黏膜相关淋巴组织淋巴瘤的诊断和治疗

 阐述了黏膜相关淋巴组织（MALT）淋巴瘤的流行病学、病因、病理特点、临床表现、诊断、治疗及手术在MALT淋巴瘤治疗中的作用和地位。重点描述了胃幽门螺杆菌（HP）感染与胃MALT淋巴瘤发生、发展之间的相关性以及胃MALT淋巴瘤不同分期的治疗原则及随访。     

Immunomodulatory treatment for mucosa-associated lymphoid tissue lymphoma (MALT lymphoma)

The pathogenesis of mucosa-associated lymphoid tissue (MALT) lymphoma has been characterized as a dynamic process driven by lymphoma cell dependency on T-cell signaling, chronic antigenic stimulation of marginal zone B-cells and activation of the nuclear factor-kappa B signaling pathway. This concept is underlined by the strong causal connection of chronic Helicobacter pylori associated gastritis and MALT lymphoma development based on perpetual auto-antigenic stimulation of Helicobacter pylori-specific T-cells, but also its association with further potential infectious triggers and autoimmune disorders for extragastric lymphoma sites. Thus, given the dependency of MALT lymphoma cells on the tumor microenvironment, this specific entity appears highly suitable for immunomodulatory treatment strategies. Several approaches have been assessed in the last years including promising data on immunomodulatory agents “IMiDs” thalidomide and lenalidomide, macrolide antibiotics and antibodies. The aim of the present review is to discuss rationales for immunomodulatory therapies in MALT lymphoma and to present the statu quo on immunomodulatory and therefore chemotherapy-free treatment strategies for these patients.     

Radiotherapy for gastric mucosa-associated lymphoid tissue lymphoma

Gastric mucosa-associated lymphoid tissue (MALT) lymphoma is a rare disease which is often associated with Helicobacter pylori (H. pylori) infection. First-line treatment of stage IE and IIE localized gastric MALT lymphoma is based on the eradication of H. pylori. The presence of H. pylori resistance factors such as translocation t (11;18), peri-gastric lymph node involvement and the degree of tumor infiltration of the gastric wall; or lack of response to antibiotic therapy are two main indications to treat with definitive radiotherapy (RT). RT is an effective treatment in localized gastric MALT lymphoma. A moderate dose of 30 Gy allows a high cure rate while being well tolerated. After treatment, regular gastric endoscopic follow-up is necessary to detect a potential occurrence of gastric adenocarcinoma.     

Molecular pathogenesis of mucosa-associated lymphoid tissue lymphoma.

Extranodal marginal zone B-cell lymphomas of mucosa-associated lymphoid tissue (MALT) type occur in a number of anatomic sites, but share overlapping morphologic and immunophenotypic features. Helicobacter pylori infection has been identified as an etiologic factor in gastric MALT lymphoma, and a growing list of other infectious organisms have recently been shown to be associated with MALT lymphomas at other anatomic sites. Although cause and effect has not been established for most of these infectious agents, our understanding of the biology has significantly improved, in part through the application of standard cytogenetic analyses. The common karyotypic alterations that characterize MALT lymphomas include the trisomies 3 and 18, the translocations t(11;18)(q21;q21), t(1;14)(p22;q32), t(14;18)(q32;q21), t(3;14)(q27;q32), and the recently described t(3;14)(p14.1;q32). This apparent complexity of cytogenetic alterations that have now been implicated in the pathogenesis of extranodal MALT lymphoma serves as a paradigm for molecular cross talk in neoplastic disease. Recent data have shown that at least three of the disparate translocations affect a common signaling mechanism, and thus unify all three under a common pathogenesis, resulting in the constitutive activation of the nuclear factor kappa B (NF-kappaB) pathway. It may be that the new MALT-related translocation involving the FOXP1 gene and other as yet undiscovered translocations may all have in common increased NF-kappaB signaling.     

A clinicopathologic study of gastric mucosa-associated lymphoid tissue lymphoma

BACKGROUND: It is still unclear which patients with gastric mucosa-associated lymphoid tissue (MALT) lymphoma will benefit from the eradication of Helicobacter pylori. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.     

合并单克隆免疫球蛋白血症的黏膜相关淋巴组织淋巴瘤临床特征分析

目的 探讨单克隆免疫球蛋白(M蛋白)血症在黏膜相关淋巴组织淋巴瘤(MALToma)中的发生率及患者临床特征.方法 回顾性分析2010年10月至2015年10月接受M蛋白检测的16例住院MALToma患者的临床资料.结果 16例MALToma患者中,6例初诊时合并M蛋白血症.其中4例为男性,中位年龄56岁(25～82岁),肿瘤原发部位多为胃肠道(4例),临床分期多为Ⅰ～Ⅱ期(4例),国际预后指数(IPI)评分多为0～2分(5例).6例合并M蛋白血症的患者中有4例分泌单克隆性IgM(3例为κ轻链,1例为λ轻链),2例分泌单克隆性IgG(均为κ轻链).6例合并M蛋白血症的患者中有4例伴有浆细胞分化(PCD),10例未合并M蛋白血症的患者有1例伴有PCD(P=0.036).此外,3例合并M蛋白血症的患者在获得疾病缓解的同时M蛋白水平均较初诊时明显下降,其中2例降至正常水平.结论 M蛋白血症可能在MALToma患者中较常见,可能与伴有PCD有关,且M蛋白水平的降低可能与临床疗效相关.     

