Gastric MALT-lymphoma and Helicobacter pylori infection

Aliment Pharmacol Ther 1997; 11 (Suppl. 1): 89 94. Gastric MALT-lymphoma and Helicobacter pylori infection E. BAYERDO RFFER, S. MIEHLKE, A. NEUBAUER & M. STOLTE* Department of Gastroenterology, Hepatology and Infectious Diseases, University of Magdeburg; Department of Hematology and Oncology, Virchow Klinikum, Humboldt University of Berlin; and * Institute for Pathology, Klinikum Bayreuth, Germany SUMMARY The presence of lymphoid tissue in the gastric mucosa is virtually pathognomonic of Helicobacter pylori infection. This lymphoid tissue has mucosa associated lymphoid tissue (MALT) characteristics suggesting that H. pylori infection may represent a stimulus for the growth of gastric MALT lymphoma. H. pylori can be detected in more than 90% of patients with low grade gastric MALT lymphoma supporting the aetiological role of the organism. The strongest evidence for the significance of H. pylori in the pathogenesis of low aetological grade gastric MALT lymphoma is provided by clinical studies showing that cure of H. pylori infection is followed by a complete regression of these tumours in most patients. This paper reviews the current knowledge about antibacterial treatment of low grade gastric MALT lymphoma, and immunological and molecular aspects in the pathogenesis of the disease. INTRODUCTION Gastrointestinal lymphomas are the most frequent extranodal lymphomas, being mainly of the non-hodgkin s type. Gastric lymphomas, which are the most common primary gastrointestinal lymphoma in western countries, are usually indolent with a prolonged disease course and, in contrast to nodal lymphoma, tend to persist in localized form for a longer period of time. In contrast to gastric carcinoma, primary gastric lymphoma is increasing in incidence., Until the early 1980s primary gastric lymphomas were characterized according to macroscopic classifications, such as that proposed by Palmer in 1950. Up until then, the tumours were most often in an advanced stage at the time of diagnosis, usually showing penetration through the entire gastric wall and often with infiltration of adjacent tissues and involvement of regional lymph nodes. Based on further histological examinations these tumours were usually mis-diagnosed as lymphosarcoma. Subsequent improvements in the endoscopic and Correspondence to: Dr E. Bayerdo rffer, Department of Gastroenterology, Hepatology and Infectious Diseases, University of Magdeburg, Leipziger Str. 44, D-39120 Magdeburg, Germany. histological diagnostic evaluation on surgical specimens have led to considerable advances in the field of early diagnosis of these neoplasms, with detection of early gastric lymphoma in specimens bearing malignant non- Hodgkin lymphoma ranging from 22 to 46%. The introduction of the mucosa-associated lymphoid tissue (MALT) concept of gastric lymphoma by Isaacson, and the discovery of Helicobacter pylori by Warren & Marshall in the early 1980s constitute two major hallmarks which subsequently led to the recognition of chronic infection with H. pylori as the most important underlying condition for the development of primary gastric MALT lymphoma. CLASSIFICATION OF PRIMARY GASTROINTESTINAL LYMPHOMAS INCLUDING THE MALT CONCEPT In 1983, Isaacson et al. originated the concept of the development of gastric lymphoma from MALT, and established criteria for the histological diagnosis of lowgrade malignant lymphoma in forceps biopsy material., According to this concept, the characteristic histological features of gastric lymphoma arising from MALT are: i) the replacement of glands by uniform dense infiltrates of centrocyte-like cells (CCL) in the lamina propria; and ii) 1997 Blackwell Science Ltd 89

90 E. BAYERDO RFFER et al. ence of MALT lymphoma and the distinction between enteropathy-associated and other T-cell lymphomas. ANTIBACTERIAL TREATMENT OF LOW-GRADE GASTRIC MALT LYMPHOMA Figure 1. This photomicrograph shows typical lymphoepithelial destruction. Its detection is required to establish the diagnosis of MALT lymphoma. clear evidence of lymphoid destruction of the glands or foveolae, i.e. lymphoepithelial lesions (Fig. 1). Growing knowledge about immunological and histopathological features of primary gastrointestinal lymphomas made it increasingly difficult to fit these distinctive entities into any of the available lymphoma classifications. Consequently, a new