Endoscopic characteristics of primary gastric lymphoma and prediction of treatment response

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

Primary gastric lymphoma associated with Helicobacter pylori in a child.

Regression of gastric lymphoma of mucosa-associated lymphoid tissue by Helicobacter pylori eradication: endoscopic observation

Helicobacter pylori and MALT Lymphoma

The eradication of Helicobacter pylori (H. pylori) is an effective treatment in gastric mucosa-associated lymphoid tissue (MALT) lymphoma associated with H. pylori infection. However, the treatment strategy in gastric MALT lymphoma patients who are H. pylori-negative or unresponsive to H. pylori eradication therapy remains controversial. In this study, we investigated the clinical efficacy of treatments other than H. pylori eradication therapy in these groups of patients. This was a retrospective single-center study based on the medical records of patients diagnosed with gastric MALT lymphoma at Yeungnam University Medical Center between January 2005 and December 2016. Patients were treated with H. pylori eradication therapy, chemotherapy, or radiotherapy according to their H. pylori infection status and stage of gastric MALT lymphoma. Of the 68 eligible patients, 50 were enrolled in the study. Of the 42 patients with H. pylori-positive gastric MALT lymphoma, 36 (81.7%) were treated with H. pylori eradication therapy as primary treatment and 25 (69.4%) achieved a complete response (CR). Patients without a CR after H. pylori eradication therapy (n=11, 30.6%) received radiotherapy as a secondary treatment. Two patients with H. pylori-positive gastric MALT lymphoma and eight with H. pylori-negative gastric MALT lymphoma received radiotherapy as the primary treatment. CR was achieved in all 21 patients treated with radiotherapy as primary or secondary treatment. The 5-year progression-free survival rate after radiotherapy was 92.9%. Radiotherapy may be a worthwhile treatment option in patients with H. pylori-negative MALT lymphoma or H. pylori-positive MALT lymphoma that is not responsive to H. pylori eradication therapy.

Helicobacter pylori (H. pylori) eradication treatment for primary gastric mucosa-associated lymphoid tissue (MALT) lymphoma has already been established. However, t (11;18) (q21;q21)/API2-MALT1 translocation-positive lesions are a type of primary gastric MALT lymphoma in which a response to eradication treatment is difficult to achieve. In addition, trisomy 18 may be associated with diffuse large B-cell lymphoma (DLBCL) transformation of gastric MALT lymphoma. A 66-year-old man was diagnosed with MALT lymphoma in the ascending colon by colonoscopy and biopsy. Two years later, esophagogastroduodenoscopy revealed chronic atrophic gastritis that was positive for H. pylori, and eradication treatment was administered. Two years and nine months later (at the age of 70), a new ulcerative lesion suggestive of MALT lymphoma appeared in the gastric body, and six months later, a similar lesion was also found in the fundus. One year later (4 years and 3 months after H. pylori eradication), at the age of 72, the lesion in the gastric body had become deeper and had propagated. A biopsy revealed a pathological diagnosis of DLBCL. Both MALT lymphoma lesions in the ascending colon and DLBCL lesions in the stomach were positive for the t (11;18) (q21;q21)/API2-MALT1 translocation, and trisomy 18q21 was also detected. After 6 courses of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) chemotherapy, all of the above lesions disappeared [complete remission (CR)], and CR has been maintained for more than 3 years. In addition, both the colonic and gastric lesions were proven to have the same clonality. Because the patient had a MALT1 translocation with trisomy 18q21, it was thought that this gastric MALT lymphoma developed independently of H. pylori infection and progressed.

Remission of a high-grade gastric mucosa associated lymphoid tissue (MALT) lymphoma following HELICOBACTER pylori eradication and highly active antiretroviral therapy in a patient with AIDS

