Marginal zone lymphoma

Marginal zone lymphomas (MZLs) comprise 3 distinct entities: extranodal MZL of mucosa-associated lymphoid tissue (MALT), splenic MZL, and nodal MZL. Gastric MALT lymphoma is the most common extranodal MZL and often develops as a result of chronic Helicobacter pylori gastritis. Such cases frequently respond to antibiotics directed against H. pylori. Antigen-driven lymphomatous disease can also be seen in the association of Borrelia burgdorferi with MALT lymphoma of the skin, Chlamydia psittaci with MALT lymphoma of the ocular adnexa, Campylobacter jejuni with immunoproliferative disease of the small intestine, and hepatitis C with splenic MZL. This article discusses the pathogenesis and clinical features of MZL and the treatment options available to patients.     

MALT lymphomas: pathogenesis can drive treatment

Marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT) lymphoma is an indolent B-cell non-Hodgkin lymphoma arising from the lymphoid tissue at extranodal sites. It is genetically characterized by different, usually mutually exclusive, genetic abnormalities that lead to activation of the nuclear factor kappa B (NF-kappaB) pathway. These lymphomas can arise in any extranodal organ or tissue; however, the stomach--where MALT lymphoma development has been strongly linked to chronic Helicobacter pylori infection--is the most common site. Other microorganisms have been associated with non-gastric MALT lymphomas, but the evidence for such associations is weaker. Treatment aimed at eradicating H pylori infection results in remission of gastric MALT lymphoma in most patients and represents a model of anticancer treatment based on the eradication of the causative factor. Treatment of non-gastric MALT lymphomas is much less well established; either radiotherapy or systemic therapy (with chemotherapy and/or rituximab [Rituxan]) can be effective, while antibiotic therapies (e.g., doxycycline in ocular adnexal lymphomas) should still be considered investigational.     

Treatment of gastric mucosa-associated lymphoid tissue lymphoma: Helicobacter pylori eradication and beyond

Gastric mucosa-associated lymphoid tissue (MALT) lymphoma is the paradigm of lymphomas developing in extranodal areas after antigen stimulation. In the stomach, Helicobacter pylori colonization induces the appearance of MALT and, eventually, MALT-derived lymphoma. This type of lymphoma is initially a localized form of disease, but may disseminate and transform into high-grade lymphoma, making full staging (as for nodal lymphomas) and endoscopic ultrasonography to evaluate the penetration of the lymphoma through the gastric wall mandatory. In localized gastric MALT lymphoma, the first step in treatment is eradication of H. pylori, which results in 60-90% regression. This response is maintained for years in most patients, with only 10-15% relapse, frequently precipitated by H. pylori reinfection. A component of high-grade lymphoma, penetration to gastric serosa or beyond and translocation t(11;18) are the main factors that make lymphoma resistant to eradication. Surgery or radiotherapy can cure localized lymphomas in 75-90% of patients. Chemotherapy with alkylating agents, combination chemotherapy and purine analogs, and anti-CD20 antibodies can also induce remission of localized lymphomas refractory to eradication, as well as locally advanced and disseminated lymphomas. The optimum chemotherapy treatment for advanced disease has not yet been established; however, combination therapy, including purine analogs with or without anti-CD20, may be a promising option. Despite histological responses and prolonged remissions, residual molecular disease can be demonstrated in most cases treated with H. pylori eradication, radiotherapy or alkylating agents, and even after more intense chemotherapy, although this does not seem to lead to late relapses. High-grade gastric MALT lymphoma should be treated with chemotherapy, with cyclophosphamide, doxorubicin, oncovin and prednisone being the best first-line option. All gastric MALT lymphomas associated with H. pylori should receive eradication treatment in addition to other required treatment.     

