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1.  Signet Ring Cell Gastric Cancer Occurring after Radiation Therapy for Helicobacter pylori-Uninfected Mucosa-Associated Lymphoid Tissue Lymphoma 
Case Reports in Gastroenterology  2011;5(2):325-329.
Helicobacter pylori infection is the major cause for mucosa-associated lymphoid tissue (MALT) lymphoma and gastric cancers. On the other hand, gastric cancers are known to arise from gastric mucosal atrophy. We here report a case of signet ring cell gastric cancer that developed after radiation therapy for MALT lymphoma in H. pylori-uninfected patient whose stomach did not show gastric mucosal atrophy. A 58-year-old female was referred to our hospital for treatment of gastric MALT lymphoma. This patient was not infected with H. pylori, and upper gastrointestinal endoscopy revealed that she did not have gastric mucosal atrophy but had submucosal tumor-like MALT lymphoma lesion in the anterior wall of the upper gastric body. Since conventional eradication therapy was ineffective, her whole stomach was irradiated as a second-line therapy. The MALT lymphoma lesion turned into complete remission state after the therapy. The patient was followed every 6 months by upper gastrointestinal endoscopy for 4 years as complete remission until a newly developed decolorized depressed lesion was detected in the greater curvature of the proximal antrum, a completely different location from the MALT lymphoma lesion. A biopsy specimen from the lesion contained signet ring cell carcinoma, and she was successfully treated by endoscopic submucosal dissection. No signs of recurrence have been detected so far. The radiation therapy for MALT lymphoma might be associated with the occurrence of this signet ring cell gastric cancer, and since MALT lymphoma is indolent in nature, this case suggests that careful consideration is required when choosing the second-line therapy for MALT lymphoma patients.
doi:10.1159/000329559
PMCID: PMC3124325  PMID: 21712948
Helicobacter pylori; Signet ring cell carcinoma; Stomach neoplasms; B-cell lymphoma; Radiotherapy
2.  Predictive value of endoscopic ultrasonography for regression of gastric low grade and high grade MALT lymphomas after eradication of Helicobacter pylori 
Gut  2001;48(4):454-460.
BACKGROUND—While a close association between gastric mucosa associated lymphoid tissue (MALT) lymphoma and Helicobacter pylori infection has been established, there are still cases which do not respond to H pylori eradication.
AIMS—To investigate the clinicopathological factors which may help predict the therapeutic efficacy of H pylori eradication in gastric MALT lymphoma.
PATIENTS—Forty one patients with gastric MALT lymphoma, including low and high grade lesions.
METHODS—After endosonographic staging was determined, H pylori was eradicated in all patients, and the subsequent gastric pathological course was then investigated.
RESULTS—Complete regression of MALT lymphoma was observed in 29(71%) patients, partial regression in five (12%), and no regression in seven (17%). Twenty six (93%) of 28 MALT lymphomas restricted to the mucosa but only three (23%) of 13 lymphomas which invaded the deep portion of the submucosa or beyond completely regressed. Kaplan-Meier analysis for the probability of complete regression of MALT lymphoma revealed a significant difference between tumours restricted to the mucosa and those invading the submucosa deeply or beyond (p<0.05). Neither the presence of a high grade component, perigastric lymphadenopathy, nor clinical staging prior to eradication correlated with the probability of lymphoma regression.
CONCLUSIONS—Assessment of deep submucosal invasion by endosonography is valuable for predicting the efficacy of H pylori eradication in gastric MALT lymphoma.


Keywords: gastric lymphoma; mucosa associated lymphoid tissue; Helicobacter pylori; endoscopic ultrasonography
doi:10.1136/gut.48.4.454
PMCID: PMC1728260  PMID: 11247887
3.  Regression of gastric high grade mucosa associated lymphoid tissue (MALT) lymphoma after Helicobacter pylori eradication 
Gut  2001;49(4):584-587.
BACKGROUND—Most low grade gastric lymphomas arising from the mucosa associated lymphoid tissue (MALT) are related to Helicobacter pylori colonisation. Cases with disease limited to the stomach can be cured after H pylori eradication and remain in remission for years. In contrast, high grade lymphomas of the stomach, although also related to H pylori, do not usually respond to eradication treatment.
CASE REPORT—A 36 year old patient was referred from another hospital with a diagnosis of a low grade gastric MALT lymphoma associated with H pylori. The patient was in stage I and while waiting for the biopsies to be reviewed H pylori eradication therapy was given as the first step of treatment. Review of the biopsies showed a high grade immunoblastic lymphoma with areas of low grade gastric MALT lymphoma (high grade gastric MALT lymphoma or diffuse large B cell lymphoma with areas of MALT type lymphoma of the WHO classification). The patient received no further treatment but has been closely followed up for 32 months with sequential endoscopies to obtain biopsies for histological studies, H pylori cultures, and polymerase chain reaction analysis of the IgH gene.
RESULTS—After H pylori eradication the patient had a complete histological response that has been maintained for 32 months. Monoclonal IgH gene rearrangement persisted for 32 months.
CONCLUSION—The response of this patient indicates the possibility that some cases of high grade gastric MALT lymphoma (possibly patients in stage I with a superficial or limited disease) may still be responsive to H pylori antigenic drive and may be cured with eradication therapy. Prospective studies should be performed to identify patients with high grade gastric MALT lymphomas that may respond to eradication therapy and be spared of other more aggressive treatments.


Keywords: mucosa associated lymphoid tissue; lymphoma; gastric lymphoma; immunoblastic lymphoma; Helicobacter pylori
doi:10.1136/gut.49.4.584
PMCID: PMC1728454  PMID: 11559658
4.  Successful antibiotic treatment of Helicobacter pylori negative gastric mucosa associated lymphoid tissue lymphomas 
Gut  2006;55(5):616-618.
