Mucosa-Associated Lymphoid Tissue Lymphomas (MALTomas)

Updated: Jan 21, 2022
Author: Sara J Grethlein, MD, MBA, FACP; Chief Editor: Emmanuel C Besa, MD 

Overview

Practice Essentials

Mucosa-associated lymphoid tissue (MALT) is scattered along mucosal linings in the human body[1, 2, 3] and constitutes the most extensive component of human lymphoid tissue. These surfaces protect the body from an enormous quantity and variety of antigens. The tonsils, the Peyer patches within the small intestine, and the vermiform appendix are examples of MALT.

The nomenclature incorporates location; therefore, MALT is understood to include gut-associated lymphoid tissue (GALT), bronchial/tracheal-associated lymphoid tissue (BALT), nose-associated lymphoid tissue (NALT), and vulvovaginal-associated lymphoid tissue (VALT). Additional MALT exists within the accessory organs of the digestive tract, predominantly the parotid gland.

Chronic inflammation of MALT from infective or autoimmune disorders can lead to the development of extranodal marginal zone B-cell lymphomas, or MALTomas. The stomach is the most common location of MALTomas, while frequent nongastric sites include the following[4] :

  • Salivary glands
  • Skin
  • Orbits and conjunctiva
  • Lung
  • Thyroid
  • Upper airways
  • Breast
  • Other gastrointestinal (GI) sites
  • Liver

MALTomas at different sites may involve different genetic lesions and may possibly have different natural histories.[4]

Symptoms of MALTomas are nonspecific and are related to the organs involved. Most patients with MALTomas have no physical findings; lymphadenopathy is rare. Staging MALTomas can be challenging. Imaging studies are not helpful for visualizing normal MALT, but they may be useful in diagnosing and staging MALTomas. Endoscopy may be helpful. Bone marrow aspiration and biopsy findings can signal bone marrow involvement.

Treatment may include proton pump inhibitors (PPIs) and antibiotics for Helicobacter pylori infection, chemotherapy, radiotherapy, and, in some instances, surgical intervention.

For patient education resources, see Lymphoma.

Pathophysiology

MALT may consist of a collection of lymphoid cells, or it may include small solitary lymph nodes. Lymph nodes contain a light-staining region (germinal center) and a peripheral dark-staining region. The germinal center is key to the generation of a normal immune response. The location of MALT is key to its function. Stimulation of B cells leads to the production of immunoglobulin A (IgA) and immunoglobulin M (IgM) within the Peyer patches, preventing adherence of bacteria and viruses to the epithelium and thus blocking entry to the subepithelial layers of the intestine.[1, 2, 3, 5]

Mucosal epithelial surfaces contain M cells, specialized cells that are so named because they exhibit microfolds on their luminal surface and have a membranous appearance. The roles of the M cells include absorption, transport, processing, and presentation of antigens to subepithelial lymphoid cells.[6, 7] These subepithelial cells include CD4+ type 1 T helper cells (THCs) and immunoglobulin D (IgD)/IgM+ B cells; the latter are antigen-presenting cells (APCs) that function as memory cells interacting with type 1 THCs.

Under these M cells and in close proximity, B cells, CD4+ T cells, and APCs (including dendritic follicular cells [DFCs]) are found.[8] Together, this group of cells constitutes a “pocket” of M cells. Within this pocket, an area of follicles associated with the epithelium (follicle-associated epithelium) is observed. These follicles, having true germinal centers, are similar to the follicles of the spleen and lymph nodes.

The direct secretion of secretory IgA onto mucosal epithelia represents the major effector mechanism of MALT. Major accumulations of lymphoid tissue are found in the lamina propria of the intestine. M cells in the intestinal epithelium overlying Peyer patches allow transport of antigens to the lymphoid tissue beneath it.

DFCs activate some clones of type 1 THCs, although less potently than B cells do. Stimulation of CD28 on type 1 THCs by B7 costimulatory molecules results in the secretion of interleukin (IL)–2 and interferon gamma by type 1 THCs. Regulation of the immune response involves the suppression of type 2 THCs (involved in humoral immunity) by interferon gamma and the production of IL-10 by type 2 THCs, which inhibits type 1 THCs.

Tolerance to antigens results from the lack of a T-cell response. Often, this is attributable to failed involvement of B-cell costimulatory molecules or cytokines. Signaling requires more than just receptor stimulation.

