Current therapeutic concepts in mucosa-associated lymphoid tissue (MALT) lymphoma

While eradication of Helicobacter pylori leads to durable remissions in up to 75?% of patients with gastric mucosa-associated lymphoid tissue (MALT) lymphoma and therefore, has been well established as first-line therapy of choice, there is no standard of care for relapsed, refractory or extragastric MALT lymphoma. Both in gastric as well as extragastric MALT lymphoma, local therapy results in high rates of local control, but MALT lymphoma may be disseminated in a significant number of patients, making systemic treatment approaches reasonable. Different classical cytostatic agents have successfully been tested in the past. However, MALT lymphoma usually runs an indolent clinical course and thus, recent trials have focussed on chemotherapeutics with a favourable toxicity profile, e.g. chlorambucil or bendamustine with or without rituximab (R), and new immunomodulatory drugs, e.g. lenalidomide. Results are promising and further, and especially more mature data with a longer follow-up are awaited. In addition, efforts have been made to characterise the activity of antibiotic therapy in extragastric MALT lymphoma, particularly in the setting of ocular adnexal manifestations. Doxycyclin-treatment achieved response rates of 45–65?% in several series, which was independent of the presence of a Chlamydophila psittaci infection. Furthermore, the macrolide antibiotic clarithromycin has become a matter of interest for the treatment of ocular adnexal MALT lymphoma as this substance exerts not only antibiotic, but also direct anti-tumor and immunomodulatory effects. In view of recent data, this short review focuses on highlights and recent results of systemic and antimicrobial therapy in MALT lymphoma.     

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).     

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.     

Nongastric mucosa-associated lymphoid tissue lymphomas

Nongastric mucosa-associated lymphoid tissue (MALT)-derived lymphomas arise from various extranodal locations and are usually related to a particular pathogenesis with a possible external (environmental or autoimmune) event inducing the disease. We reviewed 165 patients with nongastric MALT lymphoma among the 243 patients with MALT lymphoma in our database and reviewed reports in the literature to analyze the clinical features of nongastric MALT lymphomas. The site of clinical presentation was related to the lymphoma location and was usually indolent. Dissemination of the disease at diagnosis was noticed in 48% of cases because of the involvement of multiple mucosal sites (48%) or because of a nonmucosal site involvement such as bone marrow, spleen, or liver (52%). With a median follow-up of 4 years, the estimated 5-year overall survival and 5-year freedom-from-progression rates were 89% and 50%, respectively, without any difference between patients with localized or disseminated disease or among different locations. Treatment recommendations for localized disease are based on surgery, local therapy, or chlorambucil. For disseminated disease, treatment recommendations include chemotherapy with fludarabine or chlorambucil or chemotherapy with CHOP (cyclophosphamide/doxorubicin/vincristine/prednisone) in cases of large tumor mass     

Prevalence of HCV infection in nongastric marginal zone B-cell lymphoma of MALT.

BACKGROUND: Hepatitis C virus (HCV) infection is frequently associated with B-cell non-Hodgkin's lymphomas. We investigated the prevalence of HCV infection in nongastric marginal zone lymphomas of mucosa-associated lymphoid tissue (MALT) in order to define the relationship between the viral infection and the presenting features, treatment, and outcome. METHODS: We retrospectively studied 172 patients with a histological diagnosis of marginal zone B-cell lymphoma of MALT, except for stomach, and with available HCV serology, among a series of 208 patients. RESULTS: HCV infection was documented in 60 patients (35%). Most HCV-positive patients (97%) showed a single MALT organ involvement. HCV-positive patients showed a more frequent involvement of skin (35%), salivary glands (25%), and orbit (15%). The majority of stage IV HCV-positive patients (71%) had a single MALT site with bone marrow involvement. The overall response rate was similar in HCV-positive (93%) and HCV-negative patients (87%). Overall survival (OS) and event-free survival (EFS) did not differ according to HCV infection. In multivariate analysis, advanced disease (stage III-IV) was associated with a poorer OS (P = 0.0001), irrespective of HCV serostatus. CONCLUSIONS: This study shows that nongastric marginal zone lymphomas are characterized by a high prevalence of HCV infection. Patients with involvement of a single MALT site have the highest prevalence of HCV. HCV-positive nongastric lymphomas of MALT show an indolent course similar to HCV-negative patients and seem an ideal target for exploiting the antilymphoma activity of antiviral treatments.     