Background and aims
The role of antibiotic treatment in early stage gastric mucosa associated lymphoid tissue (MALT) lymphoma not associated with Helicobacter pylori infection has not been investigated.
Patients and methods
Six patients with localised gastric MALT lymphoma underwent antibiotic treatment with clarithromycin, metronidazole, and pantoprazole. Staging, including endosonography plus gastroscopy, computed tomography of the thorax and abdomen, colonoscopy, magnetic resonance imaging of the salivary glands, and bone marrow biopsy were performed to rule out distant spread of the disease. In addition, MALT specific genetic changes, including reverse transcriptase‐polymerase chain reaction for t(11;18)(q21;q21), were tested in all patients. H pylori infection was ruled out by histology, urease breath test, serology, and stool antigen testing.
Results
All six patients had MALT lymphoma restricted to the stomach, and no evidence of infection with H pylori was found. Only one patient tested positive for t(11;18)(q21;q21) while the remaining five displayed no genetic aberrations. Following antibiotic treatment, endoscopic controls were performed every three months. Five patients responded with lymphoma regression between three and nine months following antibiotic treatment (one partial remission and four complete responses). One patient had stable disease for 12 months and was then referred for chemotherapy.
Conclusions
Patients with early stage gastric MALT lymphoma negative for H pylori might still benefit from antibiotic treatment as the sole treatment modality.
doi:10.1136/gut.2005.083022
PMCID: PMC1856121  PMID: 16299027
Helicobacter pylori; mucosa associated lymphoid tissue lymphoma; antibiotic treatment
5.  Limited Role of Bone Marrow Aspiration and Biopsy in the Initial Staging Work-up of Gastric Mucosa-Associated Lymphoid Tissue Lymphoma in Korea 
Gut and Liver  2014;8(6):637-642.
Background/Aims
The aim of this study was to investigate the frequency of disseminated gastric mucosa-associated lymphoid tissue (MALT) lymphoma and the role of bone marrow study in the initial staging work-up.
Methods
A total of 194 patients with gastric MALT lymphoma was enrolled. The incidence of disseminated disease was evaluated in the initial staging work-up. The demographic data and tumor characteristics were compared according to Helicobacter pylori infection status.
Results
Localized disease of Lugano stage I accounted for 97.4% of the enrolled cases. Abdominal computed tomography revealed abdominal lymph node metastasis in five patients (2.6%). Bone marrow (BM) involvement was found in only one patient without H. pylori infection (0.5%). No patient showed positive findings on chest computed tomography or positron emission tomography. H. pylori-negative cases showed a significantly higher frequency of advanced-stage disease than H. pylori-positive cases (10.0% vs 0.6%). In patients achieving complete remission, no extragastric recurrence occurred during follow-up.
Conclusions
The incidence of disseminated disease, including BM involvement, was very low in Korean gastric MALT lymphoma patients. It might be beneficial to perform BM aspiration and biopsy as a part of staging work-up only in patients with risk factors for advanced disease such as H. pylori negativity.
doi:10.5009/gnl13284
PMCID: PMC4215450  PMID: 25368752
Lymphoma; B-cell; marginal zone; Stomach; Bone marrow; Staging
6.  A case of gastric mucosa-associated lymphoid tissue lymphoma in which magnified endoscopy with narrow band imaging was useful in the diagnosis 
Recently, we reported a case of gastric mucosa-associated lymphoid tissue (MALT) lymphoma presenting with unique vascular features. In the report, we defined the tree-like appearance (TLA) on the images of abnormal blood vessels which resembled branches from the trunk of a tree in the shiny mucosa, in which the glandular structure was lost. The 67-year-old female was diagnosed with gastric MALT lymphoma. The patient received eradication therapy for H. pylori. Conventional endoscopy revealed multiple ill-delineated brownish depressions in the stomach and cobblestone-like mucosa was observed at the greater curvature to the posterior wall of the upper gastric body 7 mo after successful eradication. Unsuccessful treatment of gastric MALT lymphoma was suspected on conventional endoscopy. Conventional endoscopic observations found focal depressions and cobblestone-like appearance, and these lesions were subsequently observed using magnified endoscopy combined with narrow band imaging to identify abnormal vessels presenting with a TLA within the lesions. Ten biopsies were taken from the area where abnormal vessels were present within these lesions. Ten biopsies were also taken from the lesions without abnormal vessels as a control. A total of 20 biopsy samples were evaluated to determine whether the diagnosis of MALT lymphoma could be obtained histologically from each sample. A positive diagnosis was obtained in 8/10 TLA (+) sites and in 2/10 TLA(-) sites. Target biopsies of the site with abnormal blood vessels can potentially improve diagnostic accuracy of gastric MALT lymphoma.
doi:10.4253/wjge.v4.i4.151
PMCID: PMC3329616  PMID: 22523617
Mucosa associated-lymphoid tissue; Magnified endoscopy; Narrow band imaging; Tree-like appearance
7.  Helicobacter pylori infection in gastric mucosa-associated lymphoid tissue lymphoma 
Gastrointestinal lymphoma is the most common type of extranodal lymphoma, and most commonly affects the stomach. Marginal zone B-cell lymphoma of the mucosa-associated lymphoid tissue (MALT) and diffuse large B-cell lymphoma are the most common histologic types of gastric lymphoma. Despite its increasing incidence, diagnosis of gastric lymphoma is difficult at an earlier stage due to its nonspecific symptoms and endoscopic findings, and, thus, a high index of suspicion, and multiple, deep, repeated biopsies at abnormally and normally appearing sites in the stomach are needed. In addition, testing for Helicobacter pylori (H. pylori) infection and endoscopic ultrasonography to determine the depth of tumor invasion and involvement of regional lymph nodes is essential for predicting response to H. pylori eradication and for assessment of disease progression. In addition, H. pylori infection and MALT lymphoma development are associated, and complete regression of low-grade MALT lymphomas after H. pylori eradication has been demonstrated. Radiotherapy and/or chemotherapy can be used in cases that show poor response to H. pylori eradication, negativity for H. pylori infection, or high-grade lymphoma.
doi:10.3748/wjg.v20.i11.2751
PMCID: PMC3961970  PMID: 24659867
Mucosa-associated lymphoid tissue; Lymphoma; Helicobacter pylori; Eradication; Remission
8.  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 
Gut  2007;56(12):1685-1687.