It is still unclear which patients with gastric mucosa-associated lymphoid tissue (MALT) lymphoma will benefit from the eradication of Helicobacter pylori. The authors studied a total of 34 patients. Twenty-three patients had primary gastric lymphoma and underwent gastric resection as initial treatment. Eleven patients with gastric MALT lymphoma who received antibiotics against H. pylori as initial treatment were also included. In all 34 patients, the presence of H. pylori, endoscopic findings, and pathologic features were evaluated. Immunohistochemical expression of Bcl-2, p53, and proliferating cell nuclear antigen (PCNA) was classified as follows: (-), no reactive cells; (+), scattered positive cells; (2+), nests of positive cells; (3+), diffuse positive cells. Patients with low grade MALT lymphoma (LG) tended to be positive for H. pylori (6 of 9), to localize within the submucosa (7 of 9), not to have lymph node involvement (7 of 8), and to have lower tumor stage compared with patients with high grade MALT components (HG). Bcl-2 protein was expressed with high frequency by LG (7 of 9). Strong expression of p 53 was more common in the HG tumors (4 of 14), and strong expression of PCNA showed a significant difference between LG (1 of 8) and HG patients (12 of 13). Investigation of the patients with long term follow-up (n = 4) revealed that LG remained superficial for a long time and showed gradual progression. Most of these tumors were Bcl-2+/p53-approximately+/-/ PCNA- approximately +. There were two patients whose superficial LG (sm/Bcl-2+/p53-/PCNA- approximately +) regressed after the disappearance of H. pylori. On the other hand, one patient developed ulcerated LG (sm/Bcl-2 /p53+/PCNA3+) after disappearance of H. pylori. The authors found complete regression of MALT lymphoma in 9 of 11 patients after H. pylori eradication. Initial tumors of these 9 patients were superficial/sm/n(-)/low grade/Bcl-2+approximately +/-/p53-approximately+ (n = 9), /PCNA-approximately+(n = 6), /PCNA 2+ (n = 3). Two local recurrence and one non-Hodgkin lymphoma in other sites were observed after initial therapy. Gastric MALT lymphoma with (H. pylori positive/superficial/sm/low grade/Bcl-2 +/p53- approximately +/PCNA- approximately +) pattern will disappear after a patient is cured of H. pylori infection.

A Multicenter Prospective Study of First-Line Antibiotic Therapy for Early-Stage Gastric Mucosa-Associated Lymphoid Tissue (MALT) Lymphoma and Diffuse Large B-Cell Lymphoma with Histological Evidence of MALT

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.

The purpose of the present paper was to investigate the clinical, endoscopic and histological features of 31 patients with gastric mucosa-associated lymphoid tissue (MALT) lymphoma to enable correct, early stage diagnosis. A retrospective study was undertaken of 31 patients with gastric MALT lymphoma. The cases were examined immunohistologically with anti-CD(20CY) and CD(45RO) antibodies for further diagnosis. Helicobacter pylori infection was also detected with modified Giemsa staining. Patients with MALT lymphoma were aged between 22 and 73 years (mean, 45.0 years), and the male:female ratio was 11:20. The patients presented with non-specific symptoms, but chronic epigastric pain was the common symptom in a large proportion of the cases. The gastric smaller curvature was involved in 83.9% of cases (26/31) and in 13/31 cases (41.9%) it was confined the antrum. Under endoscopy, large and deep ulcers were similar to cancers in the majority of patients. Only 29.0% of patients were diagnosed by endoscopy on first examination. CD(20CY) were expressed in all cases and CD(45RO) expressed in only one case among 10 cases of indefinite diagnosis. Helicobacter pylori infection was found in 87.1% of patients. These findings suggest that primary gastric MALT lymphoma has unique clinical, endoscopic and histological features. The diagnosis for primary gastric MALT lymphoma was delayed not only due to the non-specific symptoms but also due to lack of attention to its features. Endoscopy and submucosal multiple biopsy were the principal diagnostic tools in patients with gastric MALT lymphoma. CD(20CY) and CD(45RO) immunological staining are recommended, especially for patients with indefinite diagnosis of gastric MALT lymphoma.