Low-grade mucosa-associated lymphoid tissue lymphoma: a retrospective analysis of 97 patients by the Hellenic Cooperative Oncology Group (HeCOG).

BACKGROUND: The aim was to examine characteristics and treatment results of patients with mucosa-associated lymphoid tissue (MALT) non-Hodgkin's lymphomas. PATIENTS AND METHODS: Epidemiological and clinical features of 97 patients with MALT lymphoma from the Hellenic Cooperative Oncology Group registry were analysed retrospectively for their prognostic significance in progression-free survival (PFS) and overall survival (OS). Comparisons were made between patients with gastric and nongastric sites of primary lymphoma and between different therapeutic modalities. RESULTS: Sixty-five patients presented with gastric and 32 with nongastric lymphomas. The most frequent locations of nongastric lymphomas were the bowel, lung and parotid. Gastric lymphomas occurred more frequently in males and younger patients compared with nongastric lymphomas. Seventy-four per cent of patients had early (Ann Arbor stages I-II) and 26% had advanced (stages III-IV) disease. The median PFS for the entire population was 44 months. At 5 years, 47% of patients were progression free and the OS rate was 80%. The most reliable prognostic factor for PFS and OS was the Ann Arbor stage; 5-year PFS was 67% versus 13% and 5-year OS 91% versus 51% for patients with early versus advanced disease, respectively (P < 0.001). Of the patients treated with chemotherapy only, 87% achieved an objective response and 71% complete response. Surgery did not offer survival benefit compared with chemotherapy in localised gastric lymphoma. CONCLUSION: MALT lymphomas represent a distinct disease entity with widespread extranodal origin, indolent clinical course and high chemosensitivity. Ann Arbor stage was the most reliable prognostic and predictive factor.     

Is there an association between ocular adnexal lymphoma and infection with Chlamydia psittaci? The University of Rochester experience

Various subsets of extranodal marginal zone lymphomas of mucosa-associated lymphoid tissues (MALT lymphomas) have been associated with infectious organisms. Most notable of these is the association of gastric MALT lymphomas with Helicobacter pylori infection. In a recent publication Ferreri et al. [Ferreri AJ, Guidoboni M, Ponzoni M, De Conciliis C, Dell'Oro S, Fleischhauer K, et al. Evidence for an association between Chlamydia psittaci and ocular adnexal lymphomas. J Natl Cancer Inst 2004;96:586-94] reported the presence of C. psittaci DNA in 80% of 40 ocular adnexal lymphomas. Similar to the gastric MALT lymphoma data, a subset of these patients responded well to antibiotic treatment. We analyzed a set of ocular adnexal lymphomas and benign (non-neoplastic) lesions for evidence of C. psittaci DNA in patients from New York State. No evidence of C. psittaci DNA was seen in seven MALT-type ocular adnexal lymphomas, four non-MALT ocular lymphomas, one Langerhans histiocytosis, and five reactive lymphoproliferations. We eliminated several possible reasons that would cause our study to fail to find C. psittaci DNA, including the presence of PCR inhibitors, inadequate template DNA, and sequence diversity in the target region in C. psittaci. The positive data were based primarily on patients from Italy, while our study involved only patients living in the Northeastern United States. This would suggest possible geographic differences in the etiology of ocular adnexal lymphomas.     

Clinicopathologic characteristics and treatment of marginal zone lymphoma of mucosa‐associated lymphoid tissue (MALT lymphoma)

Answer questions and earn CME/CNE Extranodal marginal zone lymphoma of the mucosa‐associated lymphoid tissue (MALT lymphoma) accounts for 7% to 8% of newly diagnosed lymphomas. Because of its association with infectious causes, such as Helicobacter pylori (HP) or Chlamydophila psittaci (CP), and autoimmune diseases, it has become the paradigm of an antigen‐driven malignancy. MALT lymphoma usually displays an indolent course, and watch‐and‐wait strategies are justified initially in a certain percentage of patients. In patients with gastric MALT lymphoma or ocular adnexal MALT lymphoma, antibiotic therapy against HP or CP, respectively, is the first‐line management of choice, resulting in lymphoma response rates from 75% to 80% after HP eradication and from 33% to 65% after antibiotic therapy for CP. In patients who have localized disease that is refractory to antibiotics, radiation is widely applied in various centers with excellent local control, whereas systemic therapies are increasingly being applied, at least in Europe, because of the potentially systemic nature of the disease. Therefore, the objective of this review is to briefly summarize the clinicopathologic characteristics of this distinct type of lymphoma along with current data on management strategies. CA Cancer J Clin 2016;66:152–171. © 2015 American Cancer Society.     

