Low-grade Gastric Mucosa-associated Lymphoid Tissue Lymphoma Research Articles

Gastric lymphoma of mucosa-associated lymphoid tissue and Helicobacter pylori.

Although the majority of primary gastric lymphomas are of high-grade non-Hodgkin's type, a significant number are low-grade B cell lymphomas. The recognition that the majority of the latter have characteristic clinicopathological features that are different from those of their nodal counterparts has led to the suggestion that these lymphomas arise specifically from within organized extranodal lymphoid tissue; this tissue resembles that seen constitutively in the intestine (mostly located in the terminal ileum as Peyer's patches) and is termed mucosa-associated lymphoid tissue (MALT). The paradox of this proposal is that there is no MALT in the gastric mucosa in normal individuals from which a primary lymphoma can arise. However, it has been shown that organized lymphoid tissue with all the features of MALT can be acquired in the gastric mucosa, and this is seen most frequently, but not exclusively, in association with infection by Helicobacter pylori (H. pylori). Subsequent studies have confirmed a close association between H. pylori infection and gastric MALT lymphoma with the infection preceding the development of the lymphoma. In vitro studies have demonstrated that there is an immunologically based drive to tumor cell proliferation in low-grade gastric MALT lymphomas associated with the presence of H. pylori. Clinical studies have shown that, at least in early lesions, eradication of the organism can result in tumor regression in 60 to 92% of cases.

B-cell lymphoma of MALT type: a review with special emphasis on diagnostic and management problems of low-grade gastric tumours.

B-cell lymphoma of MALT type: a review with special emphasis on diagnostic and management problems of low-grade gastric tumours.

Helicobacter pylori infection and gastric lymphoma.

Gastric lymphoma of mucosa associated lymphoid tissue (MALT) has characteristic clinicopathological features that are different from nodal-type B cell lymphomas. Before a lymphoma can arise within the stomach, MALT has to be acquired as part of a response to an immunological stimulus. In most instances, gastric MALT is acquired in response to infection by Helicobacter pylori. There are several features of MALT lymphoma, such as plasma cell differentiation and follicular colonisation, that suggest that these lymphomas, although demonstrated on the basis of clonality studies to be neoplastic, retain some immunological drive. In vitro studies have shown that co-culturing cells derived from low grade MALT lymphomas with H. pylori results in tumour cell proliferation in a T cell dependant manner. Clinical studies have taken this discovery further and shown that patients with early low grade gastric MALT lymphoma treated with anti-Helicobacter therapy can show regression of their tumours. It is now generally accepted that eradication of H. pylori is a central component of the management of MALT lymphoma.

What Role Does Helicobacter pylori Eradication Play in Gastric MALT and Gastric MALT Lymphoma?

The concept of mucosa-associated lymphoid tissue (MALT) has been introduced to differentiate biological functions from behavior of nonnodal vs. nodal lymphoid tissues. Lymphomas arising from MALT also behave differently than typical nodal lymphomas. In contrast to other tissues, MALT in the stomach is almost exclusively a result of Helicobacter pylori infection. Thus, MALT is part of the host defense against the pathogen H. pylori. Consequently, lymphomas arising from gastric MALT may be a clonal evolution starting from the infection. In low-grade gastric MALT lymphoma, cure of the infection may induce complete histological remission in the majority of patients. Investigators have recently reported that complete remission rate is between 70% and 80%. In an extended analysis, we have treated 84 patients with low-grade gastric MALT lymphoma in stage El, using a dual regimen to eradicate H. pylori. Complete remission was observed in 68 (80%) patients; a partial remission was found in 4 patients. In contrast, 12 patients showed no change and were referred to alternative treatment. In patients in complete remission, a polymerase chain reaction assay for the rearranged immunoglobulin heavy-chain gene remained positive in many cases. Together with data from the literature, these data suggest that the majority of patients with low-grade gastric MALT lymphomas in stage El respond to eradication of H. pylori. Longer follow-up investigations are necessary to determine if remissions indicate a cure from the disease.

