B-cell receptor signaling and CD40 ligand-independent T cell help cooperate in Helicobacter-induced MALT lymphomagenesis.

Gastric B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) develops in the context of chronic inflammation caused by Helicobacter pylori infection. Most pathophysiological features of the early stages of MALT lymphomagenesis can be reproduced by experimental infection of BALB/c mice with Helicobacter species. We have previously shown that MALT lymphomas are infiltrated by T-helper cell type 2-polarized T cells and that human and murine tumor B cells carry polyreactive surface immunoglobulins. Using the murine model of the disease, in this study we show that explanted tumor B cells proliferate upon stimulation with the same panel of self and foreign antigens that are recognized by their surface antibodies. Tumor cell proliferation is strongly enhanced by the presence of intratumoral CD4(+) T cells in a CD40/CD40L-independent manner. A large proportion of tumor-infiltrating CD4(+) T cells are CD25(+)FoxP3(+) regulatory T cells (Tregs) with highly suppressive activity, which are recruited by the tumor cells through secretion of the Treg-attracting chemokines CCL17 and CCL22. The depletion of CD25(+) cells was as efficient as CD4(+) T cell depletion in blocking tumor growth in vitro and in vivo. In conclusion, our data suggest that B-cell receptor-derived signals cooperate with T-helper cell signals in driving the progression of MALT lymphoma, providing an explanation for the unique antigen dependence of this B-cell malignancy.

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.

[Sepsis-like disease in an immunocompromised patient with a travel history to Mallorca]. / Sepsisähnliches Krankheitsbild bei Immunsuppression nach früherem Mallorcaurlaub.

In immunosuppressed patients, a high rate of complications due to opportunistic infection is known. We report the case of a 36 year old patient with ulcerative colitis and a septic complication with ongoing pancytopenia. Due to colonic perforation, colectomy had to be performed. Despite this intervention, the septic constellation persisted. The pancytopenia in peripheral blood counts also persisted with the necessity of repetitive transfusions. A bone marrow biopsy showed an infiltration with Leishmania bodies in macrophages. Tissue culture allowed for typing of the parasites as belonging to the L. donovani/infantum complex, DNA sequencing confirmed infection with L. infantum. This infection must have been contracted during a vacation on Mallorca about 1.5 years earlier. Administration of liposomal amphotericin B cured the patient. Surprisingly, histological examination of the resected colon reveiled the presence of an immunoblastic B-cell lymphoma. In this case, immunosuppression was a prerequisite for the manifestation of leishmaniosis.

Clonal relationship in multifocal non-Hodgkin's lymphoma of mucosa-associated lymphoid tissue (MALT).

To elucidate the progression of gastric marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) type, we analyzed a case presenting simultaneously with MALT lymphoma of the stomach and lung, and a gastric high-grade diffuse large lymphoma. The rearranged immunoglobulin heavy chain (IgH) variable regions were analyzed using a polymerase chain reaction (PCR)-based assay. Clonal relationship was shown between the gastric high-grade and the pulmonary low-grade lymphoma. The gastric MALT lymphoma was not related to the other manifestations. Translocation t(11;18) was not detected in the gastric high-grade lymphoma. MALT lymphomas at various locations and with different histologies may derive from a common precursor cell. Lymphomas at identical sites may have different stem cells.

Etiology and therapy of Helicobacter pylori-associated gastric lymphomas.

The WHO separates marginal zone B-cell lymphomas (MZBL) of nodal and extranodal type. Both arise from memory B cells of the marginal zone. Extranodal MZBL of the mucosa-associated lymphatic tissue (MALT) have characteristic features such as homing in epithelial tissue, lymphoepithelial destruction, and a very indolent clinical course. They arise in epithelial tissues normally devoid of lymphatic cells, where the lymphatic tissue was acquired after, for instance, a chronic infection. The best example here is infection of the stomach with Helicobacter pylori ( Hp). Besides the classical association with gastric MALT lymphomas, there have been reports in which an association between Hp and diffuse large B-cell lymphoma (DLBCL) has been observed as well. Consequently, cure of Hp infection resulted in remission induction not only in gastric MALT lymphomas, but also in some patients with very limited stages of DLBCL of the stomach. In addition to the association with Hp, progress has been made with regard to MALT lymphoma biology. Translocation t(1;14) involving the Bcl-10 gene, and translocation t(11;18) involving a novel gene called MLT1, both result in activation of the crucial transcription factor NF-kappaB. These genetic events seem specific in that they have been observed only in MALT lymphomas. Once present, at least the more frequently observed translocation t(11;18) renders cells resistant to cure of Hp infection. Another clinically important question is that in many patients in complete remission after cure of Hp infection, detection of minimal residual disease is positive. Whether these cells are normal memory B cells (with the identical B-cell rearrangement as the original lymphoma clone), or dormant lymphoma cells, is unclear at present. In patients not responding to cure of Hp infection, several treatment options are discussed. MALT lymphomas have opened up a new discussion of lymphoma biology and have thus been called a model disease.