The activity of the germinal centers in the follicle-associated epithelium is key to the immune response. The germinal center provides an area where a large number of cells important in the immune response congregate. Early on in the T-cell–dependent immune response, B cells known as founder cells concentrate in the germinal center, forming the dark zone, where rapid division of these cells occurs.[9, 10, 11, 12]

Selection of B cells for participation in the immune response occurs on the basis of their interaction with antigen-antibody complexes on the surface of DFCs. This involves a series of steps that result in expression of complexes of major histocompatibility complex II (MHC II) and peptides resulting from processed antigens. This begins a process of somatic hypermutation in the dark zone, which is followed by immunoglobulin class-switching and generation of memory cells and plasma cell precursors in the apical light zone of the germinal center.

The complex interplay among antigens, cells, and cytokines results in a very efficient immune response. The efficiency of MALT depends on adequate IgA function, which, in turn, depends on production and acquisition of a joining (J) chain. This chain, a glycoprotein produced by plasma cells, is important in the formation of IgA dimers and IgM pentamers and is key in permitting secretory IgA and IgM to function as the first line of defense in mucosal epithelium. In children with recurrent tonsillitis, B cells in tonsillar crypts do not produce the J chain.

Individuals with selective IgA deficiency are prone to infections along mucosal surfaces in the respiratory, gastrointestinal (GI), and genitourinary (GU) tracts. The capability of the mucosal barrier is weakened, and a second line of defense is activated. This consists of the participation and recruitment of large numbers of immune-competent cells, resulting in the onset of an inflammatory process that eradicates the antigen and restores functionality to the mucosa. If this process is constant and intense, it may result in a chronic inflammatory process.[13]

Malignancies that occur in MALT are called MALT lymphomas or MALTomas. MALTomas are extranodal manifestations of marginal-zone lymphomas. Most MALTomas are low-grade lesions, though a minority either manifest initially as intermediate-grade non-Hodgkin lymphoma (NHL) or evolve from the low-grade form. Most MALTomas occur in the stomach and in more than 90% of cases, MALT lymphoma is associated with H pylori infection.[14]

Several cytogenetic abnormalities have been identified, the most common being trisomy 3 or t(11;18). Other common chromosomal translocations identified in MALTomas are t(1;14)(p22;q32), t(14;18)(q32;q21), and t(3;14)(p14.1;q32).[15] The specific gene abnormalities responsible for the pathogenesis of MALTomas have not yet been identified. Mutations commonly identified in NHLs are not commonly present in MALTomas, though mutations in both BCL2 and TP53 have been reported.[16] The following are genes in which mutations are most frequently found in MALTomas[15] : 

  • TNFAIP3
  • CREBBP
  • KMT2C
  • TET2
  • SPEN
  • KMT2D
  • LRP1B
  • PRDM1
  • EP300
  • TNFRSF14
  • NOTCH1/NOTCH2
  • B2M

Etiology

Although the cause of MALTomas and most other tumors is still unknown, accumulated evidence indicates a strong association between autoimmune diseases and MALTomas. Continued massive antigen stimulation is postulated to represent a critical step in the development and progression of MALTomas.

MALTomas of the salivary glands are often associated with Sjögren syndrome.[17] MALTomas of the thyroid are associated with Hashimoto thyroiditis. Crohn disease or celiac disease may be involved in the genesis of intestinal MALTomas.

In contrast to the weaker etiologic associations, a clear causal association between H pylori infection and gastric MALTomas has been definitively established. H pylori gastritis is common in individuals who develop gastric lymphomas.

Epidemiology

Non-Hodgkin lymphomas (NHLs) account for 2-3% of all malignancies, and MALTomas account for approximately 7-8% of NHLs diagnosed annually.[18] NHL represents only 4% of non–skin cancer malignancies. Although extensive studies have not been performed, no particular ethnic group or geographic area shows a strong predilection for MALTomas.

The peak incidence of MALTomas is during the seventh and eighth decades of life. However, MALTomas have been noted in children, adolescents, and young adults. No sex-related differences in MALT distribution are known, but males usually have a more extensive distribution of lymphoid tissue; some studies suggest that MALTomas are slightly more common in females than in males. No significant racial differences are known; some studies suggest that MALTomas are slightly more common in whites than in blacks.