I read with interest the recent review article by Suzuki et al.1 This paper helps gastroenterologists to understand the link between gastric mucosa-associated lymphoid tissue (MALT) lymphoma and Helicobacter pylori (H. pylori), but several questions remain unanswered: (i) the predictive factors for regression of gastric MALT lymphoma after H. pylori eradication, (ii) the characteristic endoscopic findings, (iii) how to optimize the definition and managemnet of nonresponders, and (iv) how to manage the relapse and recurrence of these tumors. The first report in 19932 has been followed by numerous reports of regression of MALT lymphoma after H. pylori eradication. However, not all gastric MALT lymphomas regress after H. pylori eradication, and thus three factors related to the prediction of tumor regression need to be considered: (i) the characteristics of gastric MALT lymphoma itself, (ii) the presence of H. pylori infection, and (iii) factors related to the host, such as the score on the international prognostic index and blood-test results. For example, even the location of the tumor has been mentioned as a predictive factor, with gastric MALT lymphomas on the proximal side being linked to autoimmunity.3 These proximal-side tumors progress very slowly and often fail to regress because they are linked to autoantigen responsive T cells.3,4 In addition, histological features of MALT lymphoma are known to be unresponsive to eradication therapy.5 An endoscopic apperance mimiking submucosal tumors and cobblestone like elevated lesions have been classified as polypoid gastric MALT lymphoma, and characterized as H. pylori-negative gastric MALT lymphoma.6,7 Although Suzuki et al. described this briefly in their review,1 H. pylori negativity needs to be defined. Since there is no single gold-standard methods for diagnosing H. pylori infection, the combination of several diagnostic methods including H. pylori IgG antibody, histology, culture, immunohistochemistry, PCR, and the urease breath test is considered to be suitable for confirming H. pylori negativity.8 In addition, the characteristics of H. pylori-negative gastric MALT lymphoma should be managed based on previous reports.9 Put simply, the treatment should differ from H. pylori eradication in these H. pylori-negative gastric MALT lymphoma due to the absence of H. pylori. However, these lymphomas also respond to antibiotic treatment in both the stomach and other parts of the gastrointestinal tracts.10 What mechanism underlies this phenomenon? Does this represent a clue for a false-negative diagnosis of H. pylori infection? What would be the possible hypothesis based on previous reports? On the other hand, non-H. pylori helicobacters related to MALT lymphoma should also be considered, such as H. helimannii and H. felis.11 Interestingly, some of these regress merely after the application of first-line H. pylori eradication therapy.12 In addition, these organisms are detected in both gastric and rectal lymphomas.13 Optimizing the definition and management of nonresponders requires consideration of three issues: (i) the minimum observation period needed to define regression, (ii) interpretating discrepancies between the histologic and endoscopic regression, and (iii) choosing between a wait and see and a second-line treatment such as gastrectomy, chemotherapy, and radiotherapy. Although a Japanese study adressed the last issue,14 the optimal strategy remains unclear. In addition to the definition and management, the relapse and recurrence of gastric MALT lymphoma after successful regression on H. pylori eradication also need to be clarified. There are some reports of the development of high-grade tumor (diffuse large B-cell lymphoma) or gastric adenocarcinoma after successful regression of gastric MALT lymphoma. What would be the mechanisms and prognostic factors in such tumors? In summary, answers to the above questions that arose when I read the review by professor Suzuki and colleagues would be of considerable interest to readers of Gut and Liver. There are already several interesting published papers written by Japanese authors that strengthen our knowledge in this field, and I strongly believe that addressing the above issues would greatly increase the interest in their review article.

Eradication of Helicobacter pylori (H. pylori) is accepted as initial treatment of stage I(E₁) gastric mucosa associated lymphoid tissue (MALT) lymphoma. However, 10-20% of gastric low grade MALT lymphomas are unresponsive to H. pylori eradication treatment. The aim of this study was to find out the predictive factors of complete remission of gastric MALT lymphoma after H. pylori eradication. From 1995 to 2006, consecutive 95 patients with modified Ann Arbor stage I(E₁) gastric MALT lymphoma were enrolled, and their medical records were reviewed. The patients were initially treated by H. pylori eradication. The complete remission was determined by endoscopic and histologic finding. Eighty eight patients (92.6%) achieved complete remission after H. pylori eradication therapy. Mean follow up time for these patients was 40+/-25 months. Seven patients (7.4%) failed to achieve complete remission. There was no significant difference in the age, sex, endoscopic appearance, and large cell component between the remission group and failure group. Among 66 patients with distal tumor, 65 patients (98.5%) achieved complete remission. On the other hand, among 13 patient with proximal tumor, 9 patients (69.2%) achieved complete remission (p=0.001). The odds ratio of proximal tumor for H. pylori eradication failure was 28.9 (95% CI=2.9-288.0). The proximally location of MALT lymphoma is a risk factor of the H. pylori eradication treatment failure. Therefore, the proximally located gastric MALT lymphoma should be carefully treated and followed.