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.
doi:10.1136/gut.2006.096420
PMCID: PMC2095715  PMID: 17639089
MALT lymphoma; H pylori eradication; histological residuals
9.  Effect of Helicobacter pylori eradication on ongoing mutation of immunoglobulin genes in gastric MALT lymphoma 
British Journal of Cancer  2005;92(2):312-319.
Gastric low-grade mucosa-associated lymphoid tissue (low-grade MALT) lymphomas has been associated with Helicobacter pylori (H. pylori) infection. Although infiltrating T cells with specificity for H. pylori are known to stimulate the development of MALT lymphomas, the effect of H. pylori eradication on rearranged immunoglobulin heavy chain (IgH) genes of low-grade gastric MALT lymphomas is unclear. Gastric biopsies from five cases were investigated by cloning and sequence analysis of rearranged IgH genes before and after the treatment for H. pylori. In all cases, IgH genes were mutated from their germline counterpart. The frequency of intraclonal sequence heterogeneity before the eradication of H. pylori varied from 0.25 to 0.49%. Clones obtained from the tumours before the eradication of H. pylori in cases 1 and 2 showed a tendency to display a mutation pattern by positive antigen selection and their monoclonarity disappeared after the eradication. The frequency of intraclonal sequence heterogeneity of the clones obtained from cases 3, 4 and 5 (0.12% in case 3, 0.10% in 4 and 0.18% in 5) after the eradication of H. pylori was lower than that in tumours before the eradication (0.30% in case 3, 0.49% in 4 and not determined in 5). These findings suggest that low-grade gastric MALT lymphomas expand due to the persistent presence of H. pylori in vivo. The characteristic feature of tumour clones obtained from the tumours after the eradication of H. pylori is a very low intraclonal heterogeneity, which may potentially be independent of H. pylori.
doi:10.1038/sj.bjc.6602262
PMCID: PMC2361844  PMID: 15655559
gastric MALT lymphoma; immunoglobulin heavy chain gene; ongoing mutation; Helicobacter pylori eradication
10.  Predictive factors for regression of gastric MALT lymphoma after anti-Helicobacter pylori treatment 
Gut  2001;48(3):297-303.
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 IE and IIE) 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.


Keywords: mucosa associated lymphoid tissue; gastric lymphoma; Helicobacter pylori
doi:10.1136/gut.48.3.297
PMCID: PMC1760135  PMID: 11171816
11.  Clinical impact of genetic aberrations in gastric MALT lymphoma: a comprehensive analysis using interphase fluorescence in situ hybridisation 
Gut  2007;56(10):1358-1363.
Background and aims
There is a need for genetic biomarkers to guide prognosis and management of gastric mucosa‐associated lymphoid tissue (MALT) lymphomas. We assessed the incidence and clinical significance of the MALT lymphoma‐associated genetic abnormalities t(11;18)/API2‐MALT1, t(1;14)/BCL10‐IGH, t(14;18)/IGH‐MALT1, t(3;14)/FOXP1‐IGH, and extra copies of MALT1 and FOXP1 in gastric MALT lymphomas from Japan.
Methods
The presence of translocations and copy number changes involving MALT1, IGH and FOXP1 were assessed in 90 cases of gastric MALT lymphoma using interphase fluorescence in situ hybridisation (FISH). In cases carrying a MALT1 translocation, FISH for API2‐MALT1 was performed, whereas in those carrying an IGH translocation, FISH was performed for BCL10, BCL6, BCL2, c‐MYC and/or CCND1.
Results
t(11;18)/API2‐MALT1 was detected in 18 of 87 (21%) cases and was significantly associated with Helicobacter pylori‐negativity, resistance to H pylori eradication and Bcl10 nuclear expression. Four of 68 (6%) cases carried a translocation involving IGH and FOXP1 (n = 1), BCL2 (n = 1) or an unknown partner (n = 2). Neither t(1;14)/BCL10‐IGH nor t(14;18)/IGH‐MALT1 was detected. Extra copies of MALT1 and FOXP1 were detected in 18 of 71 (25%) cases and 10 of 59 (17%) cases, respectively. The presence of extra copies of MALT1 was significantly associated with progression or relapse of lymphoma, and was an independent adverse prognostic factor for event‐free survival as determined by multivariate analysis.