Prognosis

Morbidity and mortality occur when neoplastic transformation into a MALToma develops. Most MALTomas are responsive to available treatment modalities, including radiation and chemotherapy. In addition, H pylori–associated tumors may respond to antibiotics.[19]

The prognosis depends on the grade of the tumor, with long-term survival possible for patients with low-grade tumors. However, achieving a cure is more difficult in patients with MALTomas in advanced stages.

Generally, low-grade MALTomas are indolent neoplasms with a fairly good prognosis. Although the intermediate-grade, diffuse, large B-cell MALTomas are more aggressive malignancies, the cure rate may be as high as 90% for stage IE disease and is approximately 30-40% for extensive stage IIIE or IVE disease. These outcomes are similar to those of non-MALT intermediate-grade NHLs.

Gastric MALTomas have a stage-dependent prognosis. The survival rate for stage IE disease is 93% at 5 years and 58% at 10 years.[20] Long-term responses to anti–H pylori treatment alone have been reported; MALTomas that are not eradicated by treatment of H pylori infection are incurable but are associated with a prolonged course. A retrospective study from China suggested that the t(11;18)(q21;q21) translocation may be an important prognostic factor for patients with gastric MALTomas.[21]

The most common morbidities associated with GI MALTomas include abdominal pain, GI bleeding, and GI obstruction. Gastric or intestinal perforation is rare.

Nongastrointestinal MALTomas are most common in the head and neck, ocular adnexa, and lungs. Several small studies have reported that observation alone may be appropriate in selected patients with ocular adnexal MALToma.

Use of the International Prognostic Index—which takes into account age, Ann Arbor stage, lactate dehydrogenase (LDH) level, the number of extranodal sites, and performance status—has better characterized low-, intermediate-, and high-risk groups. The 5-year survival rates for those groups are as follows:

  • Low risk – 99%
  • Intermediate risk – 85-88%
  • High risk – 72%

Patients with early-stage MALToma may be curable with chemotherapy. The risks and benefits of surgical or radiation therapy for MALTomas should be considered before the decision is made to proceed with such treatment.

 

Presentation

History and Physical Examination

The median age of onset for mucosa-associated lymphoid tissue (MALT) lymphomas (MALTomas) is 65 years. According to some epidemiologic studies, MALTomas are slightly more common in females than in males and are more common in whites than in blacks.

Most patients with MALTomas have no physical findings; lymphadenopathy is rare. When symptoms of MALTomas are present, they are nonspecific and are related to the organs involved. Gastric MALToma symptoms may mimic those of peptic ulcer disease or gastritis. Nonspecific signs and symptoms that may occur in patients with gastric MALTomas include the following:

  • Chronic fatigue
  • Low-grade fevers
  • Nausea
  • Constipation
  • Tarry stools
  • Epigastric pain
  • Weight loss
  • Shortness of breath

Recurrent respiratory infections may be observed in some patients, especially in patients with pulmonary MALTomas. Patients with conjunctival MALTomas may present with blurry vision or visual-field defects. Patients with MALTomas often have a history of an associated autoimmune disease.

 

DDx

Diagnostic Considerations

Failure to diagnose cancer is one of the most frequent reasons for medical malpractice actions. Accordingly, any suggestive symptoms should be thoroughly investigated. In the setting of a known cancer, failure to diagnose the correct subtype of lymphoma and subsequent use of treatment for a different type of lymphoma or other malignancy that is not optimal therapy for mucosa-associated lymphoid tissue (MALT) lymphoma (MALToma) is a medicolegal hazard.

In addition to the conditions listed in the differential diagnosis, other problems to be considered include the following:

  • Extranodal lymphoma
  • Gastric lymphoma
  • Low-grade non-Hodgkin lymphoma (NHL)

Differential Diagnoses

 

Workup

Approach Considerations

Staging mucosa-associated lymphoid tissue (MALT) lymphomas (MALTomas) can be a challenge (see Staging). Imaging studies (eg, barium contrast studies, computed tomography [CT], magnetic resonance imaging [MRI], and positron-emission tomography [PET]) are not helpful for visualizing normal MALT, but they may be useful in diagnosing and staging MALTomas.

Endoscopy may be helpful. Bone marrow aspiration and biopsy findings can signal bone marrow involvement. Histologically, MALT is characterized by large amounts of immune-competent cells in the lamina propria of the mucosal layer of many organs.

Laboratory Studies

A complete blood count (CBC) and blood chemistries may provide important information about the tissues and organs affected by MALTomas.

