c-myc gene mutation in gastric mucosa-associated lymphoid tissue (MALT) lymphoma and diffuse large B-cell lymphoma

The c-myc gene is involved in important cellular processes, including cell proliferation, differentiation, and apoptosis. We analyzed mutation of the c-myc gene in 51 patients with gastric lymphoma [27 patients with low-grade mucosa-associated lymphoid tissue (MALT) lymphoma, 11 with high-grade MALT lymphoma, and 13 with diffuse large B-cell lymphoma (DLL)], by polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analysis. We also evaluated the relationship between mutation of the c-myc gene and regression of low-grade MALT lymphoma after Helicobacter pylori (H. pylori) eradication. Mutation in exon 2 of the c-myc gene was present in 2 of 20 (10%) patients with low-grade MALT lymphoma, in 1 of 7 (14%) patients with high-grade MALT lymphoma, and none of 10 patients with DLL. The 3 patients who had mutations of the gene, showed different patterns of mobility shift, suggesting different mutations. In addition, 15 patients with low-grade MALT lymphoma received anti-H. pylori therapy. All the patients achieved eradication. Nine of the 15 (60%) patients with low-grade MALT lymphoma showed complete regression (CR), 3 (20%) showed partial regression (PR), and 3 (20%) showed no change (NC). One of the 9 (11%) CR patients had a mutation of the c-myc gene. None of the 3 PR and 3 NC patients had mutation of the gene. There was no significant difference between the frequencies among the c-myc gene mutation in CR, in PR and in NC patients. These data suggest that mutation of the c-myc gene may not be commonly associated with development of gastric MALT lymphoma and DLL, and may not be associated with regression of low-grade MALT lymphoma after H. pylori eradication.     

Metachronous gastric MALT lymphoma and early gastric cancer: is residual lymphoma a risk factor for the development of gastric carcinoma?

BACKGROUND: Helicobacter pylori plays a major role in the pathogenesis of primary gastric MALT lymphoma (GML) and gastric carcinoma. The occurrence of these two diseases metachronously in a same patient is a rare event. PATIENTS AND METHODS: Gastric biopsies and gastrectomy resection specimens of four patients who developed GML and early gastric cancer (EGC) were analysed by morphology, immunohistochemistry and molecular biology. RESULTS: Four patients (three males and one female; mean age 48 years) were diagnosed with GML. Helicobacter pylori infection was observed in three cases. Two patients had localized disease (stages IE and IIE, respectively) and were treated with H. pylori eradication therapy followed by an alkylating agent for one patient. Two patients had disseminated disease (stage IV), and were treated with an alkylating agent. Three cases were t(11;18) positive. All patients achieved initially complete lymphoma remission. Long-term endoscopic surveillance detected an EGC at the same location as the lymphoma in all patients at a mean time of 9.5 years (range 2.5-17 years) after lymphoma diagnosis. Gastrectomy specimens showed residual GML in all cases. CONCLUSION: Prolonged residual GML could constitute an additional risk factor for the development of gastric carcinoma. Long-term endoscopic surveillance is mandatory in patients treated conservatively for gastric MALT lymphoma.     

Clinicopathologic and immunohistochemical study of surgically treated primary gastric MALT lymphoma

BACKGROUND AND OBJECTIVES: B-cell MALT lymphoma is a well-recognized entity and its characterization as low-grade (LG) and high-grade (HG) lymphoma has been widely accepted. In the present study we reviewed a series of 95 surgical specimens of primary gastric MALT lymphoma selected between 1979 and 1998. Immunohistochemical expression of p53, bcl-2, and Ki67 and Helicobacter pylori (Hp) infection was evaluated, along with a correlation with clinical outcome. METHODS: A morphologic and immunohistochemical analysis, including p53, bcl-2, and Ki67 expression, was carried out in all cases. A complete follow-up was obtained in 49 patients and in these cases a survival analysis was performed. RESULTS: bcl-2 protein was highly expressed in 25 of 25 assessed LG tumors and in 20 of 24 assessed HG tumors. p53 protein was expressed in 13 of 25 assessed LG tumors and in 21 of 24 assessed HG tumors. High proliferation rate as expressed by Ki67 was detected in 15 of 25 assessed LG tumors and in 23 of 24 assessed HG tumors. Hp infection was detected in 11 of 16 assessed LG tumors and 2 of 10 assessed HG tumors. Median survival rates were 72 months for LG tumors and 24 months for HG tumors. CONCLUSIONS: A significant inverse relationship between Hp infection and histological grade was found. High p53 expression and high-proliferation rate correlated with HG tumors. However, a correlation between p53, bcl-2, and Ki67 expression with clinical outcome was not found.     