Chromosomal Aberrations in Lymphomas of the Gastrointestinal Tract

B-cell lymphomas of the gastrointestinal (GI) tract have represented a field of extensive research ever since a close association was shown with chronic inflammatory processes such as Helibacter pylon infection. Much evidence has accumulated to suggest that the mucosa-associated lymphoid tissue (MALT) induced by inflammation and autoimmune processes is the environment which gives rise to the small cell lymphomas of the GI tract (e.g. extranodal marginal B-cell lymphoma according to REAL). The small B-cell lymphoma may then progress to the large cell variants. Hence, B-cell lymphomas of the GI tract may present a model for lymphomagenesis and progression. In this review, recent cytogenetic data are discussed which yield new insights into the biology of gastrointestinal lymphomas.     

Primary extranodal lymphomas of stomach: clinical presentation,diagnostic pitfalls and management

Gastrointestinal lymphoma is the most common form of extranodal lymphoma, accounting for 30%–40% of cases. The most commonly involved site is the stomach (60%–75% of cases), followed by the small bowel, ileum, cecum, colon and rectum. The most common histological subtypes are diffuse large B-cell lymphoma (DLBCL) and marginal zone B-cell lymphoma of the mucosa-associated lymphoid tissue (MALT). Helicobacter pylori infection has been implicated in the pathogenesis of MALT gastric lymphoma, but its role in gastric diffuse large B-cell non-Hodgkin's lymphoma (NHL) is controversial. The therapeutic approach for patients with gastric NHL has been revised over the last 10 years. Conservative treatment with anthracycline-based chemotherapy alone or in combination with involved-field radiotherapy has replaced gastrectomy as standard therapy in cases with DLBCL. Additionally, MALT lymphomas are mainly treated with antibiotics alone, which can induce lasting remissions in those cases associated with H. pylori infection. Nevertheless, various therapeutic aspects for primary gastric lymphomas are still controversial and several questions remain unanswered. Among others, the role of rituximab, consolidation radiotherapy as well as H. pylori eradication in histological aggressive subtypes warrants better clarification.     

Molecular pathogenesis of mucosal-associated lymphoid tissue (MALT) lymphoma

Extranodal marginal zone B-cell lymphomas of mucosal-associated lymphoid tissue (MALT)-type occur in a number of anatomic sites, but share overlapping morphological and immunophenotypic features. Helicobacter pylori infection has been identified as an etiological factor in gastric MALT lymphoma, but the cause of MALT lymphomas at other sites remains a matter of speculation. Despite these limitations in understanding the etiology of MALT lymphoma, standard cytogenetic analysis has proved useful by demonstrating similar alterations in MALT lymphomas from different anatomic sites. The common cytogenetic alterations that characterize MALT lymphomas include t(11:18)(q21:q21), t(1;14)(p22;q32) and, more recently, t(14;18)(q32;q21). The apparent complexity of the 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 these very disparate translocations affect a common signaling mechanism, and thus unify all three under a common pathogenesis, resulting in the constitutive activation of the NF-kappaB pathway.     

Radiation therapy for localized low-grade non-Hodgkin's lymphomas

The most common low grade B-cell non-Hodgkin's lymphomas are follicular lymphomas, and extranodal marginal zone lymphomas, also known as mucosa-associated lymphoid tissue (MALT) lymphomas. Localized presentations of follicular lymphoma occur in 20-30% of cases, while for MALT lymphomas, stage I-II disease presentations occur in 70-90%. These are radiation-sensitive lymphomas. Following moderate dose local radiation treatment (30-35 Gy) for these stage I and II low grade lymphomas, the clinical results indicate long-term local control and possible cure. While local control is achieved with minimal morbidity with involved-field radiation therapy, a significant proportion of patients relapse with systemic disease outside of radiation fields. For follicular lymphoma, this occurs in approximately 50% of patients after 15 years, and for non-gastric MALT lymphoma, 30-40% after 10 years. Although patients with relapsed systemic disease are not curable with chemotherapy, the disease often behaves in an indolent fashion and prolonged survival is observed. For gastric MALT lymphomas, radiation therapy is indicated in patients whose lymphoma did not respond to Helicobacter pylori eradication therapy, or in gastric lymphoma not related to this microorganism. The subject of causative agents responsible for non-gastric MALT lymphomas is under active study and the identification of putative microorganisms will lead to improved treatment strategies for these unusual lymphomas, similar to the success in gastric lymphomas over the last decade.     

