[Radiotherapy for localized gastric and orbital MALT lymphomas]. / Radiothérapie des lymphomes malins non hodgkiniens localisés de type MALT (gastriques et de la région orbitaire).

Primary gastric and orbital MALT lymphomas are both low grade (indolent) B-cell non-Hodgkin's lymphomas. Traditionally, these tumors are radiosensitive and have a good prognosis. In localized orbital and stages IE-IIE gastric MALT lymphomas without Helicobacter pylori infection or in case of persistent H. pylori infection after eradication therapy, several retrospective studies have shown that radiotherapy was an effective and well-tolerated treatment.

EGILS consensus report. Gastric extranodal marginal zone B-cell lymphoma of MALT.

This consensus report of the EGILS (European Gastro-Intestinal Lymphoma Study) group includes recommendations on the management of gastric extranodal marginal zone B-cell lymphoma of MALT. They are based on data from the literature and on intensive discussions and votings of the experts during their annual meetings.

Differential expression of NF-kappaB target genes in MALT lymphoma with and without chromosome translocation: insights into molecular mechanism.

Mucosa-associated lymphoid tissue (MALT) lymphoma is characterized by t(11;18)(q21;q21)/API2-MALT1, t(1;14)(p22;q32)/BCL10-IGH and t(14;18)(q32;q21)/IGH-MALT1, which commonly activate the nuclear factor (NF)-kappaB pathway. Gastric MALT lymphomas harboring such translocations usually do not respond to Helicobacter pylori eradication, while most of those without translocation can be cured by antibiotics. To understand the molecular mechanism of these different MALT lymphoma subgroups, we performed gene expression profiling analysis of 21 MALT lymphomas (13 translocation-positive, 8 translocation-negative). Gene set enrichment analysis (GSEA) of the NF-kappaB target genes and 4394 additional gene sets covering various cellular pathways, biological processes and molecular functions have shown that translocation-positive MALT lymphomas are characterized by an enhanced expression of NF-kappaB target genes, particularly toll like receptor (TLR)6, chemokine, CC motif, receptor (CCR)2, cluster of differentiation (CD)69 and B-cell CLL/lymphoma (BCL)2, while translocation-negative cases were featured by active inflammatory and immune responses, such as interleukin-8, CD86, CD28 and inducible T-cell costimulator (ICOS). Separate analyses of the genes differentially expressed between translocation-positive and -negative cases and measurement of gene ontology term in these differentially expressed genes by hypergeometric test reinforced the above findings by GSEA. Finally, expression of TLR6, in the presence of TLR2, enhanced both API2-MALT1 and BCL10-mediated NF-kappaB activation in vitro. Our findings provide novel insights into the molecular mechanism of MALT lymphomas with and without translocation, potentially explaining their different clinical behaviors.

Most patients with minimal histological residuals of gastric MALT lymphoma after successful eradication of Helicobacter pylori can be managed safely by a watch and wait strategy: experience from a large international series.

BACKGROUND: Eradication of Helicobacter pylori is the established initial treatment of stage I MALT (mucosa associated lymphoid tissue) lymphoma. Patients with minimal persisting lymphoma infiltrates after successful eradication of H pylori are considered treatment failures and referred for radiation, chemotherapy, immunotherapy, or surgery. AIM: To report a watch and wait strategy in such patients. METHODS: 108 patients were selected from a larger series of patients treated at various European institutions. Their mean age was 51.6 years (25 to 82), and they were all diagnosed as having gastric marginal zone B cell lymphoma of MALT type stage I. After successful H pylori eradication and normalisation of the endoscopic findings, lymphoma infiltrates were still present histologically at 12 months (minimal histological residuals). No oncological treatment was given but the patients had regular follow up with endoscopies and multiple biopsies. FINDINGS: Based on a follow up of 42.2 months (2-144), 102 patients (94%) had a favourable disease course. Of these, 35 (32%) went into complete remission. In 67 (62%) the minimal histological residuals remained stable and no changes became evident. Local lymphoma progression was seen in four patients (5%), and one patient developed a high grade lymphoma. CONCLUSIONS: Most patients with minimal histological residuals of gastric MALT lymphoma after successful eradication of H pylori had a favourable disease course without oncological treatment. A watch and wait strategy with regular endoscopies and biopsies appears to be safe and may become the approach of choice in this situation. Longer follow up is needed to establish this definitively.

[MALT gastric lymphomas]. / Les lymphomes gastriques du MALT.