Immunologic phenotyping of circulating lymphocytes, bone marrow lymphocytes, or biopsy specimens of MALTomas can be determined by flow cytometric analysis. MALTomas have an immunophenotype resembling that of marginal-zone lymphomas.

Although MALTomas are almost always negative for CD10, CD5, and CD23, they do express CD20. They also express surface immunoglobulin that is restricted to a single type of light chain (kappa or lambda) and, often, both CD21 and CD35. Low-grade MALTomas are usually positive for BCL2, whereas intermediate-grade MALTomas are usually negative for BCL2.

Cytogenetic studies may show chromosomal abnormalities in the malignant cells of MALTomas. The most common abnormalities detected are trisomy 3, t(11;18), and, less frequently, t(1;4).

Barium Contrast, CT, MRI, and PET

Barium contrast studies of the upper gastrointestinal (GI) tract, small bowel, or colon may demonstrate the presence of masses or infiltration of the bowel wall in MALT. However, the results from these studies are often nonspecific and may be insensitive.

CT and MRI findings may help document the extent of the primary lesion and possible distant disease, but they cannot help differentiate malignant from benign lesions in MALT.

PET-CT is becoming more widely accepted as useful in the management of MALTomas. Gastric disease is less likely to be detected by this imaging modality. In one case series, PET-CT identified only 42% of cases of early MALT but yielded positive results in 100% of stage III-IV patients.[22]

Other Studies

Endoscopy may reveal mucosal rigidity and hyperplasia in patients with MALTomas. The diagnosis requires a biopsy. Endoscopic ultrasonography can be performed for GI tract lesions, but its applicability is limited. H pylori infection can also be detected in samples obtained via endoscopy.

Bone marrow aspiration and biopsy findings can show evidence of bone marrow involvement by the MALToma.

Histologic Findings

MALT is characterized by large amounts of immune-competent cells in the lamina propria of the mucosal layer of many organs.

Intercalated among the mucosal epithelial cells are the M cells, which have a membranous appearance and several external microfolds. Lymphoid tissue occupying the lamina propria of GI, genitourinary (GU), and respiratory mucosae contains an outer, dense-staining region that contains small T cells (dark zone) and a lighter-staining region that contains large cells (B cells and plasma cells).

Together, these areas constitute the germinal center, consisting of a mesh of dendritic follicular cells (DFCs) that support rapidly dividing B cells. The mantle zone surrounds the germinal center and contains small resting B cells. Germinal centers also contain CD4+ T cells and macrophages.

In the ileum, the lamina propria may contain hundreds of aggregated nodules that form Peyer patches. In the tonsils, epithelium is distributed over lymphoid tissue. Small indentations in the tonsillar tissue form tonsillar crypts. Lymphoid tissue in the tonsils is dense and more nodular. Mucosal glands may be scattered among the surface epithelium of tonsillar tissue. Stratified squamous epithelium is seen in palatine and lingual tonsils; pseudostratified and ciliated columnar epithelia are seen in the pharyngeal and tubaric tonsils, respectively.

MALTomas are B-cell lymphomas composed of small- to medium-sized lymphocytes that have irregular nuclear contours and abundant cytoplasm. Intermediate-grade MALTomas are distinguished from low-grade MALTomas by the presence of clusters or sheets of transformed blastlike cells, with or without a background of low-grade MALToma. If no background of low-grade MALToma is present, the intermediate-grade form is morphologically indistinguishable from diffuse large B-cell lymphoma.

The unifying characteristic is a diffuse infiltrate that invades epithelial structures and disrupts epithelium, causing a lymphoepithelial lesion. Reactive lymphoid follicles are present and become infiltrated and colonized by neoplastic lymphocytes. Thus, most MALTomas are low-grade B-cell lymphomas that express CD19 and CD20 and monotypic surface immunoglobulin (usually immunoglobulin M [IgM] without immunoglobulin D [IgD]). The CD23 marker (negative in almost all MALTomas) helps distinguish MALTomas from mantle cell lymphomas.

Limited reports describe chromosomal anomalies that may have significant prognostic significance. The presence of trisomy 3 may indicate a low likelihood of response to anti–H pylori antibiotic therapy. The translocation t(11;18)(q21;q21) results in the API2-MALT1 fusion transcript, but it does not appear to have a negative prognostic impact.[#Staging]

Staging

The staging of MALTomas uses the same definitions as the staging of other non-Hodgkin lymphomas (NHLs); MALTomas are, by definition, extranodal in origin.