Conclusions
t(11;18)/API2‐MALT1 is frequent, whereas IGH‐involved translocations are rare in gastric MALT lymphoma in Japan. The presence of extra copies of MALT1, often suggestive of partial or complete trisomy 18, is a frequent genetic aberration in gastric MALT lymphoma, which appears to predict adverse clinical behaviour.
doi:10.1136/gut.2007.123729
PMCID: PMC2000261  PMID: 17525089
12.  Running in the family: MALT lymphoma and autoimmune disease in mother and daughter 
Gastric B-cell lymphoma of the mucosa associated lymphoid tissue (MALT) lymphoma is one of the most common forms of extranodal lymphoma. In addition to infection with Helicobacter pylori (H. pylori), the presence of an underlying autoimmune disease has also been associated with MALT lymphoma development. To date, no familial predisposition for MALT lymphomas has been reported as opposed to other types of lymphoma. A 65-year-old woman was admitted at our institution in 1998 with a diagnosis of H. pylori positive gastric MALT lymphoma and the presence of chronic autoimmune thyroiditis was established on further work-up. H. pylori eradication did not result in regression of the lymphoma and RT-PCR showed the presence of the t(11;18)(q21;q21) translocation. About 1.5 years after H. pylori eradication, chemotherapy with cladribine resulted in complete remission. Due to lymphoma recurrence 13 mo later, radiotherapy to the stomach (46 Gy) resulted in minimal residual disease without further progression. The patient developed a second malignancy (Epstein-Bar virus-associated anaplastic large cell lymphoma in the mediastinum) in 2004 which initially responded to two courses of chemotherapy, but she refused further therapy and died of progressive lymphoma in 2006. In 2008, her 55 years old daughter with a long standing Sjögren’s syndrome was diagnosed with MALT lymphoma of the right parotid, but no evidence of gastric involvement or H. pylori infection was found. Currently, she is alive without therapy and undergoing regular check-ups. To our knowledge, this is the first report of MALT lymphoma in a first-degree relative of a patient with gastric MALT lymphoma in the context of two autoimmune diseases without a clearly established familial background.
doi:10.4251/wjgo.v4.i2.26
PMCID: PMC3296806  PMID: 22403739
Mucosa associated lymphoid tissue lymphoma; Helicobacter pylori; Autoimmunity; Familial lymphoma
13.  B-cell clonality and infection with Helicobacter pylori: implications for development of gastric lymphoma. 
Gut  1996;38(6):837-840.
BACKGROUND: Although Helicobacter pylori has been implicated in the pathogenesis of gastric mucosa associated lymphoid tissue (MALT) and MALT lymphoma, it is not known how it may trigger these lesions and whether there is an identifiable pre-neoplastic stage. AIMS: To investigate the relation between MALT, H pylori infection, and B-cell clonality (a potential marker of pre-neoplastic lesions). PATIENTS: 141 subjects with simple dyspepsia. METHODS: Gastric biopsy specimens from all patients were examined for MALT and H pylori. Of these, 25 consecutive MALT positive specimens were scored for features of MALT lymphoma and VDJ clonality studied by polymerase chain reaction. RESULTS: Overall, prevalence was 62% for H pylori and 46% for MALT. VDJ clonality was frequent in the sub-group studied (nine of 25), mostly associated with lymphoid follicles (eight of nine or 89%), and with a high scoring for MALT lymphoma. VDJ clonality was equally frequent in patients with and without H pylori (seven of 20 and two of five or 35% and 40% respectively). CONCLUSIONS: B-cell clonality is unexpectedly common in subjects with simple dyspepsia and MALT raising clinical management questions. These findings also suggest that the cascade MALT formation--B-cell clonality--MALT lymphoma may not be uniquely associated with H pylori infection.
PMCID: PMC1383189  PMID: 8984020
14.  Gastric mucosa-associated lymphoid tissue lymphomas and Helicobacter pylori infection: A Colombian perspective 
AIM: To assess the significance of chromosome translocation t(11;18)(q21;q21), B-cell lymphoma 10 (BCL-10) protein and Helicobacter pylori (H. pylori) infection in gastric mucosa-associated lymphoid tissue (MALT) lymphoma in Colombia.
METHODS: Fifty cases of gastric MALT lymphoma and their respective post-treatment follow-up biopsies were examined to assess the presence of the translocation t(11;18)(q21;q21) as identified by fluorescence in situ hybridization; to detect protein expression patterns of BCL10 using immunohistochemistry; and for evaluation of tumor histology to determine the correlation of these factors and resistance to H. pylori eradication.
RESULTS: Infection with H. pylori was confirmed in all cases of gastric MALT lymphoma in association with chronic gastritis. Bacterial eradication led to tumor regression in 66% of cases. The translocation t(11;18)(q21;q21) was not present in any of these cases, nor was there evidence of tumor transformation to diffuse large B-cell lymphoma. Thirty-four percent of the patients showed resistance to tumor regression, and within this group, 7 cases, representing 14% of all those analyzed, were considered to be t(11;18)(q21;q21)-positive gastric MALT lymphomas. Protein expression of BCL10 in the nucleus was associated with the presence of translocation and treatment resistance. Cases that were considered unresponsive to therapy were histologically characterized by the presence of homogeneous tumor cells and a lack of plasmacytic differentiation. Responder cases exhibited higher cellular heterogeneity and a greater frequency of plasma cells.
CONCLUSION: Both t(11;18)(q21;q21)-positive MALT lymphoma cases and those with nuclear BCL10 expression are considered resistant to H. pylori eradication. It is suggested that chronic antigenic stimulation is not a dominant event in resistant cases.
doi:10.3748/wjg.v18.i7.685
PMCID: PMC3281227  PMID: 22363141
Mucosa-associated lymphoid tissue lymphoma; Helicobacter pylori; Treatment; t(11; 18)(q21; q21); B-cell lymphoma 10
15.  Efficacy and cost-effectiveness of the 13C-urea breath test as the primary diagnostic investigation for the detection of Helicobacter pylori infection compared to invasive and non-invasive diagnostic tests 
Background
Helicobacter pylori (H. pylori) is one of the most common bacterial infections in humans. There is a risk factor for gastric or duodenal ulcers, gastric cancer and MALT (Mucosa Associated Lymphoid Tissue)-Lymphomas. There are several invasive and non-invasive methods available for the diagnosis of H. pylori. The 13C-urea breath test is a non-invasive method recommended for monitoring H. pylori eradication therapy. However, this test is not yet used for primary assessment of H. pylori in Germany.