INTRODUCTION: The stomach is the most common site involved in primary gastrointestinal lymphoma. Gastric lymphoma originates from the mucosa-associated lymphoïd tissue so called MALT. It comprises a group of distinctive clinicopathological entities which are important to consider for clinical management. CURRENT KNOWLEDGE AND KEY POINTS: In recent years, new diagnostic tools and new treatment strategies have improved the overall prognosis. One of the most exciting recent discoveries is the hypothesis that an infection by a bacterium, Helicobacter pylori has a decisive role in gastric lymphoma. FUTURE PROSPECTS AND PROJECTS: Recent advances, essentially due to molecular biology and cytogenetic studies may emerge with the understanding of pathogenesis and new prognostic factors of these different types of gastric lymphomas. It is the aim of our oncoming studies together with the evaluation of the new therapeutic options such as radiotherapy and monoclonal antibodies in prospective studies.

Surgical resection plus chemotherapy versus chemotherapy alone: comparison of two strategies to treat diffuse large B-cell gastric lymphoma.

BACKGROUND: The usefulness of chemotherapy to treat gastric diffuse large B-cell lymphomas (DLBCL) is well known. Whether or not chemotherapy should be performed as the only treatment or after surgical resection is debated. The aim of this study was to compare two strategies: surgical resection plus chemotherapy versus chemotherapy alone. PATIENTS AND METHODS: Between January 1988 and December 1996, 58 patients included in the trials promoted by the Groupe d'Etude des Lymphomes de l'Adulte (GELA) (LNH-87 and LNH-93) received chemotherapy and 48 included in the protocol of the Groupe d'Etude des Lymphomes Digestifs (GELD) underwent surgical resection followed by chemotherapy. They all presented with localized DLBCL (stage IE and IIE according to the Ann Arbor classification). From the GELA group, seven patients received additional radiotherapy. Gastrectomy was total in 27 of the 48 patients in the GELD group. In both groups chemotherapy included anthracyclin and alkylating agents. Chemotherapy was more intensive in the GELA group than in the GELD group. RESULTS: In the GELA and the GELD groups, distribution according to sex ratio, age (>60 or < or = 60 years), ECOG performance status (> or = 2 or <2) and staging (IE or IIE) was similar. Univariate analysis comparing prognostic factors in both groups showed significant differences: serum lactate dehydrogenase level above normal (28.6% versus 2.4%, P = 0.001), tumor size >10 cm (28.6% versus 12.5%, P = 0.04), patients with International Prognostic Index (IPI) >1 (21.4% versus 11.1%, P = 0.168) and 5-year survival (79% versus 90%, P = 0.03). Multivariate analysis of prognostic factors with a Cox model showed that IPI was the only independent prognostic factor (odds ratio 3, P = 0.03). Consequently, patients with IPI 0-1 were selected for comparison between the GELA group (44 patients) and the GELD group (40 patients). There was no significant difference between the two groups. Median follow-up was 59 months (range 3-128). Estimates of 5-year survival rates and event-free survival rates were 90.5% versus 91.1% (P = 0.303) and 85.9% versus 91.6% (P = 0.187), respectively. In the GELA group, seven of 44 patients died: five from a lymphoma-unrelated cause and two from tumor progression. In the GELD group, four of 40 patients died: two of unrelated causes and two from tumor progression. CONCLUSIONS: This study shows that in localized gastric DLBCL with IPI 0-1, a similar 5-year survival rate (>90%) is to be expected with either surgery plus chemotherapy or chemotherapy alone.

A digestive tolerance study of maltitol after occasional and regular consumption in healthy humans.

AIM: We aimed to evaluate the gastro-intestinal tolerance to an indigestible bulking sweetener containing sugar alcohol using a double-blind random cross-over study. METHOD: In order to simulate their usual pattern of consumption, 12 healthy volunteers ingested maltitol or sucrose throughout the day, either occasionally (once a week for each sugar, first period) or regularly (every day for two 9 day periods, second period). In both patterns of consumption, daily sugar doses were increased until diarrhea and/or a grade 3 (ie severe) digestive symptom occurred, at which the dose level was defined as the threshold dose (TD). RESULTS: In the first period (occasional consumption), the mean TD was 92+/-6 g with maltitol and 106+/-4 g with sucrose (P=0.059). The mean intensity of digestive symptoms was 1.1 and 1.3, respectively (P=NS). Diarrhea appeared in six and one subjects respectively (P=0.035). In the second period (regular consumption), the mean TD was 93+/-9 g with maltitol and 113+/-7 g with sucrose (P=0.008). The mean intensity of digestive symptoms was 1.7 and 1.2, respectively (P=NS). However, diarrhea appeared in eight and three subjects, respectively (P=0.04). Maltitol and sucrose TDs between the two periods were not different. CONCLUSIONS: Under our experimental conditions, in comparison to sucrose: (a) occasional or regular consumption of maltitol is not associated with severe digestive symptoms; (b) in both patterns of maltitol consumption, diarrhea frequency is higher, but it appeared only for very high doses of maltitol, much greater than those currently used; (c) maltitol does not lead to intestinal flora adaptation after a 9 day period of consumption.