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.     

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.     

Multiple organ mucosa-associated lymphoid tissue lymphomas often involve the intestine

BACKGROUND: Low grade mucosa-associated lymphoid tissue (MALT) lymphomas usually are confined to single extranodal organs. Although some case reports have been published, clinicopathologic characteristics of multiorgan MALT lymphomas remain unclear. METHODS: The authors evaluated 7 MALT lymphoma cases involving multiorgans in the past 7 years. In this period, they experienced 304 cases of MALT lymphomas. They analyzed the clinicopathologic features of these cases, including examination of clonal comparison among the lesions. RESULTS: The patients, 4 females and 3 males, were aged 55-68 years old (average, 60.1 years). Four cases showed multiple organ involvement at the initial diagnosis or after a short period. In the other three cases, primary foci were the stomach, thyroid gland, and ocular adnexa; after a rather long period (3 years or more), distant metastases were found. Although intestinal primary lymphomas are rather rare, six of the seven cases showed large intestinal involvement. Lymph node involvement was proven in only three cases. The patients were rather resistant to the various therapeutic approaches. Although six patients are alive, five are with disease. DNA analyses revealed that in five of the cases evaluated, identical clones were detected among the different affected organs. CONCLUSIONS: Multiorgan MALT lymphomas are rather rare. Most cases probably derived from a single clone, and lymphoma cells may selectively move among MALTs via a homing system with preferential involvement of the colon. Because multiorgan MALT lymphomas rarely achieve complete remission by treatment with combination chemotherapy or irradiation, MALT lymphomatous lesions should be checked carefully, especially in the large intestine.     

Long-term follow-up results of no initial therapy for ocular adnexal MALT lymphoma.

BACKGROUND: The majority of lymphomas in the ocular adnexa are low-grade B-cell lymphomas of mucosa-associated lymphoid tissue (MALT lymphoma). Although radiotherapy is the most frequently applied management, cataract and dry eye are problematic complications. PATIENTS AND METHODS: Between 1973 and 2003, the clinical features of 36 patients with ocular adnexal MALT lymphoma with no symptoms who were managed with no initial therapy after biopsy or surgical resection were retrospectively analyzed. RESULTS: The median patient age was 63 years (range 22-84) and all patients had stage I disease, consisting of 31 unilateral cases and five bilateral cases. With a median follow-up of 7.1 years, 25 (69%) did not require treatment. The median time until the initiation of treatment in the remaining 11 patients (31%) was 4.8 years. Six patients (17%) died, and among them only two (6%) died due to progressive lymphoma. Seventeen patients (47%) progressed, but histologic transformation was recognized in only one (3%). The estimated overall survival rates of the 36 patients after 5, 10 and 15 years were 94%, 94% and 71%, respectively. CONCLUSIONS: In selected patients with ocular adnexal MALT lymphoma, no initial therapy might be an acceptable approach, because 70% of patients remained untreated at a median of 8.6 years, and their survival was comparable to that of reports on immediate therapy.     

Ocular adnexal lymphoma: clinical behavior of distinct World Health Organization classification subtypes