Expression of PIK3CA and FOXP1 in gastric and intestinal non-Hodgkin’s lymphoma of mucosa-associated lymphoid tissue type

Non-Hodgkin’s lymphoma of mucosa-associated lymphoid tissue (MALT) type arises from a wide variety of extranodal sites, most frequently from the gastrointestinal tract. Recently, it has been demonstrated that karyotypic alterations involving the PIK3CA and FOXP1 genes of chromosome 3 occur in MALT lymphoma. However, their associated protein expression has not been extensively studied. Tumor tissues from 27 gastric and 23 intestinal MALT lymphomas were analyzed for PIK3CA and FOXP1 protein expression using immunohistochemistry and correlated with histological features and treatment outcomes. Expression of PIK3CA, a novel indicator, was found in 40% of gastrointestinal cases and indicated an inferior progression-free survival in both gastric and intestinal MALT lymphomas (P?=?0.001 and P?=?0.015). Tumor staining of nuclear FOXP1 (46.0%) was more common in gastric than intestinal MALT lymphomas (P?=?0.042) and was significantly associated with polymorphic histology (P?=?0.007). FOXP1 expression was identified as an adverse prognostic factor for overall survival in gastric MALT lymphomas (P?=?0.035). We further combined these two markers and observed that patients that are positive for both PIK3CA and FOXP1 had a worse overall and progression-free survival. Considering the small sample size of this study, these results should be confirmed in a large prospective study.     

Gastric diffuse large B-cell lymphoma after the diagnosis of primary MALT lymphoma of the breast��One case report

Primary breast and gastric lymphomas as manifestations of primary extranodal lymphomas are rare malignancies, and their diagnosis, prognosis, and treatment modalities remain unclear. We report for the first time the simultaneous co-occurrence of these diseases in one patient. A 60-year-old woman was diagnosed with gastric diffuse large B-cell lymphoma (DLBCL) 2.5 years after she was found to have primary mucosa-associated lymphoid tissue (MALT) lymphoma of the breast. Although the patient underwent chemotherapy, she died of leukemia that caused irreversible cytopenia of three lineages. The data show that her MALT lymphoma apparently transfigured into gastric DLBCL. This case highlights the importance of evaluating patients for Helicobacter pylori infection when they present with extranodal MALT lymphomas, except gastric ones. Positive test findings should prompt anti-H. pylori therapy to prevent MALT lymphomas from transforming into DLBCLs.     

Chlamydia psittaci in ocular adnexa MALT lymphoma: a possible role in lymphomagenesis and a different geographical distribution

Ocular adnexa MALT-lymphomas represent approximatively 5-15% of all extranodal lymphomas. Almost 75% of OAMLs are localized in orbital fat, while 25% of cases involves conjunctive. MALT-lymphomas often recognize specific environmental factors responsible of lymphoma development and progression. In particular as Helicobacter pylori in gastric MALT lymphomas, other bacterial infections have been recognized related to MALT lymphomas in specific site. Recently Chlamydia psittaci has been identified in Ocular Adnexa MALT lymphomas, with variable frequence dependently from geographic areas. Thus bacterial infection is responsible of clonal selection on induced MALT with subsequent lymphoma development. Moreover Chlamydia psittaci could promote chromosomal aberration either through genetic instability as a consequence of induced proliferation and probably through DNA oxidative damage. The most common translocation described in MALT lymphomas affects NF-kB pathway with a substantial antiapoptotic effect. Several therapeutic approaches are now available, but the use of antibiotic-therapy in specific cases, although with conflicting results, could improve the treatment of ocular adnexa MALT lymphomas. In this review we analyse the most relevant features of Ocular adnexa MALT lymphomas, underlining specific biological characteristics mainly related to the potential role of Chlamydia psittaci in lymphomagenesis.     