Gastrointestinal lymphoma: prevention and treatment of early lesions.

Gastrointestinal lymphomas comprise a group of distinct clinicopathological entities. Differences in lifestyle and environmental factors between countries could account for the variety in the distribution of the main subtypes: low-grade B-cell lymphomas of the mucosa-associated lymphoid tissue type, alpha-chain disease and enteropathy (coeliac disease)-associated T-cell lymphoma (EATL). The possibility of preventing these lymphomas implies a knowledge of their natural history together with an identification of potential predisposing factors. The development of the lymphoid hyperplasia and subsequently low-grade lymphoma with the possibility of high-grade transformation is a multifactorial process involving both antigenic and host-related factors. The pathogenic role of Helicobacter pylori and gluten has been demonstrated in gastric lymphoma and enteropathy-associated T-cell lymphoma respectively, while environmental factors, especially non-specific bacterial ones, may play a major role in the pathogenesis of alpha-chain disease. The most difficult task in preventing these lymphomas is the recognition of early lesions likely to regress after the removal of the exogenous stimulus.

Histological and immunological parameters to predict treatment outcome of Helicobacter pylori eradication in low-grade gastric MALT lymphoma.

Helicobacter pylori eradication is generally accepted as the first choice of treatment for stage IE low-grade gastric MALT lymphoma (mucosa-associated lymphoid tissue-type lymphoma). Treatment failure may be attributed to the extent of the disease and to progression into an antigen-independent phase. This study assessed the value of morphological grading and the expression of the co-stimulatory markers CD40, CD80 and CD86 and their ligands to predict clinical outcome in 23 consecutive low-grade MALT lymphoma patients treated with H. pylori eradication. Complete regression was achieved in 13/23 patients (56%), partial regression in two (9%), and no response in eight (35%). Histological grading was highly predictive of clinical response, especially in stage IE(1) patients, with complete remissions in 10/12 tumours with purely low-grade (type A) morphology and 1/8 tumours with increased numbers of blasts (type B) (p=0.0046) and was related to the expression of costimulatory markers (p=0.0061). Moreover, CD86 as a single marker proved to be of predictive value for treatment outcome (p=0.0086). These results suggest that morphological grading and immunological criteria can be defined to recognize the transition into the antigen-independent phase of gastric MALT-NHL. In addition to clinical stage, these critera may in future serve as a practical pathological guide to the choice of therapy.

Predictive factors for regression of gastric MALT lymphoma after anti-Helicobacter pylori treatment.

BACKGROUND AND AIMS: Discrepant remission rates (41-100%) have been reported for patients with localised low grade gastric mucosa associated lymphoid tissue (MALT) lymphoma after eradication of Helicobacter pylori. The aim of this study was to explain these discrepancies and to determine the predictive factors of gastric lymphoma regression after anti- H pylori treatment. PATIENTS AND METHODS: Forty six consecutive patients with localised gastric MALT lymphoma (Ann Arbor stages I(E) and II(E)) were prospectively enrolled. All had gastric endoscopic ultrasonography and H pylori status assessment (histology, culture, polymerase chain reaction, and serology). After anti-H pylori treatment, patients were re-examined every four months. RESULTS: Histological regression of the lymphoma was complete in 19/44 patients (43%) (two lost to follow up). Median follow up time for these 19 responders was 35 months (range 10-47). No regression was noted in the 10 H pylori negative patients. Among the 34 H pylori positive patients, the H pylori eradication rate was 100%; complete regression rate of the lymphoma increased from 56% (19/34) to 79% (19/24) when there was no nodal involvement at endoscopic ultrasonography. There was a significant difference between the response of the lymphoma restricted to the mucosa and other more deep seated lesions (p<0.006). However, using multivariate analysis, the only predictive factor of regression was the absence of nodal involvement (p<0.0001). CONCLUSION: In H pylori positive patients with localised gastric MALT lymphoma, carefully evaluated and treated without any lymph node involvement assessed by endoscopic ultrasonography, complete remission of lymphoma was reached in 79% of cases.