Regression of gastric MALT lymphoma after eradication of Helicobacter pylori is predicted by endosonographic staging. MALT Lymphoma Study Group

BACKGROUND & AIMS: Recent studies suggest that eradication of Helicobacter pylori may result in complete regression of low-grade lymphoma of the gastric mucosa-associated lymphoid tissue (MALT). Which patients benefit from this treatment is unknown. The aim of this study was to prospectively study whether staging by echoendoscopy predicts the outcome of treatment of MALT lymphoma by eradication of H. pylori.METHODS: Twenty-two patients positive for H. pylori with low-grade gastric B-cell MALT lymphoma were examined by echoendoscopy at the time of diagnosis. Treatment for H. pylori consisted of a 2-week course of oral omeprazole and amoxicillin. Patients were followed up by endoscopy and biopsy.RESULTS: H. pylori was eradicated in all patients. Complete regression of MALT lymphoma was observed in 12 patients (54%), partial regression in 5 patients (23%), and no response in 5 patients (23%) during follow-up. Twelve of 14 patients with lymphoma restricted to the mucosa or submucosa (stage E-I1) at echoendoscopy, but none of the 10 patients with higher stage (P < 0.01), showed complete regression of MALT lymphoma. In stage E-I1 patients, the probability of complete regression of lymphoma was 60% at 6, 79% at 12, and reached 100% at 14 months, respectively.CONCLUSIONS: Staging of gastric low-grade MALT lymphomas by endoscopic ultrasonography allows prediction of the response to therapy by eradication of H. pylori.(Gastroenterology 1997 Oct;113(4):1087-90)

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.

Gastric MALT-lymphoma and Helicobacter pylori infection.

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.

FREQUENT USAGE OF SPECIFIC IMMUNOGLOBULIN VH SEGMENTS IN GASTRIC LOW-GRADE B-CELL LYMPHOMAS OF MALT.

Background: Low-grade gastric B-cell lymphomas of the mucosa associated lymphoid tissue(MALT) are frequently associated with chronic H. pylori (Hp) infection. The fact that eradication of Hp induces regression of the lymphoma in the majority of the patients together with the presence of Hp-specific T-cells supports the notion that these lymphomas are Hp-responsive. Recent work suggests that autoreactivity may also be important in the development of lymphomas. In addition, other autoreactive diseases like systemic lupus erythematosus or rheumatoid arthritis are often associated with autoantibodies encoded by specific germline VH segments. This study was initiated to analyze VH segment usage and the pattern of somatic mutations in 25 patients with primary gastric low-grade MALT lymphoma. Methods: PCR on VHDJH rearrangements was performed using genomic DNA and generic primers for the VH-framework and JH regions. Monoclonal PCR-products were cloned and sequenced. Results: The VH-sequences detected were homologous to VH1-family segments in 20% and to VH3 and VH4-family segments in 60% and 20% respectively. All five VH1-sequences were derived from the same germline segment (DP-10, V1-69) and five of the fourteen VH3 sequences used the V3-7 (DP54) segment. Somatic mutations were found in 24 out of 25 sequences, with higher incidence of replacement mutations in the antigen contacting complementarity determinating regions(CDRs). 18 out of 25 germline VH segments had previously been isolated from various autoreactive antibodies. Conclusion: These findings support the notion that gastric MALT lymphomas develop from B-cells that have been exposed to antigen, most likely post germinal center B-cells. The high incidence of VH-alleles associated with autoreactivity and preferrence of specific germline VH segments points to the fact that autoreactivity may be important in the genesis of these lymphomas.

Pathogenesis of gastric lymphoma: The enigma in Hong Kong

Helicobacter pylori (H. pylori) infection has been postulated to be a pathogenetic factor in gastric lymphoma. However, the etiological factors for gastric lymphoma could vary in different populations. We looked for histological evidence of H. pylori infection in 53 gastrectomy specimens from Hong Kong Chinese patients with primary gastric B-lymphoma. We also screened for Epstein-Barr virus (EBV) in these cases using in situ hybridization with oligonucleotide probes for EBV-encoded small RNA1 and 2. H. pylori was found in 29 of 53 (55%), including 8 of 13 (62%) cases of low-grade lymphoma of mucosa-associated lymphoid tissue (MALT) type. These infection rates in gastric lymphoma are lower than those reported in Western populations (80%-100%) and comparable to that found in healthy Chinese blood donors (55%) or in non-ulcer dyspeptic patients (52%-57%). EBV was found in tumor cells only in one case of high-grade gastric lymphoma with low-grade MALT component which was H. pylori-negative, and in occasional nontumor-lymphoid cells in 7 other cases. These results suggest that (1) the role of H. pylori in pathogenesis of gastric lymphoma may vary in different populations; (2) very few gastric lymphomas are associated with EBV; (3) not all low-grade gastric MALT lymphomas are H. pylori-dependent.