Helicobacter and gastric MALT lymphoma.

Helicobacter pylori infection is a pre-MALT lymphoma condition. H pylori eradication leads to complete remission in 80% of low grade stage E1 lymphomas, with a yearly recurrence rate of approximately 5%. The possibility for complete remission in high grade lymphomas needs to be investigated in prospective studies. In addition, the significance of persistent B cell monoclonality (stable disease? danger of relapse? regression of monoclonality?) needs to be investigated in follow up studies.

Molecular diagnostics in low-grade gastric marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue type after Helicobacter pylori eradication therapy.

The primary gastric lymphomas are extranodal non-Hodgkin's lymphomas that likely originate from the mucosa-associated lymphoid tissue (MALT). Data suggest that chronic infection with Helicobacter pylori (H pylori) is significantly associated with the pathogenesis of low-grade gastric MALT lymphomas. This is in keeping with the observation that many patients with early low-grade MALT lymphomas have complete remissions after H pylori eradication therapy. However, the stability of these remissions remains unclear and relapses have been reported. It can be difficult to distinguish between early malignant and benign disorders of the gastric mucosa. A polymerase chain reaction (PCR) assay can detect rearrangements of the variable region of immunoglobulin heavy chains. This assay can be used to distinguish the clonality of B lymphocytes and has been investigated as a test for differential diagnosis of MALT lymphomas. Monoclonality is observed in the majority of MALT-lymphoma samples at diagnosis but has been found in gastritis samples as well. Whether the presence of monoclonal B cells is associated with the risk of lymphoma progression remains unclear. As many as 50% of patients who have complete histologic remissions of MALT lymphoma after H pylori eradication therapy have persisting monoclonal bands in follow-up PCR monitoring. Although it is unclear as to whether monoclonality indicates the presence of minimal residual disease, patients who have persistent monoclonal bands during follow-up should be considered at risk for relapse. The PCR assay for rearrangements of the variable region of the immunoglobulin heavy-chain gene appears to be of low value in the diagnosis of B-cell malignancies but could provide a useful tool in the follow-up of patients who achieve remissions after H pylori eradication.

Long-term follow-up of gastric MALT lymphoma after H. pylori eradication.

For almost 10 years, we have been familiar with the concept of mucosa-associated lymphoid tissue (MALT)-type lymphoma of the stomach caused by chronic Helicobacter pylori infection. Many epidemiologic, biologic, and molecular genetic studies have implicated H. pylori for its role in lymphoma genesis. Since the first reports on complete remission of gastric MALT lymphomas after cure of bacterial infection, many clinical studies have investigated the effect of eradicating H. pylori on the course of MALT lymphoma, and indeed were able to confirm remission of the lymphoma. To date, more than 650 patients worldwide have been treated for gastric MALT lymphoma with antibiotics, and we have gained many new insights concerning the biologic behavior of this disease, especially from the deepened knowledge of cytogenetics. Furthermore, factors relevant for the prediction of treatment outcome have been identified, which has helped to stratify patients into risk groups.

Healing of active, non-atrophic autoimmune gastritis by H. pylori eradication.

BACKGROUND AND AIMS: The antigastric antibodies present in Helicobacter pylori infection act as a marker for an ongoing antigastric autoimmune process in the gastric mucosa, which can already be diagnosed in the non-atrophic stage. In a retrospective, uncontrolled study, therefore, we investigated the question as to whether this type of gastritis can be healed by the eradication of H. pylori. PATIENTS AND METHODS: In 80 patients with an active, not yet atrophic autoimmune gastritis, we analysed a maximum of four investigations per patient over a period of up to 39.5 months. The following parameters were graded in the antral and corpus mucosa prior to and after H. pylori eradication treatment: grade and activity of the gastritis, H. pylori colonization, atrophy, parietal cell hypertrophy, and incidence of intestinal metaplasia. In addition, the typical parameters for this type of gastritis, such as grade of the periglandular lymphocytic infiltration, grade of glandular destruction and incidence of nodular ECL cell proliferates in the corpus mucosa were determined. RESULTS: In 64 patients (80%), H. pylori eradication treatment was followed by healing of the active autoimmune corpus gastritis, that is, the activity of the gastritis disappeared, and lymphocytic infiltration of the glands, glandular destruction and parietal cell hypertrophy was found to be significantly reduced. CONCLUSIONS: Our uncontrolled, retrospective study confirms the existence of an active, not yet atrophic autoimmune gastritis as a sequela of H. pylori infection.

