Gastric lymphoma of MALT, a malignant infection potentially curable by eradication of Helicobacter pylori
The gastric lymphoma of MALT is the most frequent of the lymphomas of the marginal zone of low degree of malignancy. It is now well demonstrated that the gastric lymphoma of MALT is closely related to Helicobacter pylori infection. A prolonged remission is obtained in more than 50% of the patients after eradication of the bacterium. Two tumor response factors were identified: the presence of adenopathies périgastriques in endoscopic is associated with failure in 2/3 patients; The translocation T (11; 18) which causes the fusion of two genes involved in the apoptosis of B lymphocytes is also related to the absence of effect of eradication of Helicobacter pylori. New studies are needed to find the most suitable treatment for non-responding patients. Long-term endoscopic follow-up is recommended due to an increased risk of gastric cancer in these patients even after eradication of Helicobacter pylori.
Abstract
Gastric MALT lymphoma, a malignancy potentially curable by eradication of Helicobacter pylori
Gastric MALT lymphoma is the most prevalent low-grade marginal zone lymphoma. It is now well demonstrated that gastric MALT lymphoma is strongly related to Helicobacter pylori infection. Extended remission of lymphoma is achieved in more than 50% of patients after Helicobacter pylori eradication. Two factors of tumor response were found: presence of perigastric lymph nodes at endoscopic ultrasonography was related to a failure in 2 out of 3 patients; Presence of a translocation t (11; 18) with the fusion of two genes implicated in B lymphocytes apoptosis was related to a failure in most of patients. Further studies are needed to determine the most adapted treatment in non-responding patients. A long-term endoscopic follow-up is recommended due to the increased risk of gastric adenocarcinoma in spite of Helicobacter pylori eradication.
The gastric lymphoma of MALT is the prototype of the lymphomas of the marginal zone of low malignancy. They are linked to a monoclonal proliferation of B lymphocytes that have the characteristics of lymphocytes normally present at the level of the dome of the Peyer plates that constitute the prototype of the lymphoid tissue associated with the mucous membranes (MALT) [1].
They are lymphomas of low degree of malignant evolution indolent most often localized. The slowness of the evolution had made them consider in the past as "lymphoma" until the techniques of immunohistochemistry and molecular biology make it possible to highlight the monoclonal character of the proliferation lymphocytes [2], [3]. Their close relationship with the infection with Helicobacter pylori is the cause of renewed interest in this pathology, especially on the part of Gastroenterologists.
The purpose of this presentation is to take a look at this still poorly known entity and to determine the place of the eradication of Helicobacter pylori infection in the management of the disease.
Relations pathophysiological Helicobacter pylori-gastric lymphoma of MALT
The relationship Helicobacter pylori-gastric lymphoma of MALT is based on many arguments. From an epidemiological standpoint, more than 80% of the patients are infected with the bacterium, while the rate of infection in the general population is 30 to 35% [4]. There is a higher prevalence of gastric lymphoma of MALT in areas with high prevalence of infection [5]. An elegant nested case-control study, carried out from a cohort of several hundred thousand patients who had a serum sample in a systematic review several years earlier, showed that the relative risk of To develop in 15 years a gastric lymphoma of MALT was increased by a factor 6 in the infected population compared to the uninfected population [6]. Importantly, this increase was only found for gastric lymphomas, whereas there was no relative risk increase for the population of Nodal lymphomas, which showed that the character specifically related to the bacterium of the Gastric lymphoma.
On the anatomopathologic level, there are also strong arguments for a role of the bacterium. In fact, the chorion of the gastric mucosa is almost devoid of any B lymphocyte in the absence of Helicobacter pylori infection.
The inflammatory reaction induced by the pathogen leads successively to the appearance of a B lymphocyte population of a type similar to that observed in the Peyer plates and, in some cases, to the appearance of lymphoid nodules of Structure similar to the Peyer plate. Finally, in cases where lymphoma appears, the development of a monoclonal B lymphocyte proliferation that has the peculiarity of causing "lymphoépithéliales" lesions resulting in amputation of the gastric glandular epithelium is observed [ 4].
The gastric lymphoma of MALT is therefore part of a continuum of the inflammatory reaction to Helicobacter pylori. This continuity was well highlighted by an Italian team that was able to study comparatively the samples obtained in a patient with lymphoma with those obtained about ten years ago at the time when the patient had a simple gastritis to Helicobacter pylori. Sequencing of the hypervariable part of the Immuglobulines heavy chain revealed the preexistence of the lymphocytic clone observed in the lymphomateux tissue among the polyclonal population observed in gastritis [7]. This confirms the emergence of a tumor clone in this patient initially presenting a simple Helicobacter gastritis.