Objectives
What are the clinical and health economic benefits of the 13C-urea breath test in the primary assessment of H. pylori compared to other invasive and non-invasive methods?
Methods
A systematic literature search including a hand search was performed for studies investigating test criteria and cost-effectiveness of the 13C-urea breath test in comparison to other methods used in the primary assessment of H. pylori. Only studies that directly compared the 13C-urea breath test to other H. pylori-tests were included. For the medical part, biopsy-based tests were used as the gold standard.
Results
30 medical studies are included. Compared to the immunoglobulin G (IgG) test, the sensitivity of the 13C-urea breath test is higher in twelve studies, lower in six studies and one study reports no differences. The specificity is higher in 13 studies, lower in three studies and two studies report no differences. Compared to the stool antigen test, the sensitivity of the 13C-urea breath test is higher in nine studies, lower in three studies and one study reports no difference. The specificity is higher in nine studies, lower in two studies and two studies report no differences. Compared to the urease test, the sensitivity of the 13C-urea breath test is higher in four studies, lower in three studies and four studies report no differences. The specificity is higher in five studies, lower in five studies and one study reports no difference. Compared to histology, the sensitivity of the 13C-urea breath test is higher in one study and lower in two studies. The specificity is higher in two studies and lower in one study. One study each compares the 13C-urea breath test to the 14C-urea breath test and the polymerase chain reaction (PCR) test, respectively, and reports no difference in sensitivity and specificity with the 14C-urea breath test, and lower sensitivity and higher specificity compared to PCR. The statistical significance of these differences is described for six of the 30 studies.
Nine health economic evaluations are included in the Health Technology Assessment (HTA) report. Among these studies, the test-and-treat strategy using the 13C-urea breath test is compared to test-and-treat using serology in six analyses and to test and treat using the stool antigen test in three analyses. Thereby, test-and-treat using the breath test is shown to be cost-effective over the serology based strategy in three models and is dominated by a test-and-treat strategy using the stool antigen test in one model. A cost-effectiveness comparison between the urea breath test approach and the empirical antisecretory therapy is carried out in four studies. Of these, two studies report that the strategy using the urea breath test is cost-effective over the empirical antisecretory therapy. In two studies, test-and-treat using the 13C-urea breath test is compared to the empirical eradication therapy and in five studies to endoscopy-based strategies. The breath test approach dominates endoscopy in two studies and is dominated by this strategy in one study.
Discussion
All included medical and economic studies are limited to a greater or lesser extent. Additionally, the results of the studies are heterogeneous regarding medical and economic outcomes respectively. Thus, the majority of the medical studies do not report the statistical significance of the differences in sensitivity and specificity. In direct comparisons the 13C- urea breath test shows higher sensitivity and specificity than the IgG and stool antigen tests. In comparison to the urease test, results for sensitivity are inconsistent, and the specificity is slightly higher for the 13C-urea breath test. There are not enough results for comparisons between the 13C-urea breath test and the 14C-urea breath test, histology and PCR to describe tendencies.
The included economic studies suggest that the test-and-treat strategy using the 13C-urea breath test is cost-effective compared to test-and-treat using serology as well as empirical antisecretory therapies. Due to a lack of valid studies, it is not possible to assess the breath test approach in comparison to test-and-treat using the stool antigen test and the empirical eradication therapy respectively, regarding the cost-effectiveness. The results of economic analyses comparing test-and-treat using the breath test to endoscopy strategies are too heterogeneous to draw any conclusions. Overall, none of the included economic models is able to completely capture the complexity of managing patients with dyspeptic complaints.
Conclusions/Recommendations
Based on available medical and economic studies, there is no sufficient evidence to recommend test and-treat using 13C-urea breath testing for the detection of H. pylori infection as the standard procedure for the management of uninvestigated dyspepsia in the German health care system. In addition, it must be considered that the DVGS guidelines of the Deutsche Gesellschaft für Verdauungs- und Stoffwechselkrankheiten (DVGS) recommend endoscopy based methods for the management of patients with dyspeptic complaints.
doi:10.3205/hta000076
PMCID: PMC3011289  PMID: 21289901
16.  Regression of colonic low grade B cell lymphoma of the mucosa associated lymphoid tissue type after eradication of Helicobacter pylori 
Gut  2000;46(1):133-135.
BACKGROUND—Lymphoma of the mucosa associated lymphoid tissue (MALT) arising in the stomach has been shown to be related to Helicobacter pylori infection, and total regression of gastric lymphoma after successful eradication of H pylori has consistently been reported. MALT-type lymphoma at other localisations, however, has to our knowledge not been linked to H pylori, and eradication of the bacteria has not been studied for management of such lymphomas.
PATIENT/METHOD—A 67 year old man was diagnosed with MALT-type lymphoma simultaneously involving the stomach and the colon descendens. In addition to the presence of MALT-type lymphoma, H pylori associated chronic gastritis was diagnosed, and treatment with clarithromycin, metronidazole, and omeprazole was initiated, resulting in its successful eradication.
RESULTS—Follow up performed four months later showed regression of the colonic manifestation, whereas the gastric lymphoma did not respond to antibiotic treatment, as assessed by regular follow up for 14 months, in spite of its restriction to mucosa and submucosa. The patient was therefore treated with oral cyclophosphamide (100 mg a day) resulting in partial remission after seven months of continuous treatment. Because of the presence of residual lymphoma, additional irradiation was performed, which led to complete remission of the gastric lymphoma. The patient remains in complete remission 40 months after diagnosis and 26 months after initiation of treatment.