A Comparison of Helicobacter pylori and H. heilmannii Gastritis: A Matched Control Study Involving 404 Patients

Background: Since Helicobacter heilmannii gastritis is very much rarer than H. pylori gastritis, and no systematic studies comparing these two gastritides have so far been carried out, we undertook the present study to investigate possible differences between H. heilmannii and H. pylori gastritis. Methods: In 202 patients with H. heilmannii gastritis and 202 matched control patients with H. pylori gastritis and duodenal ulcer the following variables were graded and compared: Helicobacter colonization, chronicity of gastritis, activity of gastritis, replacement of foveolar epithelium by regenerative epithelium, mucus depletion, frequency of acquired mucosa-associated lymphoid tissue (MALT), and intestinal metaplasia. Results: In contrast to the diffuse pattern of colonization in the case of H. pylori, colonization with H. heilmannii is mainly (91.2%) focal and for the most part restricted to the antrum (only 29.1% concurrent colonization of the corpus). The gradings of all gastritis variables were statistically highly significantly milder in the case of H. heilmannii gastritis. In addition, intestinal metaplasia and acquired MALT were significantly less common in patients with H. heilmannii infection. The rare cases of erosions (n=8) and ulcerations (n=8) in H. heilmannii gastritis were usually associated with the use of non-steroidal antiinflammatory drugs. In a single case of H. heilmannii gastritis a concurrent gastric carcinoma and in seven cases a low-grade gastric MALT lymphoma were found. Conclusion: In contrast to H. pylori infection the rare colonization of the gastric mucosa with H. heilmannii, mainly circumscribed and mostly in the antrum, induces a very much milder form of gastritis in the antrum and corpus, which may also be the reason for the rarity of concurrent erosions and ulcers. Whether the observed relatively frequent association of H. heilmannii infection and gastric MALT lymphoma is coincidental, and whether H. heilmannii gastritis is more commonly associated with MALT lymphoma than is H. pylori gastritis must be investigated in further studies.

Detection of immunoglobulin heavy chain gene rearrangement by polymerase chain reaction in chronic active gastritis associated with Helicobacter pylori

Chronic active gastritis associated with Helicobacter pylori (CAG-Hp) has been linked to the pathogenesis of gastric B-cell lymphomas of mucosa-associated lymphoid tissue (MALT). To determine whether monoclonal lymphoid populations are present in CAG-Hp and histological predictors of monoclonality exist, the authors examined 46 endoscopic biopsies from 41 patients with CAG-Hp. The authors scored gastric biopsies for the presence of lymphoepithelial lesions (LELs), intensity of lymphoid infiltrate, presence of lymphoid aggregates and germinal centers, coexpression of CD43 (Leu 22) on B cells, and cytoplasmic immunoglobulin light chain restriction in formalin-fixed, paraffin-embedded tissues. DNA extracts from these routinely processed tissues were analyzed for immunoglobulin heavy chain (IgH) gene rearrangement by polymerase chain reaction (PCR). Histological features, immunophenotype, gene rearrangement status, and clinical information were correlated. Six of the 46 biopsies (13%) from six of 41 patients (15%) showed a monoclonal PCR pattern. Monoclonal PCR patterns correlated with the presence of LELs ( P < .015) but not with intensity of lymphoid infiltrate, presence of germinal centers, or presence of lymphoid aggregates. LELs correlated with germinal centers ( P < .003) and intensity of infiltrate ( P < .0001). None of the cases showed cytoplasmic light chain restriction nor coexpression of CD43 on B cells by immunohistochemistry. Clinical follow-up was available in all six patients whose gastric biopsies had a monoclonal PCR pattern (median, 58 months; range, 1 to 66 months) and 33 of the 35 patients with biopsies showing a polyclonal PCR pattern (median, 41 months; range 0.1 to 63 months). No patient developed gastric lymphoma. Monoclonality of lymphoid cells was detected by IgH PCR in 13% of patients with CAG-Hp. Although the authors cannot exclude the possibility that some patients with monoclonal gastric lymphoid infiltrates may eventually develop overt lymphoma, no histological, immunophenotypic, nor clinical evidence of lymphoma was noted at presentation or on clinical follow-up. Given the high incidence of CAG-Hp in the general population and the relatively low incidence of gastric MALT lymphoma, clinicopathologic correlation is needed when interpreting tests for clonality in this setting. The presence of clonal IgH gene rearrangement in CAG-Hp supports the hypothesis that H pylori is involved in the pathogenesis of low grade gastric B-cell MALT lymphomas.