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.

Gastrointestinal lymphomas: the French experience of the Groupe D'etude des Lymphomes Digestifs (GELD).

Since 1983, the French Groupe d'Etude des Lymphomes Digestifs (GELD), under the aegis of the Fondation Française de Cancérologie Digestive, has aimed to identify the different prognostic groups of the primary digestive-tract lymphomas (PDTL) and their optimal treatment. Successive multicenter studies were conducted and 91 PDTL were evaluated. A marked improvement in their prognosis was obtained by a strategy including precise histologic typing and clinical staging followed by a therapeutic approach combining initial surgical resection, whenever possible or reasonable, followed by chemotherapy adapted to the grade of malignancy and resectability of the lymphoma. The multivariate analysis indicated that the factors for good prognosis were age (< 65 yrs), gastric localisation, stage IE and radical or even incomplete surgery. However, Helicobacter pylori eradication should be the first treatment in stage IE low-grade gastric mucosa-associated lymphoid tissue (MALT) tumors. The long-term results of such medical treatment are evaluated together with the management and the place of surgery in these localised tumors. However, owing to the limited number of patients, a large international co-operative trial is needed to confirm the findings. Thirty-one cases of multiple lymphomatous polyposis were also collected and confirmed to be a distinct entity among PDTL and the gastrointestinal counterpart of the mantle-cell-zone lymphomas. High-dose radio-chemotherapy supported by auto-transplantation improved their prognosis.

Serum antibody responses to Helicobacter pylori and the cagA marker in patients with mucosa-associated lymphoid tissue lymphoma.

The lymphoma of the mucosa-associated lymphoid tissue (MALT) of the stomach has been linked to Helicobacter pylori infection, but the mechanisms involved in B-cell proliferation remain elusive. In a search for putative H. pylori-specific monoclonal immunoglobulin production, an H. pylori strain was isolated from 10 patients with MALT lymphoma and used to detect the specific serum antibody response to the homologous strain by immunoblotting. Moreover, the antigenicity of the different strains was compared by using each of the 10 sera. We found that the different strains induced highly variable patterns of systemic immunoglobulin G antibody response, although several bacterial antigens, such as the 60-kDa urease B, were often recognized by the different sera. The cagA marker was detected in the strains by PCR with specific primers and by dot blot analysis, and the CagA protein was found in the sera of 4 of the 10 patients by immunoblotting. In conclusion, MALT lymphoma patients, like other patients with H. pylori gastritis, exhibit a polymorphic systemic antibody response, despite an apparently similar antigenic profile. The CagA marker of pathogenicity is not associated with this disease.

Homing receptor alpha4beta7 integrin expression predicts digestive tract involvement in mantle cell lymphoma.

Appropriate staging and evaluation of residual disease is critical to improving the treatment of patients with lymphoma. The specific expression of homing receptors may determine the preferential dissemination pattern of tumoral cells. We investigated the expression of the mucosal homing receptor alpha4beta7 on tumoral cells from peripheral lymph node in patients with newly diagnosed mantle cell lymphoma (MCL) to check whether it is associated with gastrointestinal involvement. Expression of the alpha4beta1 integrin and the peripheral lymph node addressin CD62L were also examined. Thirteen MCL patients presenting with peripheral lymphadenopathy were studied. Expression of the mucosal homing receptor integrin alpha4beta7 by peripheral lymph node lymphoma cells was found to be frequent (5/13) and associated with gastrointestinal involvement (5/7). In contrast, lymphoma cells from patients without gastrointestinal involvement did not express alpha4beta7 (6/6) (P = 0.03). These data suggest that alpha4beta7 integrin is expressed by a subset of MCLs and that its expression may predict digestive tract involvement in MCL, furnishing a basis for recognizing two distinct clinical and phenotypic forms, ie, "digestive homing (or digestive primitive)" versus "peripheral" MCL. Further studies on more patients will be needed to understand the impact of biological differences on the prognosis of these two clinical forms.

[Gastric lymphoma]. / Lymphome gastrique.

The stomach is the most common site involved in primary gastrointestinal lymphoma. Gastric lymphoma originates from the mucosa-associated lymphoid tissue so called MALT. It comprises a group of distinctive clinicopathological entities which are important to take in account for clinical behavior. In recent years, new diagnostic tools and modern modes of treatment have improved their overall prognosis. One of the most exciting recent discoveries is the hypothesis that an infection by a bacterium. Helicobacter pylori has a decisive role in gastric lymphoma.