CONCLUSION—In the case of concurrent gastric and intestinal low grade MALT-type lymphoma, H pylori eradication may cause regression of the intestinal lesion.


Keywords: mucosa associated lymphoid tissue; colon; Helicobacter pylori eradication; lymphoma
doi:10.1136/gut.46.1.133
PMCID: PMC1727770  PMID: 10601069
17.  Long term outcome of patients with gastric marginal zone B cell lymphoma of mucosa associated lymphoid tissue (MALT) following exclusive Helicobacter pylori eradication therapy: experience from a large prospective series 
Gut  2004;53(1):34-37.
Background: Helicobacter pylori plays a decisive role in the pathogenesis of gastric marginal zone B cell lymphoma of mucosa associated lymphoid tissue (MALT), and eradication therapy has become a widely accepted initial treatment of stage I disease.
Objective: To determine the long term outcome of patients undergoing exclusive H pylori eradication therapy.
Design: A prospective series of patients with newly diagnosed marginal zone B cell lymphoma of MALT.
Setting: Multicentre study in Germany and Austria.
Patients: Ninety five patients; 90 of these (five lost to follow up) with a mean age of 54.3 (27–85) years were followed up for at least 12 months.
Intervention: Complete staging work up revealing stage I disease and H pylori infection. Patients received triple therapy (OMC: omeprazole 20 mg twice daily, metronidazole 400 mg twice daily, and clarithromycin 250 mg twice daily; or OAC: omeprazole 20 mg twice daily, amoxycillin 1000 mg twice daily, and clarithromycin 500 twice daily) for one week.
Results: Median follow up was 44.6 (12–89) months. H pylori was successfully eradicated in 88 patients (98%); in two patients eradication therapy failed. Long term outcome was characterised by complete regression of lymphoma in 56 patients (62%), minimal residual disease in 17 patients (18%), partial remission in 11 patients (12%), no change in four patients (4%), and progressive disease in two patients (2%). Four patients with complete remission relapsed after 6, 8, 8, and 15 months, one revealing reinfection by H pylori. Regression rate was higher in stage I1 disease compared with stage I2, as diagnosed by endoscopic ultrasound.
Conclusion: The majority of patients with low grade gastric MALT lymphoma treated by exclusive H pylori eradication have a favourable long term outcome, offering a real chance of cure.
PMCID: PMC1773912  PMID: 14684573
MALT lymphoma; Helicobacter pylori; eradication therapy
18.  Treatment Outcome for Gastric Mucosa-Associated Lymphoid Tissue Lymphoma according to Helicobacter pylori Infection Status: A Single-Center Experience 
Gut and Liver  2013;8(4):408-414.
Background/Aims
Helicobacter pylori eradication therapy has been used as a first-line treatment for H. pylori-positive gastric mucosa-associated lymphoid tissue (MALT) lymphoma. However, the management strategy for H. pylori-negative MALT lymphoma remains controversial. Therefore, the aim of this study was to examine the success rate of each treatment option for H. pylori-positive and H. pylori-negative gastric MALT lymphomas.
Methods
In total, 57 patients with gastric MALT lymphoma diagnosed between December 2000 and June 2012 were enrolled in the study. The treatment responses were compared between H. pylori-positive and H. pylori-negative gastric MALT lymphomas.
Results
Of the 57 patients, 43 (75%) had H. pylori infection. Forty-eight patients received H. pylori eradication as a first-line treatment, and complete remission was achieved in 31 of the 39 patients (80%) with H. pylori-positive MALT lymphoma and in five (56%) of the nine patients with H. pylori-negative MALT lymphoma; no significant difference was observed between the groups (p=0.135). The other treatment modalities, including radiation therapy, chemotherapy, and surgery, were effective irrespective of H. pylori infection status, with no significant difference in the treatment response between H. pylori-positive and H. pylori-negative MALT lymphomas.
Conclusions
H. pylori eradication therapy may be considered as a first-line treatment regardless of H. pylori infection status.
doi:10.5009/gnl.2014.8.4.408
PMCID: PMC4113048  PMID: 25071906
Lymphoma; B-cell; marginal zone; Stomach; Helicobacter pylori; Eradication; Radiotherapy
19.  Trisomy 3 may predict a poor response of gastric MALT lymphoma to Helicobacter pylori eradication therapy 
AIM: To investigate the relation of the response to Helicobacter pylori eradication therapy to the depth of tumor invasion and chromosome abnormalities in patients with mucosa-associated lymphoid tissue (MALT) lymphoma and to determine the clinical value of aneuploidy.
METHODS: We studied 13 patients with localized gastric MALT lymphoma of stage E1. Before eradication therapy, the depth of tumor invasion was assessed by endoscopic ultrasonography in 8 patients and by endoscopic examination and gastrointestinal series in the remaining patients. To detect chromosomal abnormalities, paraffin-embedded tissue sections of diagnostic biopsy specimens underwent tissue-fluorescence in situ hybridization (FISH), using chromosome-specific α-satellite DNA probes for chromosomes 3,7,12, and 18 and YAC clones for t(11;18)(q21;q21).
RESULTS: Seven of the 13 patients had complete regression (CR) in response to H pylori eradication therapy. No patient with CR had submucosal tumor invasion. Trisomy 18 was seen in 1 patient with CR, and both trisomies 12 and 18 were present in another patient with CR. All patients with no response or progressive disease had deep submucosal tumor invasion and showed t(11;18)(q21;q21) or trisomy 3. Trisomy 7 was not detected in this series of patients.