Gastric mucosa-associated lymphoid tissue (MALT) lymphoma and diffuse large B cell lymphoma (DLBCL) show a spectrum of disease characterized by varying proportions of low-grade and high-grade components. While the natural history and optimum treatment for low-grade gastric MALT lymphoma and DLBCL is well established, the prognosis and optimal treatment of patients with both low- and high-grade components is not well established. The purpose of our study was to evaluate the clinical characteristics, survival outcomes, and prognostic factors of patients with gastric MALT lymphoma and gastric DLBCL. A retrospective review of patients with gastric MALT lymphoma, gastric DLBCL, or MALT lymphoma with a high-grade component treated at our centers from 1994 to 2006 was performed. Patients were divided into three categories: "pure MALT lymphoma," "MALT lymphoma with high-grade component" (mixed), and "pure DLBCL." Seventy-six patients were included in our study-26 with pure MALT, 22 with MALT with high-grade component ("mixed"), and 28 with pure DLBCL. Pure MALT lymphoma and mixed lymphoma patients had similar clinical characteristics, whereas pure DLBCL patients had less favorable disease characteristics with significantly poorer performance status, higher number of extranodal sites of disease, higher stage, and larger proportion of bone marrow involvement and international prognostic index (IPI) scores compared with mixed lymphoma. The majority of mixed lymphoma (72.7%) and DLBCL patients (71.4%) were treated with chemotherapy. Of patients receiving chemotherapy, a higher proportion of mixed lymphoma and DLBCL patients received anthracycline-based combination chemotherapy regimens compared with MALT lymphoma (73% vs 71% vs 8%) whereas the proportion of mixed lymphoma and DLBCL patients was similar (p = 0.919). At a median follow-up of 37 months, the 5-year overall survival was 66.9%. The 5-year overall survival was 78% for MALT lymphoma, 84% for mixed lymphoma, and 45% for DLBCL. On univariate analysis, DLBCL histology, age, performance status, serum albumin, lactate dehydrogenase, bone marrow, number of extranodal sites, stage, and IPI score were prognostic for inferior survival. On multivariate analysis, DLBCL histology remained significantly prognostic for inferior survival, independent of chemotherapy regimen (hazard ratio (HR) 6.66, 95% confidence interval (CI) 2.01-21.41, p = 0.001). Mixed histology was not prognostic for inferior survival (HR 1.13, 95% CI 0.28-4.54, p = 0.868). Other factors prognostic for inferior survival were serum albumin <37 g/L (HR 3.22, 95% CI 1.11-13.22, p = 0.034) and treatment with non-cyclophosphamide, doxorubicin, vincristine, and prednisolone chemotherapy (HR 4.89, 95% CI 1.67-14.36, p = 0.004). In conclusion, the clinical characteristics of mixed histology MALT lymphoma are similar to low-grade MALT lymphoma and significantly different from pure DLBCL. The prognosis of mixed histology MALT lymphoma is significantly better than pure DLBCL, independent of IPI and chemotherapy regimen, and pure DLBCL histology is independently prognostic of inferior survival outcome.

BackgroundHelicobacter pylori (HP) has been considered to be one of the primary causes of gastric mucosa-associated lymphoid tissue (MALT) lymphoma since 1993. Low-grade gastric MALT lymphoma with HP is widely treated with HP eradication therapy, according to each specific clinical situation. However, several studies and guidelines indicate that the modified HP eradication therapy is also valid for HP-negative gastric MALT lymphoma. The aim of this study was to perform a meta-analysis of the clinical efficacy of the modified HP eradication therapy for gastric MALT lymphoma without HP.MethodsWe searched studies that reported the response rate of the modified HP eradication therapy regimen for gastric MALT lymphoma without HP by using PubMed, Medline, and Ebsco from January 1971 until February 2019. All statistical analyses were carried out using R 3.5.3 (Mathsoft Company, Cambridge, MA, USA). The pooled response rate was expressed as a decimal. The heterogeneity test was performed using the I-squared (I2) statistic.ResultsA total of 14 studies were selected with a total of 148 patients with HP-negative gastric MALT lymphoma. The overall pooled response rate was 0.38 (95% confidence interval [CI]: 0.29–0.47). The combined estimate is I2 = 57% (P < 0.01). The study subjects were categorized by factors (area of patients). The pooled response rate of the sub-groups (Korea, Japan, China, and Western countries) was 0.63 (95% CI: 0.50–0.76), 0.16 (95% CI: 0.05–0.30), 0.38 (95% CI: 0.20–0.55), and 0.57 (95% CI: 0.08–1.00). The response rate showed that the modified HP eradication therapy was effective for patients with HP-negative gastric MALT lymphoma, especially in Korea and Western countries.ConclusionTherefore, the modified HP eradication therapy can be considered an optional therapy for patients with low-grade HP-negative gastric MALT lymphoma. However, several limitations were revealed in the meta-analysis. Further systematic reviews and research are required.