Effectiveness of local radiotherapy in primary extranodal marginal zone B-cell lymphoma of MALT or MALT lymphoma of conjunctiva: study of four cases

Primary lymphomas of the conjunctiva are extremely infrequent and usually belong to extranodal marginal zone B-cell lymphoma of MALT or MALT lymphoma. Radiotherapy with lens shielding is one of the most employed therapeutic options. Four patients with MALT lymphomas of the conjunctiva with complete and maintained response to radiotherapy are reported. The effectiveness as well as the lack of significant toxicity of radiotherapy are emphasized.     

Rituximab in treatment of primary gastric diffuse large B-cell lymphoma

Abstract In the rituximab era, the optimal treatment modality for primary gastric diffuse large B-cell lymphoma (PG-DLBCL) still remains unclear. We performed a retrospective, multicenter analysis of 65 patients with PG-DLBCL to assess the efficacy and toxicity of the addition of rituximab to conventional chemotherapy. When compared with conventional chemotherapy, there was a trend that rituximab plus chemotherapy yielded a higher complete response rate, 5-year event-free survival (EFS) rate and 5-year overall survival (OS) rate, but this was not statistically significant. In subgroup analysis, better OS was observed only for patients with advanced-stage disease when rituximab was added. When involved-field radiotherapy (IFRT) was included, EFS and OS were significantly prolonged in the conventional chemotherapy group, but not in the immunochemotherapy group. If focusing on patients with localized-stage disease receiving immunochemotherapy, the efficacies of short-course rituximab (R)-chemotherapy plus IFRT and 6-8 courses of R-chemotherapy without IFRT were comparable. In conclusion, it is necessary to carry out prospective randomized trials to help further illuminate the role of rituximab in the PG-DLBCL treatment landscape. If a patient has been treated with a non-rituximab-containing regimen, additional IFRT should be considered, and for patients with advanced-stage disease, rituximab should be considered.     

原发性胃弥漫大B细胞淋巴瘤的临床分析

目的 分析原发性胃弥漫大B细胞淋巴瘤(PG-DLBCL)患者的临床特征和预后影响因素,探讨PC-DLBCL的分期系统和治疗模式.方法 回顾性分析69例PG-DLBCL患者的临床资料,以无事件生存期(EFS)和总生存期(OS)为主要研究终点.结果 全组患者的1、3和5年无事件生存率分别为83.8%、71.1%和69.0%,平均EFS为91.3个月;1、3和5年总生存率分别为91.3%、80.3%和72.4%,平均OS为98.8个月.单因素分析结果显示,改良Ann Arbor分期为ⅠE或ⅡE1期、血清乳酸脱氢酶(LDH)水平正常、血红蛋白水平正常、血清白蛋白水平正常、国际预后指数(IPI)评分为0～1分、肿瘤长径＜5 cm、浸润深度浅的患者EFS和OS显著延长(均P＜0.05),而患者的性别、年龄、有无B症状、ECOG体力评分结果以及治疗方法与患者的预后无关(均P＞0.05).Cox多因素回归分析结果显示,改良Ann Arbor分期、血清白蛋白水平是影响PG-DLBCL患者EFS和OS的独立因素.结论 PG-DLBCL的分期系统和各种治疗措施所处的地位仍存有争议,需进一步大样本的前瞻性研究以优化PG-DLBCL的治疗方案.     

胃MALT淋巴瘤发病机制研究进展

胃粘膜相关淋巴组织(MALT)型结外边缘区B细胞淋巴瘤通常是在幽门螺杆菌(Hp)感染基础上发展起来的.Hp感染可引起淋巴细胞浸润,使胃粘膜获得MALT.在Hp刺激、自身抗原刺激和T细胞辅助下,浸润的B细胞活化增殖,偶尔发生遗传学异常进而向恶性转化.研究发现Hp感染是胃MALT淋巴瘤发生的重要病因.现综述根治Hp的临床研究及抗原选择、自身免疫在淋巴瘤发病中的作用.     