Are lymphocytic monoclonality and immunoglobulin heavy chain (IgH) rearrangement premalignant conditions in chronic gastritis?

Normal gastric mucosa is devoid of lymphoid cells. Any increase of lymphocytes suggests chronic inflammation. Infection with Helicobacter pylori (Hp) is the major cause for nonautoimmune chronic gastritis and induces a mixed cellular response resulting in an acquired lymphoid tissue, or MALT (mucosa-associated lymphoid tissue). Hp has also been implicated in the genesis of gastric MALT-lymphoma. Polymerase chain reaction-based assays to detect the expansion of monoclonal B-cells have also been used to corroborate the diagnosis. In a considerable number of cases monoclonal B-cells remain detectable in follow-up biopsies, with the lymphoma being in complete histological remission. The clinical relevance of this finding is not clear yet. However, there also exist different reports that monoclonal B-cells can be found in gastric biopsies of patients with neither a histological sign nor a present or past history of lymphoma. In the light of these findings we address the question whether B-cell monoclonality can be seen as a premalignant condition in chronic gastritis and conclude that as of now the relevance of the finding of B-cell monoclonality remains unclear. As of now the only and gold standard for the diagnosis of gastric MALT-lymphoma is histopathology.

Problems with platelet counting in thrombocytopenia. A rapid manual method to measure low platelet counts.

Because most automated platelet counters cannot be relied on in thrombocytopenia, clinicians face a problem when decision making is based on platelet counts. Therefore we evaluated a visual platelet counting method from a blood smear with white blood cells (WBCs) as reference (PCW = platelet count based on WBC). Platelet counting for 74 thrombocytopenic (<120 x 10(9)/L) children was performed with PCW and with an automated counter (impedance principle); both methods were compared with evaluation by phase-contrast microscopy as the standard method. The PCW correlated well with the phase-contrast microscopy evaluation (y = -0.38 + 1.01x, r2 = 0.99). For platelet counts <20 x 10(9)/L the maximal deviation was 2 x 10(9)/L. The correlation between automated counts and the standard method was poor. The regression was y = 9.63 + 0.94x, r2 = 0.86. For platelet counts <20 x 10(9)/L the maximal deviation was 37 x 10(9)/L; on average, 7 x 10(9)/L platelets were counted in excess when compared with the standard method. PCW, in contrast to the automated impedance method, discriminated platelets from nonplatelet particles such as debris, fragments of red blood cells (hemolytic-uremic syndrome [HUS]) and of blast cells, and identified platelets of abnormal size. In addition, the appearance ofplatelets, WBCs, and RBCs gave clues to the etiology of thrombocytopenia, such as leukemia, infection, HUS, familial macrothrombocytopenia, and immune thrombocytopenia. PCW is a fast, reliable platelet counting method requiring less experience than the phase-contrast method. Visual evaluation from a stained smear clearly differentiates platelets and nonplatelet particles in contrast to most automated counters. In addition, the original smear can be preserved and reevaluated.

Long-term persistence of monoclonal B cells after cure of Helicobacter pylori infection and complete histologic remission in gastric mucosa-associated lymphoid tissue B-cell lymphoma.