  • Stage IE – Lymphoma is present in only 1 area or organ outside the lymph nodes
  • Stage IIE – Lymphoma is present in only 1 area or organ outside the lymph nodes and in the lymph nodes around it; other lymph nodes on the same side of the diaphragm may also be involved
  • Stage IIIE – Lymphoma is present on both sides of the diaphragm; it may also have spread to an area or organ near the lymph nodes or the spleen
  • Stage IV – Lymphoma is widespread to several organs, with or without lymph node involvement

The International Extranodal Lymphoma Study Group (IELSG) has published a simplified MALT prognostic index (MALT-IPI)1 that was constructed using three individual features with the greatest prognostic significance for event-free survival (EFS)[23] :

  • Age ≥70 years
  • Ann Arbor stage III or IV
  • Elevated lactate dehydrogenase level

The MALT-IPI identifies 3 groups based on the presence of those features:

  • Low risk (0 factors present)
  • Intermediate risk (1 factor present)
  • High risk (2 or 3 factors present)

The 5-year EFS rates in the low-, intermediate-, and high-risk groups were found to be 70%, 56%, and 29%, respectively. The MALT-lymphoma International Prognostic Index (MALT-IPI) also significantly discriminated patients with different progression-free, overall, and cause-specific survival, and the prognostic utility was retained in gastric and nongastric lymphomas.[23, 24]

 

Treatment

Approach Considerations

Mucosa-associated lymphoid tissue (MALT) lymphomas (MALTomas) are classified as extranodal marginal-zone lymphomas of MALT type.[19] Management differs, depending on whether the MALToma is gastric or nongastric.

Gastric MALTomas are the most common and well-studied MALTomas. These neoplasms are intimately associated with Helicobacter pylori, which is present in more than 90% of pathologic specimens of MALTomas.[14] Generally, in terms of outcome and quality of life, conservative treatment is preferable to surgical therapy or radiotherapy in patients with these lesions.[25]

Nongastric MALTomas most commonly occur in the head and neck,[26, 27, 28] lung,[29] and orbit.[22, 30] These nongastric  MALTomas are not associated with H pylori and are treated by means of standard modalities, including radiation therapy, chemotherapy, and administration of monoclonal antibodies. In general, patients with stage IE-II disease can be treated with locoregional radiation therapy or surgery.

Patients whose condition subsequently recurs, as well as those with stage III/IV disease at presentation, are treated with regimens typically used for follicular lymphoma (eg, rituximab, CVP [chlorambucil, vincristine, prednisone], fludarabine, and FND [fludarabine, mitoxantrone, dexamethasone]).

However, patients who have nongastric MALToma that has transformed to large B-cell lymphoma should be treated with regimens that are appropriate for the latter disease (eg, R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone]).

A study that followed patients with gastric MALTomas who were treated with anti–H pylori antibiotic therapy found an excellent remission rate for the gastric MALTomas but an increased risk of developing gastric cancer later. In addition, this population had an increased risk of developing non-Hodgkin lymphoma.[31] A study by Gong et al suggests that H pylori eradication therapy may be worthwhile as an initial treatment for gastric MALTomas even in patients who test negative for H pylori, regardless of stage.[32, 33]

Inappropriately aggressive surgical, radiation, or medical therapy that results in serious injury or long-term disability is a potentially serious medicolegal hazard in the management of MALTomas.

Pharmacologic Therapy

Proton pump inhibitors and antibiotics

Treatment with a proton pump inhibitor (PPI) and antibiotics to eradicate H pylori is the most important modality used in the therapy of gastric MALTomas. Triple therapy with a combination of amoxicillin, clarithromycin, and a PPI results in eradication rates of 70-85%; for penicillin-allergic patients, an alternative regimen of metronidazole, clarithromycin, and PPIs achieves the same result. This approach results in regression in more than 75% of cases of low-grade MALToma[34] and a minority of cases of intermediate-grade MALToma.

The presence of t(11;18)(q21;q21) translocations has been shown to predict a poor response to therapy. In cases in which no initial response to anti–H pylori therapy is observed, an alternative regimen is recommended for use during the second course of treatment.