胃黏膜相关淋巴组织淋巴瘤的治疗策略

目的:总结国内外对胃黏膜相关淋巴组织(MALT)淋巴瘤的病因学、诊断和治疗的最新进展。方法:应用检索MDELINE及CHKD期刊全文数据库检索系统,以"黏膜相关淋巴瘤"和"胃淋巴瘤"为关键词。纳入标准:1)胃MALT淋巴瘤的病因学和基因病理学特征;2)胃MALT淋巴瘤临床特征和分期;3)胃MALT淋巴瘤的治疗。共纳入分析23篇参考文献。结果:H.Pylori感染是胃MALT淋巴瘤的主要病因,抗感染治疗可以使近80%H.Pylori阳性胃MALT淋巴瘤完全消退。因此,抗感染治疗成为早期胃MALT淋巴瘤的标准一线治疗。抗感染无效或复发的患者可以采取放疗、化疗和分子靶向治疗等综合治疗手段。结论:过去人们对胃MALT淋巴瘤常常行手术切除,术后辅助化疗或放疗。但随着近年来对其病因学和生物学行为的认识,目前治疗以非手术治疗为主,目的是保全器官功能,提高患者生活质量。     

Rituximab-induced remission of a gastric MALT lymphoma

Gastric MALT lymphoma is usually associated with H. pylori infection, and responds to treatment with antibiotics and a proton pump inhibitor. We report a case of H. pylori negative gastric MALT lymphoma. The patient was followed conservatively for 2 years until she developed gastrointestinal bleeding with significant anemia. She was treated with rituximab 375 mg/m2 weekly for four doses, which resulted in a biopsy proven complete remission. Rituximab therapy is a reasonable, well tolerated treatment alternative for MALT lymphomas not associated with H. pylori.     

Other cancers in patients with gastric MALT lymphoma

Patients with Hodgkin's disease and nodal non-Hodgkin's lymphomas seem to have an excess risk for other cancers. A high incidence of other cancers has also been found in some series of patients with gastric MALT lymphomas. In a series of 136 patients with gastric MALT lymphomas the occurrence and features of other cancers have been described. In order to evaluate their occurrence statistically (excluding skin cancers) standard incidence ratios (SRI) have been calculated, using the incidence rates of a Cancer Registry in Spain as a reference. A Cox's multivariate proportional hazard model was fitted in order to evaluate the influence of age, sex, histological grade and treatment with chemotherapy or chemotherapy plus radiotherapy in the development of other non-skin cancers occurring after the diagnosis of MALT lymphoma. Other cancers were detected in 16 of the 136 patients (11.7%); the other cancer was detected prior to MALT gastric lymphoma in 6 patients (4.41%), concomitantly in 4 (2.9%) and after diagnosis of the lymphoma in 6 (4.41%). Other cancers occurred in 14.4% of the male and in 8.3% of the female patients; in 12% of the patients with low grade and in 11% of the patients with high grade lymphomas. Of the 6 cancers that occurred after diagnosis of the gastric lymphoma, 3 did in the 80 patients (3.7%) that had been treated with chemotherapy, 1 in the 3 cases (33%) treated with chemotherapy and radiotherapy and 2 in the 53 patients (3.7%) who had not received chemotherapy or radiotherapy. The most frequent other cancers were lymphoid neoplasms and gastric carcinoma. There was not an excess of other cancers in the whole cohort or in the sex or histological grade strata. There was an excess close to significance (SIR =2.59; 95% CI:0.98-6.88) in the patients under 50 years of age. In the Cox's analysis, age, sex, histological grade and treatment did not influence the occurrence of other cancers after the diagnosis of lymphoma. In conclusion, in patients with gastric MALT lymphoma other cancers also occur. An excess incidence was not demonstrated, although it may exist in patients under 50 years. Of special importance is the occurrence of gastric cancer that appears concomitantly or after gastric lymphoma.     