PURPOSE: Cure of Helicobacter pylori infection is associated with remission induction in the majority of patients with low-grade gastric mucosa associated lymphoid tissue (MALT) lymphoma in localized stages; however, limited data exist as to whether these patients may be cured of their lymphoma. The present study was performed to investigate whether the polymerase chain reaction (PCR) for the rearranged immunoglobulin heavy chain region may be used to define "molecular" remission. PATIENTS AND METHODS: Ninety-seven patients who suffered from low-grade gastric MALT lymphoma stage I(E) were observed with central pathology and molecular biology after cure of H pylori infection. PCR was performed with the use of consensus primers for the framework regions 1, 2, and 3 and monoclonality was corroborated by sequence analysis. In selected cases, microdissection was performed to study the origin of the monoclonal B cells. RESULTS: Of the 97 patients, 77 obtained complete endoscopic and histologic remission (CR). Twenty of 44 patients with PCR monoclonality at diagnosis and with sufficient molecular follow-up displayed monoclonal bands for a median time of 20.5 months after CR (range, 0 to 50.4 months). These B cells were related to the original lymphoma clone by sequence analysis. Microdissection analysis identified basal lymphoid aggregates as the source of these monoclonal B cells. Local relapse occurred in and was observed by PCR in four patients. All four patients displayed monoclonal PCR before relapse, and three of these four showed ongoing PCR monoclonality throughout their course, indicating the persistence of malignant cells. CONCLUSION: Half of all patients with gastric MALT lymphoma show long-term PCR monoclonality up to several years after cure of H pylori infection and CR. Patients with monoclonal PCR should be observed closely, whereas long-term PCR negativity may indicate cure of the disease.

Helicobacter pylori eradication therapy in gastric high grade non Hodgkin's lymphoma (NHL).

BACKGROUND: Primary gastric low-grade lymphoma of the mucosa associated lymphoid tissue (MALT) develops on the background of a chronic Helicobacter pylori (H. pylori) infection. Stable remissions can be induced by H. pylori eradication therapy as shown in clinical trials. In 8 cases of high-grade gastric lymphomas remissions after H. pylori eradication were observed retrospectively. AIM: We started a pilot-trial to investigate the value of H. pylori eradication therapy in early gastric high-grade B-cell lymphoma prospectively. PATIENTS AND METHODS: So far, two H. pylori positive patients with high-grade B-cell lymphoma of the stomach stage Ann Arbor I E are included. They received a triple eradication-therapy (Clarithromycin 500 mg/d, Metronidazol 800 mg/d and Omeprazol 40 mg/d) for 7 days. Endoscopic controls are preformed every 4 weeks. RESULTS: Both patients became H. pylori negative after eradication therapy. One patient achieved complete remission (CR) 38 days after eradication. The continuous complete remission lasts now for 170 days. The second patient received only a partial remission (PR) 4 weeks after eradication and showed a slight progress 4 weeks later. He presently receives chemotherapy (CHOP). CONCLUSIONS: Patients with early high-grade gastric B-cell lymphomas should receive H. pylori eradication only within clinical trials. It seems to be possible to induce remissions of early high-grade gastric B-cell lymphomas with exclusive H. pylori eradication therapy. The stability of remission remains to be unclear and should be evaluated by following up the patients closely.

Eradication of Helicobacter pylori and stability of remissions in low-grade gastric B-cell lymphomas of the mucosa-associated lymphoid tissue: results of an ongoing multicenter trial.

The normal human stomach is devoid of any organized lymphatic tissue. Acquisition of mucosa-associated lymphatoid tissue (MALT) in the stomach is considered to be a direct consequence of chronic infection with Helicobacter pylori. Thus, MALT appears to be part of the host defense against the pathogen H. pylori. Consequently, lymphomas arising from gastric MALT may be seen as an end point of a clonal evolution starting from the infection. Cumulative data from several studies show that eradication of H. pylori induces complete histologic remissions in about 70%-80% of the patients. Here we present data of an extended analysis of an ongoing multicenter trial. Eighty-four patients with low-grade gastric MALT lymphoma in stage EI were treated using a dual regimen to eradicate H. pylori. Complete remission was observed in 68 (81%) patients; a partial remission was found in seven (8%) patients. In contrast, nine (11%) patients revealed "no change" and were referred for alternative treatment strategies. The majority of these cases were found to harbor high-grade lymphomas in deeper mucosal areas. Polymerase chain reaction (PCR) performed on the VDJ rearrangements of the immunoglobulin heavy chain yielded monoclonal bands in 50 of 65 analyzed patients (77%) at diagnosis. Interestingly, in patients analyzed during follow up after achieving complete histologic remission, ongoing PCR monoclonality was found in 19 of 39 eligible patients (49%). Several patients who developed local relapse of the lymphoma were found in the group with ongoing PCR monoclonality. Together with data from the literature, these results suggest that the majority of low-grade gastric MALT lymphomas in stage EI respond to eradication of H. pylori. Longer follow-up investigations are necessary to determine whether remissions really indicate a cure from the disease and to elucidate whether PCR monoclonality after complete histological remission is predictive of increased relapse rate.

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.

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

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.