PURPOSE: To evaluate the clinical behavior and treatment outcome of ocular adnexal lymphomas classified by the World Health Organization system, with emphasis on marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT). MATERIALS AND METHODS: The clinicopathologic materials from 98 consecutive patients treated for ocular adnexal lymphoma were reviewed. Fourteen patients had prior lymphoma and 84 patients had primary disease (75% Stage I, 6% Stage III, and 19% Stage IV). Radiation (photons/electrons) was administered to 102 eyes to a median dose of 30.6 Gy. The mean follow-up was 82 months. RESULTS: The most common subtypes among the primary patients were MALT (57%) and follicular (18%) lymphoma. The 5-year actuarial local control rate in 102 irradiated eyes was 98%. Among the low-grade lymphomas, the 5-year local control rate correlated with the radiation dose in the MALT lymphoma subgroup (n = 53): 81% for <30 Gy and 100% for > or =30 Gy (p <0.01). For the non-MALT low-grade lymphomas such as follicular lymphoma (n = 30), the local control rate was 100% regardless of dose. For 39 Stage I MALT lymphoma patients treated with radiation alone, the distant relapse-free survival rate was 75% at 5 years and 45% at 10 years. Distant relapses were generally isolated and successfully salvaged by local therapy. The overall survival for this subgroup was 81% at 10 years, with no deaths from lymphoma. CONCLUSIONS: Dose-response data suggest that the optimal radiation dose for MALT lymphoma of the ocular adnexa is 30.6-32.4 Gy in 1.8-Gy fractions and follicular lymphoma is adequately controlled with doses in the mid-20 Gy range. The substantial risk of distant relapse in Stage I ocular adnexal MALT lymphoma underscores the importance of long-term follow-up for this disease and the need for additional comparative studies of MALT lymphoma of different anatomic sites.     

Primary thyroid lymphomas

Opinion statement Primary thyroid lymphoma is a rare disease that continues to produce diagnostic and therapeutic dilemmas. There was great difficulty in distinguishing thyroid lymphoma from anaplastic thyroid carcinoma but, because of new immunocytochemical staining techniques and increased cytopathologic knowledge, our ability to diagnose thyroid lymphoma has improved drastically over the past decade. Surgery that was once the mainstay of treatment for this disease, now plays a minimal role. Current treatment regimens for primary thyroid lymphoma consist of chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisone) and external beam radiation. The overall and distant relapse rates have been shown to be significantly lower in those patients receiving combined modality therapy compared to chemotherapy or radiation alone. Although the role of surgery has changed over time, it continues to play an important role, especially in confirming diagnoses through open biopsies, potentially providing local control in the more indolent subtypes, and may play a role in the palliation of symptoms for large obstructive lymphomas. The evolving classification of extranodal lymphomas has brought about a better understanding of the biologic behavior of these tumors. Most thyroid lymphomas are B-cell origin, with six different histologic subtypes, but there appears to be two distinct clinical and prognostic groupings of these rare tumors. The more indolent lymphomas are the subgroup of mucosa-associated lymphoid tissue (MALT) lymphomas comprising approximately 6% to 27% of thyroid lymphomas. This subgroup, when localized to the thyroid (stage IE), responds well to total thyroidectomy or radiation with a complete response rate of more than 90%, leading some authors to recommend surgery as primary therapy in the treatment of localized MALT lymphomas. Therefore, surgery as a primary treatment for thyroid lymphomas would only be recommended under ideal conditions, such as MALT subtype stage IE only, and completely resectable with minimal morbidity. Unfortunately, this scenario is rarely the case. The more common subtype, comprising up to 70% of cases, is diffuse large B-cell lymphoma. This subtype appears to have the most aggressive clinical course with almost 60% of these tumors diagnosed with disseminated disease. Up to 40% of all diffuse large cell lymphomas appear to have undergone transformation from a MALT lymphoma, but they behave in a similar fashion to diffuse large cell lymphomas. Treatment for these tumors should include chemotherapy and radiation. The overall 5-year survival for this aggressive group is less then 50%. Surgery is rarely beneficial in diffuse large cell lymphoma and the mixed large cell subtypes because the disease is generally disseminated and surgical excision of all disease is not possible or associated with increased morbidity. However, there may be a role for palliative surgical debulking to alleviate obstructive symptoms while the patient is undergoing standard chemotherapy and radiation.     

Molecular analysis of mucosa-associated lymphoid tissue (MALT) lymphoma of ocular adnexa.