Surgery and chemotherapy versus chemotherapy as treatment of high-grade MALT gastric lymphoma

Background and Objectives Treatment of high-grade MALT (mucosa-associated lymphoid tissue) gastric lymphoma remains uncertain. To assess efficacy and toxicity of the most common therapies—surgery followed by chemotherapy or chemotherapy alone—we began a controlled clinical trial in patients in early stage (I and II). Methods One hundred and two patients were randomized to be treated with surgery followed by six cycles of CEOP-Bleo (cyclophosphamide, epirubicin, vincristine, prednisone, and bleomycin at standard doses) (52 cases) or with chemotherapy alone (49 cases). Results Complete response rates were 94% [95% confidence interval (CI): 88–99%] and 96% (93–100%), respectively. Actuarial curves at 5 yr showed that event-free survival were 70% (95% CI: 59–74%) in patients treated with surgery and chemotherapy, that were not statistically significant to 67% (95% CI: 51–69%) in the patients who received chemotherapy (p=0.5). Also, overall survival that was not statistically significant: 78% (95% CI: 70–88%) in the combined treatment and 76% (95% CI: 70–87%) in chemotherapy (p=0.8). Acute and late toxicity were mild and well controlled. No acute leukemia or second neoplasm has been observed. Conclusions The use of surgery and chemotherapy did not improve outcome in patients with early-stage high-grade gastric MALT lymphoma. It is apparent that chemotherapy alone is sufficient treatment in this select group of patients.     

Role of GSTT1 and M1 null genotypes as risk factors for B-cell lymphoma: influence of geographical factors and occupational exposure

The interrelationship between genetic susceptibility and carcinogenic exposure is important in the development of haematopoietic malignancies. Both factors need to be considered to enable assessment of disease risk associated with a given individual under certain environmental conditions. GSTT1 and GSTM1 are two genes whose proteins are involved in the detoxification of potential carcinogens. We have studied the prevalence of GSTT1 and GSTM1 null polymorphisms using a novel PCR multiplex protocol in a group of 158 patients with B-cell lymphoma (BCL, 138 with non-Hodgkin lymphoma and 20 with Hodgkin lymphoma) and 214 healthy controls. A questionnaire regarding occupational exposure and lifestyle factors was also completed by both groups. GSTM1 null genotype showed no significant differences between patients and controls (46.9% and 55.6%, respectively). In contrast, GSTT1 null genotype was observed in 25.3% of patients and 15.4% of controls (P=0.013; OR=1.85; CI (95%):1.11-3.09), suggesting a role for the GSTT1 null genotype in the development of BCL. This effect was even more evident in females (27.5% vs. 14%: P=0.014). No significant association was observed between GST genotypes and disease risk in relation to smoking or occupational exposure.     

Differentiation of low-grade gastric MALT lymphoma and high-grade gastric MALT lymphoma: the clinical value of Ga-67 citrate scintigraphy--a pilot study

Ga-67 citrate scintigraphy has been routinely and extensively used to evaluate non-Hodgkin's lymphoma (NHL) for more than 20 years. Gastric lymphoma of mucosa-associated lymphoid tissue (MALT) is by far the most common extranodal primary NHL. Gastric MALT lymphoma can be classified as low-grade (LG) or high-grade (HG). Low-grade gastric MALT lymphoma can be cured by eradication of Helicobacter pylori; but radiotherapy and/or chemotherapy and/or surgery are the major methods of treatment for the HG gastric MALT lymphoma. However, it is difficult to differentiate these two groups by clinical parameters and endoscopic findings. The purpose of this study was to determine whether Ga-67 citrate scintigraphy can distinguish the LG gastric MALT lymphoma from the HG gastric MALT lymphoma. Twenty-one patients (11 men and 10 women ranging in age from 38 to 83 years) with histologically confirmed gastric MALT lymphoma were enrolled. Twelve patients had LG and nine patients had HG. All 21 patients underwent Ga-67 citrate scintigraphy before treatment. The results of Ga-67 citrate scintigraphy were classified as positive or negative. In the LG group, nine patients had negative results and three patients had positive results. In the HG group of nine patients, all patients had positive results. Among the three patients who had positive results in the LG group, the uptake of gastric MALT lymphoma was lower than that of the liver. The Ga-67 citrate scintigraphy is of good clinical value for the differentiation of the LG gastric MALT lymphoma and the HG gastric MALT lymphoma. We think that the major value of Ga-67 citrate scintigraphy will be in following the patients with HG gastric MALT lymphoma after treatment to assess response of therapy and to detect possible recurrence and perhaps in determining transformation from the LG to HG gastric MALT lymphoma. However, further investigation is needed to understand the relationship between the uptake of Ga-67 citrate in gastric MALT lymphoma and transformation.     