CONCLUSION: The depth of tumor invasion is an accurate predictor of the response of stage E1 MALT lymphoma to H pylori eradication therapy and is closely associated with the presence of chromosomal abnormalities. Trisomy 3 may predict the aggressive development of MALT lymphoma.
doi:10.3748/wjg.v11.i1.89
PMCID: PMC4205391  PMID: 15609403
Helicobacter pylori infection; Gastric MALT lymphoma; Trisomy 3
20.  Remission of primary low-grade gastric lymphomas of the mucosa-associated lymphoid tissue type in immunocompromised pediatric patients 
We report the remission of primary gastric lymphoma of the mucosa-associated lymphoid tissue (MALT) type in two immunocompromised pediatric patients. Patient 1, a 14-year-old boy in an immunocompromised state of unknown cause, complained of repeated abdominal pain. Examinations revealed gastric MALT with local invasion and lymph node involvement. Serum anti-Helicobacter pylori (H pylori) antibody was positive. H pylori eradication was abandoned due to its adverse effects. The MALT lesion spontaneously regressed over the next 24 months without any treatment for lymphoma. Patient 2, a 6-year-old boy, underwent cord blood transplantation for the treatment of adrenoleukodystrophy. He was administered immunosuppressants for graft-versus-host disease after transplantation. Nausea and hematochezia appeared and further examinations revealed gastric MALT with H pylori gastritis. Treatment consisting of medication for the H pylori infection alone eradicated the H pylori and completely resolved the patient’s MALT lesion, as well. Patients 1 and 2 were followed up over periods of 10 years and 3 years, respectively, without any signs of relapse. In conclusion, gastric lymphoma of the MALT type can be cured by conservative treatment even in immunocompromised pediatric patients.
doi:10.3748/wjg.v12.i16.2625
PMCID: PMC4088002  PMID: 16688815
Pediatric gastric lymphoma; Mucosa-associated lymphoid tissue; Immunocompromised states
21.  Helicobacter pylori (H. pylori) molecular signature in conjunctival mucosa-associated lymphoid tissue (MALT) lymphoma 
Histology and histopathology  2004;19(4):1219-1226.
Summary
Conjunctival mucosa-associated lymphoid tissue (MALT) lymphoma is an extranodal marginal zone B-cell lymphoma that is characterized by an exaggerated clonal expansion of B cells, which implicate a pathological proliferative response to antigen(s) including bacteria. Helicobacter pylori (H. pylori) infection is recognized as one of the causative agents of gastric MALT lymphoma; however, it has not been reported in extra gastric MALT lymphoma. We studied 5 patients (4 adults and 1 child) with salmon-colored conjunctival lesions. One patient also had a history of abnormal bone marrow biopsy a year earlier with lymphoid aggregates involving 5% of the overall bone marrow. The conjunctival lesions of the 5 patients were biopsied. Histopathological diagnoses were consistent with conjunctival MALT lymphoma. Lymphoma and normal conjunctival cells were microdissected using laser capture microscopy or manual techniques. DNA was extracted and subjected to PCR amplification using H. pylori gene-specific primers from the urease B and vac/m2 gene. Cells from chronic conjunctivitis (normal lymphocytes), conjunctival human T-cell lymphotropic virus type-1/adult T-cell leukemia/lymphoma (HTLV-1/ATL), and orbital B-cell lymphoma were also microdissected, processed and analyzed. PCR amplification and Southern blot hybridization demonstrated H. pylori DNA in the conjunctival MALT lymphoma cells of 4/5 cases. The negative case was the one with a history of abnormal bone marrow. In contrast, H. pylori gene was not detected in normal conjunctival cells from the cases of MALT lymphoma or the lymphocytes, ATL and orbital B-lymphoma cells from the controls. These data suggest that H. pylori may play a role in conjunctival MALT lymphoma.
PMCID: PMC1971129  PMID: 15375765
Mucosa-associated lymphoid tissue (MALT) lymphoma; Helicobacter pylori (H. pylori); Conjunctiva; microdissection; PCR
22.  Blood groups Lewis(b) and ABH expression in gastric mucosa: lack of inter-relation with Helicobacter pylori colonisation and occurrence of gastric MALT lymphoma. 
Gut  1997;41(1):37-42.
BACKGROUND: Blood group Lewis(b) antigens mediate Helicobacter pylori attachment to gastric mucosa with attachment being particularly strong in subjects with ABH blood group O. AIMS: To determine whether H pylori colonisation or the occurrence of gastric mucosa associated lymphoid tissue (MALT) lymphomas might be related to gastric Lewis(b) expression or occurrence of particular ABH blood groups on gastric mucosa. PATIENTS: Gastric resection specimens from 89 cases with gastric MALT lymphoma and gastric mucosal biopsy specimens from 95 patients undergoing upper endoscopy due to upper gastrointestinal complaints, including five cases with gastric MALT lymphoma, were studied. METHODS: H pylori was visualised with the Warthin-Starry stain. Immunostaining (Lewis(b), Lewis(a), A, B) was performed by applying a three step immunoperoxidase technique and indirect immunofluorescence staining on formalin fixed and paraffin wax embedded tissue. In 40 patients red blood cell Lewis phenotype and ABH blood groups were additionally determined by haemagglutination assay. RESULTS: Gastric surface epithelial cells showed an immunoreactivity to blood groups A, B, and AB in 80 (43.5%), 22 (12%), and 11 (6%) cases respectively and no immunoreactivity to any of these blood group substances (blood group O) in 71 (38.5%) patients. Lewis(b) expression of all gastric surface epithelial cells (secretor status) was found in 130 (70.7%) cases. Lewis(a) expression of all gastric surface epithelial cells (non-secretor status) was found in 36 (19.6%) cases, secretor status remained unclassified in 18 (9.8%) patients. Colonisation with H pylori was found in 134 (72.8%) cases. The occurrence of H pylori was neither significantly associated with secretor status nor with certain ABH blood groups. The infiltration of gastric mucosa with MALT lymphoma was highly significantly associated with H pylori colonisation (p < 0.0003) but neither with secretor status nor with certain ABH blood groups. There was no inter-relation between secretor status or ABH blood groups and type, stage, grade of, and survival after MALT lymphoma. CONCLUSION: This study failed to show an inter-relation between secretor status or particular ABH blood groups and either H pylori infection or the occurrence of gastric MALT lymphomas.