classification for primary gastrointestinal lymphoma was formulated by the European Lymphoma Study Group headed by Isaacson in April 1988, particularly including the concept of the MALT origin of primary gastric lymphoma (Table 1). This classification is basically in agreement with that published almost simultaneously by Hall et al., both of them containing the differentiation between lymphomatous polyposis, mediterranean lymphomas, and those of the Burkitt type. The classification proposed by Isaacson et al. may certainly be preferred as it is more accurate with respect to recent aetiological and pathomorphological evidence, particularly the exist- While lymphoid tissue is a common element of the normal small intestine and colon it is completely absent from the healthy stomach. The development of lymphoid follicles in the gastric mucosa is considered part of the immune response to infection of the gastric mucosa with H. pylori., The first evidence for an association between H. pylori and primary gastric MALT lymphoma was shown in a retrospective study by Wotherspoon et al. who found that H. pylori infection is present in 92% of patients with gastric MALT lymphoma. However, the differential diagnosis between reactive lymphoid infiltrates due to H. pylori infection and early gastric lowgrade MALT lymphoma may often be difficult, especially when dense lymphoid cell infiltration of the gastric mucosa without evidence for lymphoepithelial lesions is present. Against this background, eradication of H. pylori was initially proposed as a useful method to differentiate between reactive lymphoid infiltration and potential underlying lymphoma. Further epidemiological evidence for an association between H. pylori infection and gastric MALT lymphoma comes from a nested case-control study showing that individuals with H. pylori infection had a six-fold higher risk for the subsequent development of gastric lymphoma while there was no significant difference in prior H. pylori infection between patients with extra-gastric non- Hodgkin s lymphoma and controls. Given the histopathological and epidemiological association between H. pylori gastritis and gastric MALT lymphoma, the question was soon raised whether eradication of the organism might inhibit further tumour growth or even result in tumour regression. In a B cell lymphoma Low-grade MALT lymhoma High-grade MALT lymphoma (with or without low-grade components) Mediterranean lymphoma (immunoproliferative small intestinal disease) Malignant lymphoma, mantle cell type (lymphomatous polyposis) Burkitt s and Burkitt-like lymphoma Other low-grade and high-grade lymphomas corresponding to nodal lymphoma T-cell lymphoma Enteropathy-associated lymphoma Other types without enteropathy association Table 1. Classification of primary gastrointestinal lymphoma including the MALT concept

GASTRIC MALT-LYMPHOMA AND HELICOBACTER PYLORI INFECTION 91 Table 2. The Ann Arbor classification system for extranodal lymphomas as modified by Musshoff E I E II E III E IV Lymphoma restricted to gastrointestinal tract on one side of the diaphragm EI Infiltration limited to mucosa and submucosa EI Lymphoma extending beyond submucosa Lymphoma additionally infiltrating lymph nodes on the same side of the diaphragm EII Infiltration of regionary lymph nodes EII Infiltration of lymph nodes beyond regional Lymphoma infiltrating gastrointestinal tract andor lymph nodes on both sides of the diaphragm Localized infiltration of associated lymph nodes together with diffuse or disseminated involvement of extragastrointestinal organs prospective treatment study Wotherspoon et al. were able to demonstrate that in five of six patients H. pylori eradication resulted in a total regression of low-grade B- cell MALT lymphoma as determined by histomorphological and molecular measures. Simultaneously, an additional six cases of regression of lowgrade MALT lymphoma after cure of H. pylori infection were reported by Stolte & Eidt. Consequently, larger studies with longer follow-up periods have been undertaken to further confirm and establish the effect of H. pylori eradication on the course of low-grade gastric MALT lymphoma. A study from our group initially included 33 patients with primary gastric low-grade MALT lymphoma in the clinical stage EI according to the Ann Arbor System as modified by Musshoff (Table 2). Complete histological regression of lymphomas was