It has been shown in recent years that the growth of lymphoma-characteristic lymphocyte clone remains dependent on antigenic stimulation, which accounts for the beneficial effect of eradication of Helicobacter pylori. Thus, in vitro studies have shown that tumour cell growth can be achieved when Helicobacter pylori strains are added to the culture medium provided that T lymphocytes are present. In fact, there was a certain specificity of the reaction according to the strains, better growth being obtained with strains of Helicobacter pylori from patients with lymphoma [8]. However, subsequent studies did not show any impact of virulence factors, particularly the presence of the islet of Pathogenicity Cabotaje in the pathophysiology of lymphoma [9].
Several mechanisms have been proposed to explain the absence of feedback of lymphocyte proliferation in response to Helicobacter pylori infection. The team of Elios et al. showed that B cells of MALT Lymphomas escaped the proliferation-limiting mechanisms normally controlled by T lymphocytes via perforines-mediated cytotoxicity and Fas-mediated apoptosis [10].
Acquisition of genetic anomalies [11], [12]
Infection with Helicobacter pylori not only induces the acquisition of MALT-like tissues at the stomach level, but also promotes the malignant transformation of B cells. On the one hand, Helicobacter pylori induces and maintains an active proliferation of B cells that can develop genetic anomalies, but it also attracts and activates neutrophilic polynuclears that have a genotoxic capacity as a result of Release of reactive metabolites of oxygen. Many genetic anomalies have been described during lymphoma without any understanding of the pattern. The most classic is Down syndrome, which is found in about 30% of gastric lymphomas and is the most anciently known genetic anomaly. This anomaly occurs early, but its role in the progression of lymphoma is not clear. Many other anomalies have been reported in a more anecdotal way. One of the most recently described is translocation T (11; 18) (Q21; q21) [13]. This translocation is found in 30 to 40% of the gastric lymphomas of malt and is also found in the lymphomas of the marginal area of the malt type of the other mucous sites [14], [15]. However, it is not found in nodal B lymphomas or other lymphomas in the non-mucosal marginal zone or other non-Hodgkin lymphomas. In addition, it is not present in large-cell diffuse gastric B lymphomas, even in those containing a small-cell contingent suggesting a filiation between MALT lymphoma and large cell lymphoma [15] (table I). This translocation results in the fusion of two genes involved in apoptosis, the API2 gene and the MALT1 gene. As we will see later, this translocation appears to be associated with the empowerment of lymphoma in relation to Helicobacter pylori infection. [16] [17] [18]
Clinical presentation
The non-specific character of the symptoms that lead to the diagnosis of MALT is one of the most important messages for gastroenterologists. Indeed, any endoscopist is likely to be confronted with the diagnosis of gastric lymphoma of MALT. Patients generally consult for pain epigastric indistinguishable pain ulcerative and in a third of cases are seen during a digestive hemorrhage or the balance of anemia by chronic bleeding [19]. General signs are absent most often, limiting themselves to moderate weight loss. The presence of larger general signs, including fever and/or sweats, is, however, suggestive of large-cell B lymphoma.
On the biological level, LDH and B2 Microglobulinémie are generally not augmented, contrary to what can be observed in large-cell gastric lymphoma.
The endoscopic aspect is also very often non-specific with in one third of the cases an aspect of ulcer, in a third of the cases an aspect which evokes superficial lesions of the mucosa to type of erosions, even mucous blisters, and finally In the last third of cases, a more or less ulcerated aspect of a tumor is most often summed up in an aspect of tumor-like large folds.
It is exceptional that low-grade lymphoma of the MALT type is the cause of a large tumor. The existence of an obstructive stomach tumor must primarily evoke the diagnosis of high-grade lymphoma.
The multifocal trait of lymphoma imposes multiple biopsies on both the endoscopic recognized lesion and the other territories, even if they appear morphologically normal. According to the currently accepted standards, 20 to 30 biopsies are required for the diagnosis of lymphoma as well as Helicobacter pylori infection. The use of formaldehyde as a fixer is to be preferred, because it allows, on the one hand, a study in standard histology and, on the other hand, the practice of techniques of molecular biology requiring the extraction of DNA. The immediate freezing of biopsy fragments allows the immunohistochemical study and extraction of the RNA needed to search for translocation T (11; 18). Evidence of the monoclonality of the hypervariable part of the immunoglobulin heavy chain is best performed under frozen biopsy, but can also be performed on formalin-fixed biopsies. The search for Helicobacter pylori infection is carried out in histology. It can be supplemented by the culture with study of the susceptibility of the strains to antibiotics.
The extension balance is used to classify the lymphoma according to the ANN Arbor classification revised by Mushoff [20]. The loco-regional extension is appreciated by the abdominal tomography and the endoscopic. Computed tomography only shows massive infiltration of the gastric wall and adenopathies of more than one cm. The endoscopic can be used to analyze the layer structure of the wall, its thickness, the presence of adenopathies greater than or equal to 5 mm in diameter. The remote extension balance is carried out by the search for another location on the digestive tract with computed tomography, colonoscopy and possibly the transit of hail, as well as the search for a location in the other territories of MALT , particularly at the ENT and pulmonary level. Finally, a systematic medullary biopsy must be performed.