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.     

Gastric MALT lymphoma: From concept to cure

Gastric MALT lymphomas are clinically and histologically quite distinct from comparable low-grade B-cell lymphomas of lymph nodes. Their histology suggests that immunological mechanisms might be operative in their growth. Given that there is normally no lymphoid tissue in gastric mucosa and that Helicobacter pylori (H. pylori), the only common bacterial antigen in the stomach, results in the accumulation of gastric MALT, the possibility that this organism is implicated in the pathogenesis of gastric lymphoma has been extensively investigated. It appears that most, but not necessarily all, gastric MALT lymphomas arise in MALT acquired in response to H. pylori infection and develop by stepwise accumulation of genetic abnormalities. Early molecular events in the evolution of gastric MALT lymphoma from acquired MALT include trisomy 3, t(11;18)(q21;q21), genetic damage leading to genetic instability, as indicated by the so-called replication error repair (RER) phenotype, and both p53 and c-mycmutations. At this stage in their development, the growth of the lymphomas is driven by contact between the neoplastic B cells and H. pylori specific intra-tumoral T cells. Eradication of H. pyloricauses the tumour to enter a latent phase resulting in clinical regression. Later events, such as t(1;14)(p22;q32), appear to be linked to a capacity for autonomous growth, loss of sensitivity to H. pylori and dissemination of the lymphoma beyond the stomach and gastric lymph nodes. Cloning of the breakpoint in t(1;14) has allowed the identification of a new tumour suppresser gene, bcl10. High grade transformation of MALT lymphoma has been associated with p53 inactivation, deletions of p16 and t(8;14).     

Helicobacter pylori eradication therapy for high-grade mucosa-associated lymphoid tissue lymphomas of the stomach with analysis of p53 and K-ras alteration and microsatellite instability

Recent studies have shown that 70-80% of low-grade mucosa-associated lymphoid tissue (MALT) lymphomas regress in response to eradication of Helicobacter pylori (H. pylori). However, there are no reports on whether gastric high-grade MALT lymphomas regress after H. pylori eradication. We performed H. pylori eradication therapy in 4 patients with stage I, high-grade MALT lymphoma after obtaining their informed consent. H. pylori infection was observed in all 4 patients. The patients were treated with proton-pump inhibitor-based eradication therapy for 1 or 2 weeks, and then underwent endoscopic examination and biopsy sampling. H. pylori eradication was achieved in all 4 patients. Six months after eradication treatment, 2 patients showed complete regression of the lymphoma and 2 patients showed no change. The 2 patients with non-responding lymphoma were then treated with an additional chemotherapy (CHOP regimen), whereupon the tumors completely regressed. These patients, followed-up at least 18 months after eradication treatment, showed no recurrence. We also examined genetic alteration of the p53 and K-ras genes and microsatellite instability in these high-grade MALT lymphomas. One patient with a tumor that showed no change after H. pylori eradication, had a loss of heterozygosity of the p53 gene. No other genetic alterations were detected among the patients. Our results indicate that the eradication of H. pylori may be effective not only for patients with low-grade MALT lymphoma but also for patients with high-grade MALT lymphoma. The treatment may be efficacious as a first-line therapy for patients with high-grade MALT lymphoma. However, our sample size was limited and further studies are needed to clarify the issue.     