Images
PMCID: PMC1027225  PMID: 9274469
23.  Successful treatment of mucosa-associated lymphoid tissue lymphoma in a patient with gastric and rectal lesions with metachronous and ectopic development 
Rare Tumors  2011;3(2):e24.
A 75-year-old female, who had an abnormal stomach x-ray finding, was admitted to the hospital for further examination and therapy. Upper GI endoscopy showed reddish and swollen folds on the greater curvature of the gastric body and a biopsy was of this lesion revealed malignant lymphoma (small cell type or mucosa-associated lymphoid tissue (MALT) lymphoma suspected). The patient was infected with Helicobacter pylori (H. pylori), however, in response to the patient's wishes, a total gastrectomy, omentectomy and splenectomy were performed and the histological diagnosis was gastric MALT lymphoma. Two courses of CHOP therapy (cyclophosphamide (CPM) 750 mg/m2/day, day 1, adriamycin (ADM) 50 mg/m2/day, day 1, vincristine sulfate (VCR) 1.4 mg/m2/day, day 1, prednisolone 100 mg/body, day 1–5) were administered as adjuvant chemotherapy. A colonoscopic examination performed about 4.5 yr after the operation revealed rectal submucosal tumors and the biopsied specimens were diagnosed as malignant lymphoma. A transanal focal resection was performed and the histological diagnosis was metachronous and ectopic development of MALT lymphoma. The histological finding was similar to the gastric lesion. About 4 and 7 yr after the first development of rectal MALT lymphoma, MALT lymphomas developed repeatedly in the rectal lesion, however, these were resected repeatedly and no developmenthas occurred during the past two years. This report presents a very rare case of metachronous and ectopic MALT lymphoma development in the gastric and rectal lesions.
doi:10.4081/rt.2011.e24
PMCID: PMC3132128  PMID: 21769323
mucosa-associated lymphoid tissue lymphoma; metachronous development; ectopic development; CHOP therapy; eradication of H. pylori.
24.  Gastric MALT lymphoma and Helicobacter pylori. 
Primary gastric low-grade B-cell lymphomas are neoplastic mimics of mucosa associated lymphoid tissue (MALT) as exemplified by Peyer's patches in the terminal ileum. Architectural and immunophenotypic properties of the neoplastic cells suggest that they originate from MALT-derived marginal zone B-cells. Paradoxically, the normal human stomach is devoid of organized MALT within which a lymphoma can develop. Lymphoid tissue is acquired in the stomach in response to antigenic stimulation, predominantly associated with Helicobacter pylori infection. Studies of patients with low-grade MALT lymphoma have confirmed a high incidence of H. pylori infection and suggest that the infection predates neoplastic transformation. Certain morphological features of MALT lymphomas suggest that the tumor cells remain responsive to antigen drive. Given the close association between gastric MALT lymphoma and H. pylori, it is possible that this organism provides such a drive. In vitro studies have shown that the tumor cells proliferate in a T-cell-dependent way to the presence of H. pylori. Several studies have now demonstrated that eradication of the organism in patients with low-grade gastric MALT lymphoma can result in regression of the tumor. In cases with a high-grade component, the associated low-grade part may regress, but most high-grade gastric MALT lymphomas are unresponsive to this conservative therapy.
Images
PMCID: PMC2588981  PMID: 9041690
25.  Overexpression of miR-142-5p and miR-155 in Gastric Mucosa-Associated Lymphoid Tissue (MALT) Lymphoma Resistant to Helicobacter pylori Eradication 
PLoS ONE  2012;7(11):e47396.
microRNAs (miRNAs) are small non-coding RNAs that can function as endogenous silencers of target genes and play critical roles in human malignancies. To investigate the molecular pathogenesis of gastric mucosa-associated lymphoid tissue (MALT) lymphoma, the miRNA expression profile was analyzed. miRNA microarray analysis with tissue specimens from gastric MALT lymphomas and surrounding non-tumor mucosae revealed that a hematopoietic-specific miRNA miR-142 and an oncogenic miRNA miR-155 were overexpressed in MALT lymphoma lesions. The expression levels of miR-142-5p and miR-155 were significantly increased in MALT lymphomas which do not respond to Helicobacter pylori (H. pylori) eradication. The expression levels of miR-142-5p and miR-155 were associated with the clinical courses of gastric MALT lymphoma cases. Overexpression of miR-142-5p and miR-155 was also observed in Helicobacter heilmannii-infected C57BL/6 mice, an animal model of gastric MALT lymphoma. In addition, miR-142-5p and miR-155 suppress the proapoptotic gene TP53INP1 as their target. The results of this study indicate that overexpression of miR-142-5p and miR-155 plays a critical role in the pathogenesis of gastric MALT lymphoma. These miRNAs might have potential application as therapeutic targets and novel biomarkers for gastric MALT lymphoma.
doi:10.1371/journal.pone.0047396
PMCID: PMC3509063  PMID: 23209550

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