Treatment with chemotherapy, surgery, or radiotherapy (alone or in combination) has not been demonstrated to be superior to antibiotic treatment. Because of this, a conservative approach, with oncologic and endoscopic follow-up, is advisable.

Because most gastric MALTomas are low-grade lesions, they may remain localized and may not progress for several years. Locally advanced disease that has infiltrated the muscularis mucosa, serosa, or perigastric lymph nodes has a significantly lower response rate.

Patients who are stage IE-II disease who are H pylori–negative typically receive radiation therapy or rituximab.

Chemotherapy

Chemotherapy for MALTomas has not been studied extensively, but historically, the usual treatment has been the chemotherapy used for low-grade non-Hodgkin lymphoma (NHL).

The traditional monotherapy regimens employed for MALTomas have included chlorambucil, cyclophosphamide, or fludarabine. In addition, standard combination regimens such as CHOP have been used successfully. Conjunctival MALTomas have been treated with interferon alfa-2a. Gastrointestinal MALTomas are first treated with an antibiotic regimen designed to eradicate H pylori.

It is widely recommended that chemotherapy should be used in cases where antibiotic regimens fail, though this practice has not been extensively studied. The treating physician’s clinical judgment is crucial in this circumstance; he or she should choose secondary regimens that work against other NHLs.

The single agents chlorambucil and cyclophosphamide have been reported to achieve remissions in three quarters of patients with low-grade gastric MALTomas. The anti-CD20 monoclonal antibody rituximab has been reported to achieve remissions in patients with gastric MALTomas who either were not responsive to anti–H pylori therapy or were not infected with H pylori.

Amiot et al conducted a single-center retrospective study to evaluate effectiveness of gastric MALToma treatment in 106 H pylori–negative patients. Outcomes of oral alkylating monotherapy, rituximab monotherapy, and combination therapy with both drugs were compared. At 2-year followup, both complete remission and overall response were significantly better in patients who received combination therapy (92% and 100% respectively) than in those treated with alkylating agents alone (66% and 68%) or rituximab alone (64% and 73%). However fewer adverse effects were reported with rituximab alone than with either regimen containing alkylating agents.[35]

In a randomized controlled trial by Zucca et al, complete remission at 5-year followup was better in patients treated with chlorambucil plus rituximab than in those treated with chlorambucil alone (78% vs 65%, respectively) but overall response rates were similar (90% vs 87%). However, the differences in remission rates did not translate into improved survival; both groups had an overall survival rate of 89%.[36]

The large-cell, intermediate-grade forms of MALToma require standard chemotherapy similar to that used for other intermediate-grade NHLs (eg, diffuse large B-cell lymphoma).

Radiation Therapy

The efficacy of radiation therapy for gastric MALTomas has been demonstrated in several small trials. Patients with gastric MALToma who will receive the maximal benefit from radiation therapy are those whose disease is in a limited area that could be incorporated in a single radiation treatment field and in whom antibiotic treatment has failed.[37]

Treatment with radiation therapy has achieved long-term remissions (lasting for 8 years or longer in one series) in selected patients with gastric MALToma. The optimal radiation dose, the patient characteristics determining candidacy for radiotherapy, and the role of radiation in the treatment armamentarium for gastric MALToma are not well delineated, but the dose generally recommended is in the range of 30-36 Gy.

Secondary malignancies may occur in a small fraction of patients with gastric MALToma who undergo radiotherapy. Caution is warranted in patients with tumor infiltration into the serosa; successful treatment may lead to gastric perforation, necessitating immediate surgical intervention.

Radiotherapy may be very effective for orbital soft-tissue MALTomas.

Gastrectomy, Debulking, and Excisional Biopsy

Surgery has an important, albeit limited, role in the treatment of gastric MALTomas. The morbidity associated with a partial or total gastrectomy is considerable, and in most cases, neither operation is necessary. The efficacy of antibiotics, chemotherapy, and monoclonal antibody therapy has dramatically reduced the need for these procedures. Similarly, debulking is only rarely performed.

Surgery management of nongastrointestinal MALToma predominantly involves excisional biopsy of the lungs or orbital soft tissue. The presence of microscopic disease in other sites and the efficacy of other treatment modalities have made surgical therapy an adjunctive rather than a curative component of treatment.

Long-Term Monitoring

Patients with MALTomas should continue to receive serial examinations at increasing frequencies for several years after the successful completion of therapy. A gastroenterologist is an integral member of the treatment team for follow-up of the results of therapy for gastric MALTomas. No special diet is required for patients with MALTomas.