Lymphomas of mucosa-associated lymphoid tissue (MALT) are a distinct subgroup of extranodal B-cell non-Hodgkin's lymphomas. Most studies have failed to demonstrate the clonal rearrangement of BCL-1, BCL-2 or c-MYC genes for MALT lymphomas. Further, alteration of the p53 gene is rarely demonstrated in low-grade MALT lymphomas, but can be detected in high-grade disease. Lymphomas of the ocular adnexa represent approximately eight percent of all extranodal lymphomas, most of which are MALT lymphomas, but few studies had explored the alterations of BCL-1, BCL-2, c-MYC and p53 genes specifically for ocular MALT lymphomas. We investigated the changes to BCL-1, BCL-2, c-MYC and p53 genes in these lymphomas for Taiwanese patients. Clonal rearrangement for immunoglobulin heavy-chain (IgH), BCL-1, BCL-2, c-MYC and p53 genes was examined for 16 cases of ocular MALT lymphoma. Restriction-length polymorphism and polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) of the DNA, corresponding to exons 5 through 9, followed by DNA sequencing, were utilized to analyze the possible mutations of the p53 gene for these tumors. Thirteen of the cases revealed rearranged IgH genes using Southern blotting or PCR. No rearrangement of BCL-1, BCL-2, c-MYC or p53 genes was discovered, with point mutation of the p53 gene in one case. As for other types of MALT lymphomas, BCL-1, BCL-2 and c-MYC genes are not implicated in the pathogenesis of the ocular sub-group. Although alteration of the p53 gene is rare for low-grade ocular MALT lymphoma, its role in disease progression merits further research.     

MALT lymphomas

Opinion statement Mucosa-associated lymphoid tissue (MALT) lymphomas occur in a variety of organs, including the orbit, conjunctiva, salivary glands, skin, thyroid gland, lungs, stomach, and intestine. These tumors are often localized and of indolent clinical behavior. Diagnosis is made by pathologic evaluation of a tissue biopsy. Careful staging is mandatory and tailored to the initial presentation. Staging includes a history and physical, chemistries, computed tomography scan, and bone marrow biopsy. This information is supplemented with an ear, nose, and throat consultation, esophagogastro-duodenoscopy, colonoscopy, endoscopic ultrasound of the stomach, and cytogenetic/immunohistochemical analysis of the tumors. Treatment is tailored to organ involvement and stage at presentation. Eradication of Helicobacter pylori using a triple anti-H. pylori regimen approved by the US Food and Drug Administration is standard therapy for all H. pyloripositive gastric MALT lymphomas. Endoscopic ultrasound- and computed tomographystaged gastric MALT stage IE tumors will achieve a complete response with this approach in approximately 60% to 90% of patients (the more superficial the tumor [T1/T2], the better the response). Patients with tumors that are T4 node-positive Musshoff stage IIE1 and IIE2 or tumors with adverse cytogenetics should receive radiotherapy or surgery with or without radiotherapy. Tumors with a significant high-grade component or large cell tumors with a minor low-grade MALT component should receive CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone)-based chemotherapy. Localized MALT lymphomas of the orbit, conjunctiva, salivary glands, and thyroid gland are treated successfully with radiotherapy. Surgery as first-line therapy for gastric MALT lymphomas was replaced by attempts at organ preservation. In the past, margin-free surgical excision or tumor debulking followed by radiation therapy and chemotherapy has been highly effective for gastric MALT lymphomas. Therefore, surgical excision of large cell or bulky tumors of the stomach, thyroid, lung, and salivary gland, followed by adjuvant radiotherapy or chemotherapy, may still be an important consideration in selected patients. Surgery still has a role for patients with relapsed or refractory lowgrade disease and life-threatening hemorrhage. Disseminated MALT lymphomas are incurable and are treated primarily with chemotherapy according to symptoms.     

Treatment of non-Hodgkin's lymphoma.

