Clinical features and prognosis of gastric MALT lymphoma with special reference to responsiveness to H. pylori eradication and API2-MALT1 status

BACKGROUND AND AIM: Clinicopathologic characteristics and prognosis of Helicobacter pylori eradication-resistant gastric MALT lymphoma have not been well clarified. We analyzed a consecutive series of gastric MALT lymphomas at our institution regarding treatment, clinical course, and prognosis, with special reference to responsiveness to H. pylori eradication and presence of API2-MALT1. METHODS: Subjects were 92 consecutive patients with gastric MALT lymphoma. Seventy were H. pylori positive, and 87 received H. pylori eradication therapy. The remaining five cases were API2-MALT1 positive and did not receive eradication treatment. Second-line treatments were radiation therapy, total gastrectomy, and chemotherapy (rituximab, rituximab plus CHOP, or rituximab plus 2-chlorodeoxyadenosine). RESULTS: Gastric MALT lymphoma was classified into three groups, except one case with API2-MALT1 who responded to H. pylori eradication therapy: responders without API2-MALT1 (group A, N = 56, 65%), nonresponders without API2-MALT1 (group B, N = 16, 19%), and nonresponders with API2-MALT1 (group C, N = 14, 16%). Most cases in group A attained complete remission (CR) in 2 or 3 months and CR persisted for an average of 51.1 months (3-134 months). Recurrence was only seen in one case. In groups B and C, radiation therapy, chemotherapy, and total gastrectomy resulted in CR in 13, 5, and 2 cases, respectively. In 5 group B patients and 6 group C patients who did not undergo second-line therapy, disease did not progress for an average of 10.4 and 40.1 months, respectively. In 1 group C case who did not receive second-line treatment, lymphoma metastasized to the lung 12 yr after eradication. All group B patients and all but 2 group C patients remain alive; one of these deaths was from gastric carcinoma developing 7 yr after eradication. CONCLUSION: Gastric MALT lymphoma responding to H. pylori eradication demonstrated good prognosis, and for nonresponsive cases, second-line treatments resulted in CR. However, careful observation for development of gastric carcinoma and disease progression is essential during follow-up of API2-MALT1-positive MALT lymphoma when patients decline second-line treatment.     

Successful Treatment of Helicobacter Pylori-Negative Gastric MALT Lymphoma With Rituximab

Helicobacter pylori infection is strongly associated with low-grade gastric lymphoma, commonly known as mucosa-associated lymphoid tissue (MALT) lymphoma. H. pylori eradication leads to complete remission in 80% of early stage MALT lymphomas. The treatment for early stage H. pylori-negative gastric MALT lymphoma is evolving. Rituximab, a chimeric anti-CD20 antibody, has shown response rates of approximately 50% with minimal toxicity in patients with B-cell non-Hodgkin lymphoma. We describe herein the clinical, endoscopic, and histologic features of a patient with H. pylori-negative gastric MALT lymphoma treated successfully with rituximab.     

BCL10 nuclear expression and t(11;18)(q21;q21) indicate nonresponsiveness to Helicobacter pylori eradication of Chinese primary gastric MALT lymphoma

The eradication of Helicobacter pylori (H. pylori) with antibiotics induces complete remission in 75% of patients with gastric MALT lymphoma. We investigated the efficacy of H. pylori eradication and assessed the predictive value of BCL10 nuclear expression and t(11;18)(q21;q21) regarding resistance to H. pylori eradication in primary gastric mucosa-associated lymphoid tissue lymphoma (MALT lymphoma) patients from mainland China. Twenty-two gastric MALT cases (Stage I_E) underwent H. pylori eradication with antibiotics, and sequential endoscopic-bioptic follow-ups were performed and assessed with regular morphologic and immunohistochemical examinations. BCL10 nuclear expression and interphase fluorescence in situ hybridization (FISH) for MALT1 and API2/MALT1 were tested. Thirteen out of the 22 cases (59.1%) achieved complete regression (CR) after the eradication of H. pylori. The longest follow-up period in the 22 patients was 68 months, with 12 patients longer than 24 months. For the 13 CR patients, the longest follow-up period after H. pylori eradication was 53 months, with 6 patients longer than 24 months. BCL10 nuclear expression was detected by immunohistochemical staining in 9 cases, including 7 (77.8%) of 9 cases who showed no response (NR) and 2 (15.4%) of 13 patients who achieved CR following eradication therapy (P < 0.05). t(11;18)(q21;q21) was evaluated by interphase FISH in 18 cases including 11 CR and 7 NR patients after H. pylori eradication. t(11;18)(q21;q21) was found in 4 (57.1%) of 7 patients who showed NR following H. pylori eradication, but one in 11 CR patients (P < 0.05). A total of 59.1% of patients with early gastric MALT lymphoma recruited in this study achieved CR after H. pylori eradication. BCL10 nuclear expression and t(11;18)(q21;q21)-positive gastric MALT lymphomas are likely to be related to a failure to respond to H. pylori eradication in Chinese patients. Both G. Dong and C. Liu are treated as co-first authors.     