126 例原发胃弥漫大B 细胞淋巴瘤的临床特点及预后分析

目的：分析胃弥漫大B 细胞淋巴瘤（DLBCL ）的临床特点和预后,以期更好的指导治疗。方法：回顾性收集1999年1 月至2012年3 月中国医学科学院肿瘤医院收治的初治、胃原发DLBCL 患者的临床资料,分析其人口学特点、分期、病理诊断、并发症、治疗和预后等特征。结果：共计纳入研究患者126 例,中位年龄49（16～81）岁,男女比例为6 8 ：58。病理诊断为单纯DLBCL 96例、MALT伴大B 细胞转化27例、伴浆样细胞分化3 例。早期患者114 例（90.5%）,其治疗方式包括单纯化疗37例、化疗+ 放疗39例、手术+ 化疗± 放疗38例。中位随访48个月,全组患者PFS 和OS分别为75.6% 和82.7% ,早期和晚期患者的PFS 分别为77% 和41.7%（P = 0.005）。 早期患者采用单纯化疗、化放疗联合和含手术治疗的PFS 分别为67.3% 、77.8% 和77.8%（P = 0.588）。 国际预后指数（IPI）评分为0 分、1 分和> 1 分患者的PFS 分别为85.4% ,74.4% 和55.6%（P = 0.011）。 Ⅰ期和Ⅱ期患者的PFS 分别为81.2% 和66.1%（P = 0.018）。 LDH 正常和升高患者的PFS 分别为86.6% 和63.3%（P = 0.006）。 病理类型为单纯DLBCL 和含有MALT成分、生发中心（GCB ）和非生发中心（non-GCB ）、年龄> 60岁等与预后无关。结论：早期病变比例占胃原发DLBCL 患者的绝大多数。早期患者预后良好,手术切除并不能提高疗效。早期患者中IPI> 1 分、LDH 升高和临床分期II 期提示预后不良。     

原发性胃弥漫大B细胞淋巴瘤69例临床分析

目的:探讨原发性胃弥漫大B细胞淋巴瘤(primary gastric diffuse large B-cell lymphoma,PGDLBCL)的诊断、治疗和预后。方法:回顾性分析2007年1月—2009年12月收治的69例PGDLBCL患者的临床表现、诊断、治疗和预后以及临床病理因素与疗效和预后的关系。结果:PGDLBCL患者占本院同期收治淋巴瘤患者的10.44%(69/661),其中男性29例,女性40例,中位年龄为54岁(21～78岁)。主要临床表现为腹痛、腹胀和黑粪。本组患者接受以化疗为主的综合治疗,完全缓解率为37.7%(26/69),部分缓解率为46.4%(32/69),总有效率为81.4%(58/69)。单因素分析结果显示,血清乳酸脱氢酶水平升高患者的疗效较差(P<0.05)。全组患者的1、2和3年总生存率分别为89.2%、84.2%和81.3%。单因素分析显示,年龄、国际预后指数(international prognostic index,IPI)和血清乳酸脱氢酶水平是影响预后的因素;多因素分析结果显示,仅血清乳酸脱氢酶水平是影响预后的因素。结论:PGDLBCL以女性居多,多采用以化疗为主的综合治疗,治疗中应注意消化管出血和穿孔的预防与处理。乳酸脱氢酶是重要的预后因素。     

Nongastric marginal-zone B-cell MALT lymphoma: prognostic value of disease dissemination

The aim of this study is to describe the clinical features and define the prognostic significance of disease dissemination in a large series of nongastric marginal-zone B-cell mucosa-associated lymphoid tissue (MALT) lymphomas. We studied 208 patients with nongastric marginal-zone B-cell MALT lymphoma diagnosed and treated from 1991 to 2004. Ninety percent of the patients had a single site of MALT involvement--skin (26%), salivary glands (18%), orbit (14%), Waldeyer's ring (13%)--and 39% and 28% had nodal involvement and bone marrow involvement, respectively. After a median follow-up of 2.7 years, the median event-free survival (EFS) time was 2.4 years, and the median overall survival (OS) time was not reached. On univariate analysis, the features significantly associated with longer EFS and OS times were the following: single MALT site involvement (OS), localized disease (EFS and OS), no nodal disease (EFS and OS), skin and orbit lymphoma (OS), and stage IV disease without bone marrow involvement (OS). On multivariate analysis, both bone marrow and nodal involvement were associated with shorter OS. This study describes the clinical features and the natural history of nongastric marginal-zone lymphomas and highlights that the dissemination to lymph nodes and bone marrow is associated with a poorer outcome.