Ocular adnexal mucosa-associated lymphoid tissue lymphoma treated with radiotherapy.

Forty-two patients with stage IE ocular adnexal mucosa-associated lymphoid tissue (MALT) lymphoma were retrospectively analyzed. Five-year local control and progression-free survival rates were 100 and 77%, respectively. The most common relapsed site was the contralateral orbit. Thirty Gy of local irradiation seemed to be quite effective and safe.     

14例肺原发性黏膜相关淋巴组织淋巴瘤疗效分析

目的 分析肺原发性黏膜相关淋巴组织淋巴瘤的临床特征和预后。方法 回顾分析1999—2012年间14例肺原发性黏膜相关淋巴组织淋巴瘤患者临床资料,其中Ⅰ_E期8例、Ⅱ_E期5例、Ⅲ_E期1例。4例单纯手术治疗,5例术后放疗或化疗,3例化放疗,2例单纯化疗。结果 中位年龄为55岁,男女之比为1∶1.33。中位随访时间为48.3个月。全组患者均存活,3例患者出现治疗失败。全组患者2、4年无进展生存率分别为91%和69%。治疗失败发生在疗后25~37个月,失败部位为双肺、纵隔淋巴结、右肺和脑膜。结论 肺原发黏膜相关淋巴组织淋巴瘤为惰性淋巴瘤,预后良好;临床上可根据患者病变范围和身体状况选择适当治疗。     

Role of radiation therapy in the treatment of stage I/II mucosa-associated lymphoid tissue lymphoma.

BACKGROUND: Few large studies exist on the outcome of patients treated for stage I/II mucosa-associated lymphoid tissue (MALT) lymphoma. PATIENTS AND METHODS: We retrospectively reviewed the records of 77 patients consecutively treated for stage I (n = 66) or II (n = 11) MALT lymphoma at our institution. Progression-free survival (PFS), freedom from treatment failure (FFTF), and overall survival (OS) were calculated using the Kaplan-Meier method. RESULTS: The median follow-up time was 61 months (range 2-177 months). Fifty-two patients (68%) received local radiation therapy (RT) alone, 17 (22%) had surgery followed by adjuvant RT, five (6%) had surgery alone, two (3%) had surgery and chemotherapy, and one patient had chemotherapy alone. The median RT dose was 30 Gy (range 18-40 Gy). The 5-year PFS, FFTF, and OS rates were 76%, 78%, and 91%, respectively. The 5-year PFS (79% versus 50%; P = 0.002) and FFTF (81% versus 50%; P = 0.0004) rates were higher for patients who received RT as compared with patients who did not. CONCLUSIONS: The prognosis following treatment of stage I/II MALT lymphoma is excellent. RT improves PFS and FFTF and has an important role in the curative treatment of patients with localized disease.     

黏膜相关淋巴组织淋巴瘤治疗研究进展

黏膜相关淋巴组织淋巴瘤是起源于淋巴结外的低度恶性淋巴瘤,是最常见的边缘区B细胞淋巴瘤(MZL),约占惰性非霍奇金淋巴瘤(NHL)的30％～50％.其发病部位广泛,治疗方法多样.现就近年来黏膜相关淋巴组织淋巴瘤的治疗研究进展进行综述.     

Phase II study of oxaliplatin in patients with recurrent or refractory non-Hodgkin lymphoma

BACKGROUND: Oxaliplatin is a platinum derivative with a broad range of anticancer activity. The objective of the current Phase II trial was to investigate the activity of oxaliplatin in patients with recurrent or refractory non-Hodgkin lymphoma (NHL). METHODS: Patients with recurrent and refractory NHL who received a maximum of 3 previous chemotherapy regimens were considered eligible if they had an Eastern Cooperative Oncology Group performance status of 0-2 and adequate organ function. Oxaliplatin was administered in an outpatient setting at a dose of 130 mg/m(2) by 2-hour intravenous infusion every 21 days for < or = 6 cycles in the absence of disease progression. RESULTS: Thirty-one patients (23 with aggressive NHL and 8 with indolent NHL) were enrolled, of whom 30 were assessable for toxicity, response, and survival. The median patient age was 62 years, and 20% of the patients previously received platinum-containing therapy. Eighty-three percent of the patients were refractory to their last treatment regimens. Grade 3 and 4 toxic effects (according to the National Cancer Institute's Common Toxicity Criteria [version 2.0]) included sensory neuropathy (10%), neutropenia (17%), and thrombocytopenia (20%). Objective responses occurred in 8 (27%; 95% confidence interval, 13-47%) of the patients. Responses were observed in platinum-naive patients as well as in those previously treated with platinum. The overall median failure-free survival duration was 3.0 months (range, 0.1-18.1 months). CONCLUSIONS: Oxaliplatin had favorable single-agent activity in previously treated patients with refractory lymphoma. The favorable safety profile and the ease of its administration in outpatient settings warrant investigating it in combination with other active drugs for the treatment of recurrent and refractory NHL.     