H. pylori negative gastric MALT lymphoma with API2-MALT1 translocation treated by endoscopic submucosal dissection: A case report

Rationale:API2-MALT1 positive gastric mucosa-associated lymphoid tissue (MALT) lymphomas are considered to have favorable prognosis. We report a case of API2-MALT1 positive gastric MALT lymphoma, treated by endoscopic submucosal dissection (ESD).Patient concerns:A 51-year-old man underwent esophagogastroduodenoscopy (EGD) for the annual health checkup examination.Diagnoses:The EGD showed a reddish depressed lesion with small reddish spots in the lower gastric body. There was no endoscopic atrophy in the entire stomach and Helicobacter pylori (H. pylori) serum test was negative. Infiltration of small lymphocytes was shown in the gastric tissues obtained by the endoscopic biopsy. The fluorescence in situ hybridization using the biopsy samples confirmed the presence of genetic translocation of API2-MALT1, suggesting that the lesion is API2-MALT1 positive MALT lymphoma.Interventions:Since endoscopic ultrasound suggested that the lesion was localized within the lamina propria mucosae, we performed ESD to achieve the en bloc resection of the lesion.Outcomes:Conclusive diagnosis of gastric MALT lymphoma was made based on the resected specimen. Lateral and vertical margins were negative. No lymphoma cells were detected using endoscopic biopsy after 5 years.Lessons:Our report suggests that ESD can be considered as alternative treatment for API2-MALT1 positive gastric MALT lymphoma if the lesion was localized within the gastric mucosa.     

Clinical impact of genetic aberrations in gastric MALT lymphoma: a comprehensive analysis using interphase fluorescence in situ hybridisation

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.     

Helicobacter pylori-negative gastric mucosa-associated lymphoid tissue lymphomas: A review

Since Isaacson and Wright first reported on the extranodal marginal zone B-cell lymphoma of the stomach in 1983,following studies have clarified many aspects of this disease.We now know that the stomach is the most affected organ by this disease,and approximately90% of gastric mucosa-associated lymphoid tissue(MALT) lymphomas are related to Helicobacter pylori(H.pylori) infection.This implies that approximately 10% of gastric MALT lymphomas occur independent of H.pylori infection.The pathogenesis of these H.pylori-negative gastric MALT lymphomas remains unclear.To date,there have been several speculations.One possibility is that genetic alterations result in nuclear factor-kappa B(NF-κB) activation.Among these alterations,t(11;18)(q21;q21) is more frequently observed in H.pylori-negative gastric MALT lymphomas,and such translocation results in the synthesis of fusion protein API2-MALT1,which causes canonical and noncanonical NF-κB activation.Another possibility is infection with bacteria other than H.pylori.This could explain why H.pylori eradication therapy can cure some proportions of H.pylori-negative gastric MALT lymphoma patients,although the bacteria responsible for MALT lymphomagenesis are yet to be defined.Recent advances in endoscopy suggest magnifying endoscopy with narrow band imaging as a useful tool for both detecting gastric MALT lymphoma lesions and judging the response to treatment.A certain proportion of H.pylori-negative gastric MALT lymphoma patients respond to eradication therapy; hence,H.pylori eradication therapy could be considered as a first-line treatment for gastric MALT lymphomas regardless of their H.pylori infection status.     

Update on MALT lymphomas

Gastric mucosa associated lymphoid tissue (MALT) lymphoma is a histologically distinct tumour derived from MALT acquired as a result of Helicobacter pylori infection. Eradication of H. pylori causes clinical regression of the lymphoma in 75% of cases. In seeking to identify those cases resistant to this therapy, and in the interests of further understanding the biology of MALT lymphoma, genetic alterations of MALT lymphomas have been investigated. Three translocations, t(11;18)(q21;q21), t(1;14)(p22;q32) and t(14;18)(q32;q21) are specifically associated with MALT lymphoma and the genes involved have been identified. T(11;18) results in a chimeric fusion between the API2 and MALT1 genes and is specifically associated with gastric MALT lymphomas that do not respond to eradication of H. pylori. T(1;14) and t(14;18) deregulate BCL10 and MALT1 expression, respectively. These three chromosomal translocations that involve different genes appear to share common oncogenic properties by targeting the same nuclear factor kappa B (NF kappa B) oncogenic pathway.     