Analysis of antral biopsy specimens for evidence of acquired mucosa-associated lymphoid tissue in HIV1-seropositive and HIV1-negative patients.

There is conflicting evidence concerning the prevalence of Helicobacter pylori gastritis in HIV1-infected patients. Furthermore, a possible influence of immunodeficiency on the acquisition of mucosa-associated lymphoid tissue (MALT) in the antral mucosa remains to be elucidated. Seventy-seven consecutive HIV1-infected patients (mean age, 40.2 years) were compared in a prospective study with 77 HIV1-negative age-matched patients, using immunohistochemical stainings. In HIV1-infected patients the prevalence of H. pylori gastritis was lower and the inflammatory reaction less pronounced than in controls. Lymphoid follicles and intraepithelial B cells were significantly more often detected in HIV1-negative patients. Evidence of acquired MALT is only rarely found in HIV1-infected patients. These findings might contribute to the explanation of why low-grade gastric MALT lymphomas have not been reported in HIV1-infected patients so far.

Nucleolar Organizer Regions (NORs) Staining and Proliferating Cell Nuclear Antigen (PCNA) Immunostaining in Mucosa-Associated Lymphoid Tissue (MALT) Gastric Lymphomas

Nucleolar organizer region-associated proteins (AgNOR) and proliferating cell nuclear antigen (PCNA) have been studied by means of a silver staining technique and immunohistochemistry, in paraffin-embedded, gastrectomy specimens of 12 low-grade and 13 high-grade gastric MALT lymphomas respectively. A significant difference was found between the AgNOR count and PCNA index of low-grade lymphomas (mean AgNOR count 2.5 and mean PCNA index 8.33%) and high-grade lymphomas (mean AgNOR count 8.67 and mean PCNA index 49.7%). It is suggested that both methods are useful adjuncts to histopathology for the distinction between low and high grade gastric MALT lymphomas. We also found heterogeneity in AgNOR counts and PCNA index among individual cases of either low or high grade MALT gastric lymphomas. This suggests that the AgNOR count and PCNA index is helpful in the individual approach of the proliferation rate of each tumour, a parameter of potential importance for predicting the biological behaviour of the tumour and the prognosis of the disease.

Regression of primary low-grade B-cell gastric lymphoma of mucosa-associated lymphoid tissue type after eradication of Helicobacter pylori

Certain features of primary low-grade B-cell gastric lymphoma of mucosa-associated lymphoid tissue (MALT) suggest the tumour is antigen-responsive. Given the close association between gastric MALT lymphoma and Helicobacter pylori, these organisms might be evoking the immunological response, and eradication of H pylori might inhibit the tumour. 6 patients in whom biopsies showed histological and molecular-genetic evidence of low-grade gastric B-cell MALT lymphoma with H pylori infection were treated with antibiotics. In all cases H pylori was eradicated and in 5, repeated biopsies showed no evidence of lymphoma. These results suggest that eradication of H pylori causes regression of low-grade B-cell gastric MALT lymphoma, and that anti- H-pylori treatment should be given for this lymphoma.

Low grade B cell mucosa associated lymphoid tissue lymphoma of the stomach: clinical and endoscopic features, treatment, and outcome.

A retrospective study of the clinical and endoscopic features of low grade gastric lymphomas of mucosa associated lymphoid tissue (MALT) in 16 patients together with treatment and outcome was undertaken. Immunohistochemical studies of fresh tissue easily distinguished MALT lymphoma from benign reactive lymphoid hyperplasia (pseudolymphoma) and showed that tumour cells had the characteristic phenotype indicative of their origin from MALT. Persistent epigastric pain was the main presenting complaint, and was often associated with acute bleeding, anaemia, or weight loss. Eight patients had a past history of recurrent peptic ulcers or gastritis. The endoscopic appearance suggested malignancy in only half the cases and was compatible with gastritis or a benign peptic ulcer in the remainder. There was extragastric involvement of other mucosal sites in eight patients (mainly the lung, but also the parotid gland and small bowel), but rarely was bone marrow and never the spleen or peripheral lymph nodes affected. Conservative treatment with long term cyclophosphamide was effective in both stage I and stage IV disease, and all the patients are alive after a median follow up of 4.5 years. These findings confirm that low grade gastric MALT lymphomas are usually indolent tumours with non-specific endoscopic aspects and show that dissemination to other mucosal sites was more frequent than previously reported. Monochemotherapy could be an effective alternative treatment to surgery.