Many of the advances in the management of non-Hodgkin's lymphomas have been based on more precise understanding of the various cell types that constitute these disorders. During the past year, we have seen some dramatic changes in the therapeutic approach to low-grade lymphomas. Until recently, the usual approach to these disorders was a purely palliative one, but a number of publications from the past year describe a more intensive approach with the goal of developing a curative modality. The use of combination chemotherapy in addition to radiation therapy for the early Ann Arbor stages as well as the use of high-dose chemotherapy with bone marrow transplantation in patients with high-risk factors has been reported recently. In the area of intermediate-grade lymphomas, most of the recent publications have described prognostic factors associated with various chemotherapy protocols. One of the most interesting recent developments is related to the dose-intensity issue. A consensus appears to be developing in regard to the correlation of dose intensity with clinical outcome. Despite the fact that new third-generation regimens have been associated with cures in 50% to 66% of the patients, a significant fraction of patients require salvage chemotherapy. Some of the new salvage regimens are discussed, as is the use of calcium channel blockers to reverse multiple-drug resistance. Finally, management of the high-grade lymphomas, specifically the small noncleaved cell type, has been associated with a cure rate in the range of 50% in two recently published studies. Patients who are human immunodeficiency virus-positive with small noncleaved cell lymphoma can be cured of their underlying malignancy, but many of them later develop complications of acquired immunodeficiency syndrome, to which they usually succumb.     

Impact of the microenvironment on the pathogenesis of mucosa-associated lymphoid tissue lymphomas

Approximately 8% of all non-Hodgkin lymphomas are extranodal marginal zone B cell lymphomas of mucosa-associated lymphoid tissue (MALT), also known as MALT lymphomas. These arise at a wide range of different extranodal sites, with most cases affecting the stomach, the lung, the ocular adnexa and the thyroid. The small intestine is involved in a lower percentage of cases. Lymphoma growth in the early stages is associated with long-lasting chronic inflammation provoked by bacterial infections (e.g., Helicobacter pylori or Chlamydia psittaci infections) or autoimmune conditions (e.g., Sjögren’s syndrome or Hashimoto thyroiditis). While these inflammatory processes trigger lymphoma cell proliferation and/or survival, they also shape the microenvironment. Thus, activated immune cells are actively recruited to the lymphoma, resulting in either direct lymphoma cell stimulation via surface receptor interactions and/or indirect lymphoma cell stimulation via secretion of soluble factors like cytokines. In addition, chronic inflammatory conditions cause the acquisition of genetic alterations resulting in autonomous lymphoma cell growth. Recently, novel agents targeting the microenvironment have been developed and clinically tested in MALT lymphomas as well as other lymphoid malignancies. In this review, we aim to describe the composition of the microenvironment of MALT lymphoma, the interaction of activated immune cells with lymphoma cells and novel therapeutic approaches in MALT lymphomas using immunomodulatory and/or microenvironment-targeting agents.     

Extranodal Marginal Zone Lymphoma of Mucosa‐Associated Lymphoid Tissue of the Salivary Glands: A Multicenter,International Experience of 248 Patients (IELSG 41)

Background.

The salivary gland is one of the most common sites involved by nongastric, extranodal marginal zone lymphomas of mucosa-associated lymphoid tissue (MALT). A large series of patients with long-term follow-up has not been documented. This multicenter, international study sought to characterize the clinical characteristics, treatment, and natural history of salivary gland MALT lymphoma.

Methods.

Patients with biopsy-confirmed salivary gland MALT lymphoma were identified from multiple international sites. Risk factors, treatment, and long-term outcomes were evaluated.

Results.

A total of 247 patients were evaluated; 76% presented with limited-stage disease. There was a history of autoimmune disorder in 41%, with Sjögren disease being the most common (83%). Fifty-seven percent of patients were initially treated with local therapy with surgery, radiation, or both; 37 of patients were treated with systemic therapy initially, with 47% of those receiving rituximab; and 6% of patients were observed. The median overall survival (OS) was 18.3 years. The median progression-free survival (PFS) following primary therapy was 9.3 years. There was no difference in the outcomes between patients receiving local or systemic therapy in first-line management. On multivariate analysis, age <60 years and low to intermediate international prognostic index were associated with improved OS and PFS; Sjögren disease was associated with improved OS.

Conclusion.

Salivary gland MALT lymphoma has an excellent prognosis regardless of initial treatment, and patients with Sjögren disease have improved survival. Risks for long-term complications must be weighed when determining initial therapy.

Implications for Practice:

Patients with salivary gland extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT) have an excellent prognosis, particularly those with associated Sjögren''s disease. A wide range of available therapies may provide similar durable rates of disease control and survival. Therefore, an important goal in selection of therapy should be to minimize morbidity from treatment. When determining initial therapy for these patients, practitioners should consider the potential side effects and long-term toxicities of treatment.