A case of H. pylori and API2-MALT1 gene-negative gastric mucosa-associated lymphoid tissue lymphoma with a carcinoma-like signet-ring cell lymphoepithelial lesion]

A 60-year-old woman presented in February 2003 with an ulcer on the lesser curvature of the anglus. The endoscopic biopsy specimens showed epithelial signet-ring cell associated with lymphoid infiltration, suggesting a diagnosis of gastric cancer. Histopathological examination confirmed the diagnosis of low-grade B-cell lymphoma of MALT with epithelial signet-ring cell lymphoepithelial lesion, which was negative for H. pylori and t (11;18) (q21;q21) translocation (API2-MALT1 gene). This case was treated with H. pylori eradication and additional radiation therapy, and the tumor was disappeared.     

Helicobacter pylori and gastric mucosa-associated lymphoid tissue lymphoma:Recent progress in pathogenesis and management

Recent progress in the research regarding the molecular pathogenesis and management of gastric mucosaassociated lymphoid tissue(MALT)lymphoma is reviewed.In approximately 90%of cases,Helicobacter pylori(H.pylori)infection plays the causative role in the pathogenesis,and H.pylori eradication is nowadays the first-line treatment for this disease,which leads to complete disease remission in 50%-90%of cases.In H.pylori-dependent cases,microbe-generated immune responses,including interaction between B and T cells involving CD40 and CD40L co-stimulatory molecules,are considered to induce the development of MALT lymphoma.In H.pylori-independent cases,activation of the nuclear factor-κB pathway by oncogenic products of specific chromosomal translocations such as t(11;18)/API2-MALT1,or inactivation of tumor necrosis factor alpha-induced protein 3(A20)are considered to contribute to the lymphomagenesis.Recently,a largescale Japanese multicenter study confirmed that the long-term clinical outcome of gastric MALT lymphoma after H.pylori eradication is excellent.Treatment modalities for patients not responding to H.pylori eradication include a"watch and wait"strategy,radiotherapy,chemotherapy,rituximab immunotherapy,and a combination of these.Because of the indolent behavior of MALT lymphoma,second-line treatment should be tailored in consideration of the clinical stage and extent of the disease in each patient.     

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.     

Predictive value of endoscopic ultrasonography for regression of gastric low grade and high grade MALT lymphomas after eradication of Helicobacter pylori

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.     

原发性胃淋巴瘤凋亡抑制蛋白2-黏膜相关淋巴瘤转位基因1融合基因检测的意义

目的 研究原发性胃淋巴瘤(PGL)内镜活检组织中凋亡抑制蛋白2-黏膜相关淋巴瘤转位基因1（API2-MALT1）融合基因检测的可行性,探讨该融合基因在PGL的表达及其在PGL诊断、治疗等方面的临床价值。方法对32例疑诊为PGL者进行超声内镜检查和黏膜活检,活检标本分别进行组织病理、免疫组织化学检查和用荧光定量RT-PCR测定API2-MALT1融合基因。总结、分析诊断明确的PGL中API2-MALT1融合基因的表达以及该融合基因与PGL诊断、分型和治疗等方面的关系。结果32例疑诊PGL者中14例经病理检查和免疫组织化学检查确诊为PGL,其中胃黏膜相关淋巴组织(MALT)淋巴瘤11例,胃弥漫性大B细胞淋巴瘤(DLBCL)3例。API2-MALT1融合基因检测阳性5例,均为胃MALT淋巴瘤,约占胃MALT淋巴瘤(5/11)的45％。3例DLBCL患者API2-MALT1融合基因检测均阴性。API2-MALT1融合基因阴性组病变浸润深度和淋巴结浸润状况较阳性组严重。5例API2-MALT1融合基因阳性者中幽门螺杆菌(Hp)阳性2例,9例阴性者中Hp阳性5例。API2-MALT1融合基因阳性组5例行抗Hp治疗皆无效,但化学治疗有效;阴性组中5例Hp阳性者完全缓解2例,4例Hp阴性者抗Hp治疗无效。结论 API2-MALT1融合基因是胃MALT淋巴瘤的常见遗传学异常。内镜定位活检标本通过荧光定量PCR法检测该融合基因在临床上是可行的,该融合基因的检测对PGL诊断、治疗和预后评估均有一定的价值。     

Regression of gastric high grade mucosa associated lymphoid tissue (MALT) lymphoma after Helicobacter pylori eradication

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.