documented in 70% of patients and another 12% of patients showed partial regression. These histological findings were further supported by molecular investigations employing polymerase chain reaction (PCR) showing complete disappearance of monoclonal B cells after cure of the infection in more than 80% of patients. Fifty patients have now been included in this study. During a median follow-up of 24 months, only one of the 50 patients suffered relapse of gastric MALT lymphoma without being reinfected with H. pylori. Another patient in this study showed complete regression of his gastric MALT lymphoma following cure of H. pylori infection; however, a high-grade lymphoma of the nasal cavity developed during follow-up. A prospective study by Roggero et al. including 26 patients with primary lowgrade gastric MALT lymphoma demonstrated disappearance or almost total regression of lymphomatous tissue in 60% of patients. A median follow-up of 12 months in those patients who responded to antibacterial therapy revealed that 14 of 15 patients were free of lymphoma. Although these exciting reports of regression of MALT lymphoma following cure of H. pylori infection are substantially changing our considerations in the treatment of this gastric malignancy, one has to keep in mind that based on current data this therapeutic approach can only be recommended for low-grade tumours: stage EI according to the Ann Arbor classification shown in Table 2., For high-grade tumours or those at stage EI or higher, surgical intervention (R0-resection, i.e. all grossly visible tumours can be removed at surgery), chemotherapy or radiotherapy are the required treatment modalities. A recent prospective study employing endoscopic ultrasound to determine the depth of infiltration of MALT lymphoma into the gastric wall suggested that the outcome of treatment of gastric MALT lymphoma by cure of H. pylori infection can be predicted by endosonographic staging. Complete regression of the MALT lymphoma after H. pylori eradication was observed in all patients in whom the extent of the MALT lymphoma was restricted to the gastric mucosa or submucosa (EI ). In contrast, those patients with a lymphoma infiltrating the muscularis or serosa (EI ) showed only partial or no tumour regression after cure of the infection. Thus, endosonographic staging of gastric MALT lymphoma appears useful to identify patients in whom regression of MALT lymphoma can be achieved by eradication of H. pylori. IMMUNOLOGICAL AND MOLECULAR ASPECTS OF H. PYLORI-ASSOCIATED GASTRIC MALT LYMPHOMA The close epidemiological association between H. pylori infection and gastric MALT lymphoma, and the striking findings of tumour regression after successful cure of H. pylori infection strongly suggest that H. pylori may

92 E. BAYERDO RFFER et al. stimulate an immune response in the gastric mucosa, leading to the emergence of a monoclonal B-cell population, frequently found in areas of H. pylori-infected mucosa heavily infiltrated by inflammatory cells. Tissue culture studies have shown that H. pylori induces cellular proliferation specifically in low-grade B-cell MALT lymphoma of the stomach but not in low grade B-cell lymphomas of other anatomical sites such as salivary gland or thyroid. This stimulating effect was specific for H. pylori but not for other bacterial species such as Eschericia coli or Campylobacter jejuni. Furthermore, B-cell proliferation in these tumours was shown to be secondary to specific activation of T-cells and release of cytokines by H. pylori. As mentioned above, the main characteristics of gastric MALT lymphomas are the presence of centrocyte-like cells and lymphoepithelial lesions. However, detection of these histological features may sometimes be difficult due to underlying dense, lymphocytic gastritis. Therefore, other diagnostic measures such as immunochemistry or PCR are used to identify clonal B cell populations. Evaluation of the usefulness of PCR to diagnose gastric lymphoma has shown that after H. pylori eradication, disappearance of monoclonality may occur considerably later than regression of the lymphoma (up to 28 months later). Savio et al. found that in only one of six cases evaluated with PCR and histological examination were polyclonality and regression of the tumour detected at the same timepoint. These data suggest that in the post-treatment follow-up histology remains the method of choice