At the end of this assessment, most of the gastric lymphomas of MALT are found to be located in the stomach (IE stage) and/or the périgastriques ganglia (stage IIE). In 10-15% of cases, another location is found, the most frequent being pulmonary and osteo-medullary (stage IV) locations [19].
Tumor response to anti-Helicobacter pylori treatment
It is now well demonstrated that the eradication of Helicobacter pylori infection is likely to lead to the regression of the tumor process. The results of the main series of the literature are shown in table II. A complete remission, that is, a disappearance of endoscopic and histological lesions, is observed in 50 to 80% of cases according to the series [21] [22] [23] [24] [25] [26] [27] [28]. The variability of the results depends on the time left between the eradication treatment and the control of lymphoma as well as the loco-regional extension of lymphoma. A minimum period of six months is to be observed in order to have a reliable evaluation of the tumor response. In some cases, a partial response, i.e. a regression of endoscopic lesions with persistence of histological lesions, is observed at six months. A complete answer is possible in the following months [21]. Therefore, it is not lawful to consider another treatment in the event of a partial response before a period of one year after the bug exterminator treatment. The lack of response results in more stability of lesions than in increased progression of endoscopic lesions, in particular.
The endoscopic allows the analysis of the thickness of tumor infiltration in the gastric wall and the demonstration of adenopathies satellites. However, it has no interest in evaluating the extension of surface lymphoma to the extent that superficial lymphoma has no échoendoscopique translation [29] [30] [31] [32]. The échoendoscopique aspect of lymphoma has proven to be predictive of the tumor response to the eradication of Helicobacter pylori infection. Most studies agree to find a relationship between the response rate to eradication of Helicobacter pylori infection and parietal infiltration, especially when associated with the presence of adenopathies recurrence. In this regard, the two French multicentric studies agree perfectly by showing that only the presence of detectable adenopathies in the endoscopic is predictive of a wrong response under treatment [27], [28]. In our personal series, the response rate is 75% in the absence of adenopathies versus 33% in the case of Adenopathies [28]. This study further demonstrates that neither the endoscopic aspect nor the percentage of large cells in the tumour infiltration to histology can be taken into account in predicting the tumor response (table III).
Recently, T (11; 18) translocation has been shown to be predictive of non-response to the bug exterminator treatment of Helicobacter pylori infection [16], [33] (table IV). This translocation is found more frequently in advanced-stage lymphomas [17]. Whatever the stage of lymphoma, it seems to mean in all cases an absence of response to the eradication of Helicobacter pylori infection [18]. In the absence of translocation T (11; 18) more than 80% of the stage I lymphomas respond to the eradication of the infection. Other factors likely account for the treatment resistance of 20% of patients without translocation t (11; 18).
Long-term evolution
The long-term evolution of patients responding to the eradication of Helicobacter pylori infection is very favorable. The German series is the oldest. It shows the stability of clinical and endoscopic healing [22], [34]. On the other hand, there is a persistence of B lymphocyte monoclonality, despite the histological regression of lesions in 40% of cases [35]. Isaacs et al. have also shown the possibility of obtaining positive biopsy samples either histologically or molecularly during the follow-up of patients initially responding and not developing long-term lesions Significant macroscopic. Some observations suggest the persistence of a residual disease in a large number of patients without real evolutionary recovery in the absence of Helicobacter pylori reinfection [36].
There is no consensus on the management of non-responding patients. The surgical treatment (total gastrectomy) that effectively regulates the problem of gastric disease is less and less practiced due to its nutritional consequences and the low scalability of the disease. Several studies have reported excellent results with radiation therapy [37], [38]. Chemotherapy per OS by alkylating agents (chlorambucil or cyclophosphamide) provides a complete remission in about 70% of cases [39]. It is possible that the addition of a monoclonal anti-CD20 antibody (rituximab) treatment allows better control of the disease [40].
The practice of a systematic endoscopic and biopsy follow-up of patients with gastric lymphoma of MALT treated in a conservative manner has led to the demonstration of a particular scalability of chronic Helicobacter gastritis to Gastric adenocarcinoma. Several cases of gastric adenocarcinoma found simultaneously with lymphomas had already been reported [41]. It is now well demonstrated that gastric adenocarcinoma can occur in the months or years following the eradication of Helicobacter pylori infection. Such a phenomenon can be observed in patients who have responded to the eradication of infection [42]. The study of our personal series showed the persistence of the scalability of gastritis to the occurrence of pre-neoplastic lesions (atrophy, metaplasia), despite the eradication of the bacterium. Anatomopathologic analysis of the operative parts of three patients who developed scarred cancer in the initial localization of lymphoma suggests that the carcinogenesis process could be promoted by the persistence of a disease residual [43].
Conclusion
Great progress has been made in the management of gastric lymphomas of MALT. Eradication of Helicobacter pylori infection is validated as the first step in treatment. Its success is primarily conditioned by the lack of translocation t (11; 18). The problem now is the treatment of non-responders and the long-term surveillance of patients who appear to be at risk for gastric cancer.
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