Gastric low-grade mucosal-associated lymphoid tissue-lymphoma: Helicobacter pylori and beyond

The stomach is the most frequently involved site for extranodal lymphomas, accounting for nearly two-thirds of all gastrointestinal cases. It is widely accepted that gastric B-cell, low-grade mucosal-associated lymphoid tissue (MALT)-lymphoma is caused by Helicobacter pylori (H. pylori) infection. MALT-lymphomas may engender different clinical and endoscopic patterns. Often, diagnosis is confirmed in patients with only vague dyspeptic symptoms and without macroscopic lesions on gastric mucosa. H. pylori eradication leads to lymphoma remission in a large number of patients when treatment occurs at an early stage (I-II(1)). Neoplasia confined to the submucosa, localized in the antral region of the stomach, and without API2-MALT1 translocation, shows a high probability of remission following H. pylori eradication. When both bacterial infection and lymphoma recur, further eradication therapy is generally effective. Radiotherapy, chemotherapy and, in selected cases, surgery are the available therapeutic options with a high success rate for those patients who fail to achieve remission, while data on immunotherapy with monoclonal antibodies (rituximab) are still scarce. The 5-year survival rate is higher than 90%, but careful, long-term follow-up is required in these patients since lymphoma recurrence has been reported in some cases.     

Non-Hodgkin's lymphomas in the Middle East. A study of 417 patients with emphasis on special features

A total of 417 evaluable patients with non-Hodgkin's lymphomas were diagnosed between January 1974 and December 1983 at the American University of Beirut Medical Center in Beirut, Lebanon. Of these, 179 (43%) patients had nodal lymphomas, and 183 (44%) had extranodal lymphomas. The commonest lymphoma was diffuse large cell (27%), followed by large cell immunoblastic (21%). The histopathologic pattern was follicular in 18% of the nodal lymphomas and in 5.3% of the extranodal forms. The most common site of extranodal lymphoma was the gastrointestinal tract (46.5%), followed by Waldeyer's ring (19%). Small intestinal lymphomas were three times more common than gastric lymphomas. Immunoproliferative small intestinal disease (IPSID) was diagnosed in 20 of 59 patients who had primary small intestinal lymphoma. Of the 34 patients who had Waldeyer's ring lymphoma, 7 had gastrointestinal involvement at some time during the course of the disease. Nodal lymphomas were associated with poor prognostic factors: 82% were diffuse; 77% had advanced disease at presentation; 77% had intermediate- or high-grade malignancy lymphoma; 40% had marrow involvement; and 46% had B symptoms. In children, the most common lymphoma was Burkitt's, and 80% of pediatric lymphomas were high-grade malignancy. In conclusion, this study delineates the special features of non-Hodgkin's lymphomas in the Middle East: The presence of IPSID; the high incidence of extranodal forms, in particular the intestinal ones; and the rarity of follicular lymphomas.     

Low-grade non-hodgkin lymphomas

The most common low-grade non-Hodgkin lymphomas are of B-cell origin. This review will focus on follicular lymphomas and extranodal marginal zone lymphomas, also known as mucosa-associated lymphoid tissue (MALT) lymphomas. These are radiation-sensitive lymphomas. Moderate doses (30-35 Gy) for these stage I and II low-grade lymphomas result in long-term local control and possible cure. Involved-field radiation therapy is the standard approach and produces minimal morbidity. However, a significant proportion of patients relapse with systemic disease outside of radiation fields. For follicular lymphoma, this occurs in approximately 50% of patients after 15 years and for nongastric MALT lymphoma 30% to 40% after 10 years. Patients with relapsed disease are not curable with chemotherapy, but the disease often remains indolent and prolonged survival is observed. For gastric MALT lymphomas associated with Helicobacter pylori but which did not respond to antibiotic therapy, radiation treatment is indicated and almost always curative. For localized MALT lymphomas not related to microorganisms, radiation therapy is the initial standard therapy regardless of anatomic location. Patients with stage III and IV low-grade lymphoma and local symptoms are often successfully palliated with a low dose regimen of 2 x 2 Gy (total dose 4 Gy).     