to detect lymphoma in gastric biopsies, while PCR provides a method to confirm the histological diagnosis. Additional work from our group has shown that PCR using specific primer for the CDR3-region is a highly sensitive method to detect monoclonal B cells in gastric biopsy samples of patients with MALT lymphoma. More importantly, monoclonality was diagnosed by PCR before histopathology revealed MALT lymphoma with lymphoepithelial lesions. Three of 15 patients with H. pylori gastritis, without any lymphoepithelial lesions, displayed monoclonal bands which disappeared during follow-up. However, compared to the other 12 patients with polyclonal PCR results, regression of gastritis took significantly longer in these three patients, similar to those patients with histologically confirmed MALT lymphoma, suggesting that in these three patients a possible MALT lymphoma may have been missed by histology. In our opinion, PCR for detection of monoclonality may not be necessary in patients with a clear histopathological diagnosis of MALT lymphoma with typical lymphoepithelial lesions. However, PCR should be performed in those patients in whom lymphoma is strongly suspected but lymphoepithelial lesions are not seen. While the above mentioned studies strongly support the association between gastric MALT lymphoma and H. pylori, an important question remains whether stimulation by chronic H. pylori infection alone is enough to induce development of gastric MALT lymphoma, or whether genetic changes in the host contribute to the transition from lymphoid hyperplasia to malignant lymphoma. There is evidence that allele imbalance at different tumour suppressor gene loci may occur during transition from H. pylori gastritis to MALT lymphoma. Moreover, other genetic abnormalities such as trisomy 3 are frequently observed in MALT lymphoma. suggesting a possible additional role of genetic host factors in the development of this type of tumour. It is further known that identical lymphoma clones can occur at different mucosal sites possibly due to a certain homing pattern of these B-cell clones. Recently, development of a high-grade lymphoma in the nasal cavity was reported in a patient who previously had a low-grade gastric MALT lymphoma which completely regressed after cure of H. pylori infection. Molecular studies employing PCR for the framework 3 and the joining region of the immunoglobulin heavy chain for analysis of the pretreatment gastric lymphoma and the lymphoma of the nasal cavity, were performed. Comparison of rearrangement patterns revealed that both tumours evolved from a different clonal population of B cells suggesting that a possible underlying predisposition may be important in the development of MALT lymphoma in some patients. GASTRIC MALT LYMPHOMAS AND OTHER HELICOBACTERS The ability to induce mucosal alterations eventually leading to MALT lymphoma appears not to be restricted to H. pylori. For instance, life-long infection with H. felis leads to lymphoepithelial lesions in BALBc mice. Interestingly, in this strain of mice no signs of acute inflammation occur after H. felis infection. However, during long-term follow-up approximately 25% of infected animals showed pathomorphological changes strongly resembling human gastric MALT lymphoma, while none of the uninfected control animals did. In contrast, other strains of murine infection with H. felis may lead to severe damage of the gastric mucosa

GASTRIC MALT-LYMPHOMA AND HELICOBACTER PYLORI INFECTION 93 resulting in gastric atrophy without development of lymphoma. Infection with H. heilmannii (formerly Gastrospirillum hominis) is rare in humans, commonly found in the gastric antrum and is associated with less pronounced mucosal inflammation compared to H. pylori gastritis. We recently described a case of primary gastric MALT lymphoma associated with H. heilmannii infection in a 79-year-old female patient with a large flat polypoid tumour in the gastric corpus. The diagnosis was confirmed histologically by detection of typical lymphoepithelial lesions. Cure of H. Heilmannii infection led to complete endoscopic and histological regression of the tumour and to simultaneous disappearance of monoclonal B cells. These studies demonstrate that development of gastric MALT lymphoma may also be stimulated by infection with other members of the genus Helicobacter. 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