoscopic ultrasonography is an appropriate procedure to assess the depth of tumoral infiltration in primary gastric lymphoma. The aims of the present study were to characterize the endoscopic ultrasonographic aspects of low-grade gastric lymphoma of mucosa-associated lymphoid tissue and to determine the value of this procedure in medical treatment assessment. Methods: Between 1991 and 1996, 15 patients with low-grade gastric lymphoma of mucosa-associated lymphoid tissue were treated with oral cyclophosphamide and/or anti- Helicobacter pylori treatment. Endoscopic ultrasonography was carried out at the time of the diagnosis in all patients, 8 of whom (4 in complete remission and 4 with a stable or progressive disease) had at least one endoscopic ultrasonography examination within the treatment period (median follow-up 17 months). Results: The initial procedure showed an increased gastric wall thickness from 6 to 12 mm in 8 patients, equal to 5 mm in 5 patients, and normal in 2 patients. The thickening was predominantly of the mucosa alone and/or the submucosa but never extended beyond the muscularis propria. No lymph node was found. Gastric wall thickness returned to normal in the 4 patients in complete remission and remained thick in 3 of the 4 patients with a stable or progressive disease. Of these 3 patients, at least one set of biopsy samples, carried out during follow-up, showed the absence of lymphoma, but histology performed subsequently found evidence of disease. Conclusions: Endoscopic ultrasonography differentiates superficial from infiltrative types of gastric lymphoma of mucosa-associated lymphoid tissue, which may have a prognostic significance and confirms remission or persistence of the disease with medical treatment during follow-up. When the gastric wall remains thick, even if histology is negative, repeated biopsies should be performed to detect evolving disease or relapse. (Gastrointest Endosc 1997;46:328-33)

Cure of Helicobacter pylori infection and duration of remission of low-grade gastric mucosa-associated lymphoid tissue lymphoma.

Low-grade B-cell lymphomas arising in mucosa-associated lymphoid tissue (MALT) are most frequently localized in the gastrointestinal tract. More than 90% of gastric MALT lymphomas are diagnosed in patients with chronic, Helicobacter pylori-associated gastritis. High remission rates for these lymphomas have been observed after the cure of H. pylori infection. Data are lacking, however, with regard to the duration of the remissions. To address this question of remission duration, we have followed 50 patients in whom H. pylori infections were eradicated, and we determined whether the patients in complete remission displayed evidence of residual monoclonal B cells during follow-up. Patients were treated with amoxycillin and omeprazole for 2 weeks in an attempt to cure H. pylori infections. Follow-up included endoscopic investigations with biopsy sampling. Monoclonal B cells in biopsy specimens were detected by means of a polymerase chain reaction (PCR)-based assay. H. pylori infections were cured in all 50 patients. The median follow-up for the 50 patients is currently 24 months (729 days; range, 135-1411 days). Forty patients achieved complete remission of their lymphomas, but five have subsequently relapsed. The median time of continuous complete remission for the 40 patients was 15.4 months (468 days; range, 0-1198 days). Among six patients whose Iymphomas did not respond to H. pylori eradication, four revealed high-grade lymphomas upon surgery. PCR indicated the presence of monoclonal B cells during follow-up in 22 of 31 assessable patients in complete remission. Complete remissions of low-grade gastric MALT Iymphomas after the cure of H. pylori infection appear to be stable, although most patients display evidence of monoclonal B cells during follow-up. Whether these patients are truly cured of their Iymphomas remains to be determined.

Endoscopic ultrasound in the evaluation of gastric small lymphocytic mucosa-associated lymphoid tumors.

Low-grade, small lymphocytic lymphomas of the mucosa-associated lymphoid tissue (MALT) have recently been shown to be associated with Helicobacter pylori infections. Regression of these tumors has been reported with antibiotic therapy. Here we evaluate endoscopic ultrasound (EUS) as on objective method to evaluate pretreatment disease and posttherapy response. We retrospectively reviewed 20 patients initially diagnosed elsewhere with MALT lymphoma. All patients had their initial endoscopic biopsies (EGDs) reviewed at Memorial Sloan-Kettering Cancer Center (MSKCC). All patients had EUS performed at the time of consultation and on completion of therapy if treated at our center. Antral biopsies were stained with a modified Steiner preparation to determine infection by H pylori. Gastric low-grade lymphoma was confirmed in 16 of 20 patients; 11 of 16 had previously received antibiotic therapy for biopsy-positive H pylori infection. All gastric lymphomas had an abnormal EUS: eight with discrete tumor masses and eight with gastric wall infiltration (submucosa, n = 4; muscularis propria, n = 3; serosa, n = 1). On completion of lymphoma treatment with chemotherapy, radiotherapy, or surgery, 11 of 16 patients underwent follow-up EUS. Five patients received care elsewhere and did not return for posttreatment EUS. The gastric wall was normal with no evidence of disease on EUS-guided biopsy in eight of 11 patients. The remaining three patients had abnormal gastric walls. One was biopsy-negative and two had residual lymphoma. Four patients were found to have benign lymphoid aggregates in association with H pylori on initial EGD and EUS biopsies. All four patients were previously untreated with antibiotics. EUS showed prominent mucosa, but no significant findings within the gastric wall. EUS appears useful to stage objectively and evaluate therapeutic outcome in the management of gastric, low-grade MALT lymphomas. It also helps to distinguish benign lymphoid aggregates from lymphoma associated with H pylori infection. EUS findings may have a significant impact on assessment and therapeutic recommendations.