Complete regression of low-grade mucosa-associated lymphoid tissue (MALT) lymphoma in the gastric stump after eradication of Helicobacter pylori

Recent studies have suggested that Helicobacter pylori (H. pylori)-associated gastritis may play an important role in the pathogenesis of primary gastric lymphoma. Recently, triple therapy using proton pump inhibitor, amoxicillin, and clarithromycin, has been established for the eradication therapy of H. pylori infection, and is also recommended for the treatment of the superficial type of low-grade gastric MALT (mucosa-associated lymphoid tissue ) lymphoma. MALT lymphoma of the gastric stump is rare, and total resection or chemotherapy for MALT lymphoma of the gastric stump has been previously reported. Therefore, there is no evidence that eradication therapy is effective for low-grade MALT lymphoma of the gastric stump. Our case illustrates the remarkable efficacy of eradication of H. pylori for low-grade MALT lymphoma of the gastric stump without other modalities such as surgery and systemic chemotherapy.     

Primary gastric mantle cell lymphoma in a patient with long standing history of Crohn's disease

The stomach is the most common site of primary extranodal lymphoma. Virtually all cases are of B-cell lineage, including extranodal marginal zone B-cell lymphomas of mucosa-associated lymphoid tissue (MALT lymphoma) and diffuse large B-cell lymphomas. While secondary gastric involvement from nodal mantle cell lymphoma (MCL) or in the course of primary intestinal MCL (lymphomatous polyposis) have been described, primary gastric MCL has not been reported so far. A 74-year-old man with a 14 year-history of Crohn's disease was admitted at a general hospital due to epigastric pain refractory to therapy with proton-pump inhibitors. Endoscopy disclosed a large polypoid tumor with an ulcerated surface at the greater curvature of the gastric antrum. Endosonography demonstrated the tumor to be limited to the stomach with only local lymph node involvement. Histology of gastric biopsies revealed a dense atypical lymphoid infiltrate composed of small to medium sized cells with slightly irregular nuclear contours. Immunohistochemichally, the cells were positive for CD20, CD79a, CD43 and cyclin D1, but negative for CD3, CD5 and bcl-6. They stained for IgM and showed lambda-light chain restriction. Fluorescent in situ hybridisation studies showed the presence of the t(11;14) characteristic for MCL. No further evidence of lymphoma was found on extensive clinical staging. Following chemotherapy the patient is disease free at 24 months after diagnosis. This is the first case of a primary localized gastric MCL. The lack of CD5 expression underscores the importance of performing thorough immunohistochemical studies, particularly to exclude MALT lymphoma.     

Histopathologic features and expression of Bcl-2 and p53 proteins in primary gastric lymphomas

The aim of this study is to present a histopathologic and immunohistochemical analysis of primary gastric lymphomas which were reclassified according to the concept of mucosa associated lymphoid tissue (MALT). The resected specimens from 41 patients with primary gastric lymphoma were investigated retrospectively. Immunohistochemical study was done to analyze the immunophenotype and bcl-2 and p53 proteins expression. Twenty three of the cases had tumors mainly located in the antrum. Histologically, 12 were low grade and 20 were high grade B-cell lymphoma of MALT, 9 other B-cell nonHodgkin's lymphomas. Helicobacter pylori was identified in 72% of the cases. According to Musshoff's modification, most of the MALT lymphoma cases had stage I or II disease. There was significant difference between low and high grade cases, in respect to depth of invasion in gastric wall. Immunohistochemically, the neoplastic cells in all MALT lymphomas expressed B-cell phenotype. Bcl-2 protein was found to be expressed in 59% and p53 protein expression was detected in 72% of cases. Among the B-cell lymphoma of MALT, bcl-2 positivity decreased and p53 positivity increased significantly as the histological grade advanced. So, an inverse correlation was observed between the expression of bcl-2 and p53. In conclusion, most primary gastric lymphomas are low or high grade B-cell MALT lymphomas and appear to arise in MALT acquired as a reaction to Helicobacter pylori infection. Expression of bcl-2 and p53 in gastric lymphomas may be associated with transformation from low-grade to high-grade disease.