40例早期胃外黏膜相关淋巴组织淋巴瘤的治疗结果

目的 分析胃外黏膜相关淋巴组织(MALT)淋巴瘤的临床特征和预后.方法 回顾性分析40例首程治疗的Ⅰ_E～Ⅱ_E期原发胃外MALT淋巴瘤,其中男女比例为1:2,中位年龄54岁.原发病部位为肠道10例,眼附属器9例,甲状腺8例,肺5例,韦氏环2例及其他部位6例.Ⅰ_E期27例,Ⅱ_E期13.17例患者接受放疗(其中7例合并化疗),18例接受化疗(未合并放疗),5例单纯手术切除.结果 中位随访58个月.5年总生存率和无进展生存率分别为86%和82%.Ⅰ_E期和Ⅱ_E期5年总生存率分别为92%和76%(χ~23.66,P=0.060),无进展生存率分别为85%和76%(χ~2=1.04,P=0.300).原发眼附属器MALT淋巴瘤的5年总生存率和无进展生存率均为100%.17例接受放疗的患者无局部区域复发,局部区域控制率为100%,而23例未接受放疗者局部区域复发率为13%(3例).结论 Ⅰ_E期胃外MALT淋巴瘤可取得较好的治疗效果,放疗仍是标准治疗手段,原发眼附属器MALT淋巴瘤预后最好.     

Primary mucosa-associated lymphoid tissue lymphoma of the breast

Mucosa-associated lymphoid tissue (MALT) lymphoma is an extranodal indolent lymphoma with histopatholigic features similar to those of marginal zone B-cell lymphomas. Primary breast MALT lymphomas were first described by Lamovec and Jancar as a low-grade B-cell lymphoma in 1987. Herein, a case is presented of a patient with primary MALT lymphoma of the breast. Issues in diagnosis and breast-conservation treatment, as it pertains to primary MALT lymphoma of the breast, will be discussed.     

31例胃肠道淋巴瘤临床病理学研究

本文分析了31例胃肠道淋巴瘤的临床及病理学研究。男性发病高于女性，平均年龄56．6岁，发生部位以胃最为常见占77％（24／31），小肠、回盲肠及盲肠、大肠各2例，直肠1例，临床症状无特异性。病理学以裂、无裂细胞淋巴瘤多见。对16例采用免疫组化染色证实B细胞性恶性淋巴瘤占94％（5／16），T细胞性恶性淋巴瘤1例为6％。     

胸腺ＭＡＬＴ淋巴瘤的临床病理分析

目的　探讨胸腺ＭＡＬＴ淋巴瘤的临床病理特征及治疗方案。方法　结合检索已报道的胸腺ＭＡＬＴ淋巴瘤４２例患者资料以及本院诊治的１例,共４３例病例,对上述病例的临床病理特征进行归纳总结。结果　胸腺ＭＡＬＴ淋巴瘤多见于东亚人种,女性居多,临床上多无症状,常伴有自身免疫性疾病,影像学检查和组织学检查是明确诊断该病的主要方法。大部分患者通过手术可以同时获得明确诊断和有效治疗。结论　胸腺ＭＡＬＴ淋巴瘤虽然罕见,但具有独特的临床病理特征,可以作为鉴别诊断的线索;手术对该淋巴瘤的诊断和治疗均具有重要意义。     

Monoclonal immunoglobulin production is a frequent event in patients with mucosa-associated lymphoid tissue lymphoma.

PURPOSE: Mucosa-associated lymphoid tissue (MALT) lymphoma comprises 7% of all newly diagnosed non-Hodgkin's lymphomas and is therefore among the most common lymphoma entities. Monoclonal gammopathy due to production of a monoclonal immunoglobulin by lymphoma cells is a well-known phenomenon associated with various types of B-cell non-Hodgkin's lymphomas. The objective of the present study was to evaluate the incidence and clinical relevance of paraprotein (PP) production in patients with MALT lymphoma. EXPERIMENTAL DESIGN: Fifty two patients were prospectively evaluated with regard to differentiation of the MALT lymphoma cells, t(11;18) translocation, monoclonal immunoglobulin production, Helicobacter pylori (HP) status, stage, treatment, and clinical outcome. RESULTS: Nineteen of 52 MALT lymphoma patients (36%) had PP (8 IgMkappa, 6 IgGkappa, 4 IgMlambda, and 1 IgAkappa). The histologic feature of plasmacytic differentiation correlated significantly with the production of PP (P = 0.001). No correlation was found between PP and clinical stage, HP status, and t(11;18) status. PP was, however, negatively associated with response to eradication of HP in gastric MALT lymphoma, and PP levels declined significantly in patients responding to chemotherapy or radiation. Importantly, both immunofixation and serum electrophoresis have to be performed to detect low PP levels. CONCLUSIONS: In conclusion, PP levels may probably be used as a potential prognostic tool for response to HP eradication, and serial measurements may also allow for noninvasive assessment of response to radiation or chemotherapy in patients with MALT lymphoma.