 

Guidelines

Guidelines Summary

Gastric MALT Lymphoma

National Comprehensive Cancer Network (NCCN) guidelines recommend the following studies to establish a diagnosis of gastric MALT lymphoma[18] :

  • Endoscopic biopsy; fine needle aspiration (FNA) is never acceptable
  • Immunohistochemistry panel: CD20, CD3, CD5, CD10, BCL2, kappa/lamda, CD21 or CD23, cyclin D1, BCL6
  • Cell surface marker analysis by flow cytometry: kappa/lambda, CD19, CD20, CD5, CD23, CD10
  • Helicobacter pylori stain; if positive, then polymerase chain reaction (PCR) or fluorescence in situ hybridization (FISH) for  t(11;18)

The following studies may be useful in select circumstances:

  • Molecular analysis for detection of antigen receptor gene rearrangements or if plasmacytic differentiation is present, MYD88 mutation status 
  • FISH or cytogenetics for detection of  t(1;14),  t(3;14),  t(11;14),  t(11;18)
  • FISH or PCR:  t(14;18)

The European Society for Medical Oncology (ESMO) recommends serology, urea breath test, and/or stool antigen test for H pylori in cases where immunohistochemistry findings are negative.[38]

The NCCN guidelines recommend antibiotic therapy for stages I and II in H pylori–positive patients, followed by endoscopy/biopsy for restaging at 3 months or sooner if symptomatic. Further treatments include second-line antibiotics, if H pylori testing remains positive, and involved-site radiation therapy (ISRT) if lymphoma positive. Patients who are t(11;18) positive can be treated with rituximab if ISRT is contraindicated. For patients who are H pylori negative, ISRT is the preferred treatment. Rituximab is the alternative if ISRT is contraindicated.[18]

Patients with advanced stage disease should be observed unless they have one of the following indications for treatment[18] :

  • Candidate for a clinical trial
  • Symptoms
  • GI bleeding
  • Threatened end-organ function
  • Bulky disease
  • Steady or rapid progression
  • Patient preference

For first-line therapy, the NCCN prefers the following regimens[18] :

  • Bendamustine + rituximab 
  • RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone)
  • RCVP (rituximab, cyclophosphamide, vincristine, prednisone)
  • Rituximab
  • Ibritumomab tiuxetan (category 2B)
  • Lenalidomide + rituximab (category 2B)

The ESMO guidelines are in general agreement with NCCN for the treatment of gastic MALT lymphoma.[38]

Nongastric MALT Lymphoma

The NCCN guidelines recommend the following studies to establish a diagnosis of nongastric MALT lymphoma[18] :

  • Immunohistochemistry panel: CD20, CD3, CD5, CD10, BCL2, kappa/lamda, CD21 or CD23, cyclin D1
  • Cell surface marker analysis by flow cytometry: kappa/lambda, CD19, CD20, CD5, CD23, CD10

The following studies may be useful in select circumstances:

  • Molecular analysis for detection of antigen receptor gene rearrangements or if plasmacytic differentiation is present,  MYD88 mutation status 
  • FISH or cytogenetics for detection of  t(3;14),  t(11;14),  t(11;18)
  • FISH or PCR:  t(14;18)

For stage I and II, the preferred treatment is ISRT. Surgery may be considered for certain sites (ie, thyroid, colon/small bowel and lumpectomy for breast). Rituximab and observation are options in select cases.[18]

For advanced stages, the treatment options are ISRT, observation in select cases or first-line therapy regimens as listed above for gastric MALT lymphoma.[18]

 

 

Medication

Medication Summary

In patients who have Helicobacter pylori infection in association with a mucosa-associated lymphoid tissue (MALT) lymphoma (MALToma), especially if it is a gastric MALToma, the first line of therapy is treatment of the H pylori infection. In asymptomatic patients with low-grade MALTomas who are not infected with H pylori or whose MALToma does not respond to H pylori treatment, options include observation as opposed to active intervention.

If treatment is required, treatments similar to those used for other low-grade non-Hodgkin lymphomas (NHLs) are used. Monotherapy with agents such as chlorambucil, cyclophosphamide, fludarabine, or rituximab may be employed. Combinations of chemotherapy agents, with or without rituximab, may also be used. Patients with large-cell MALTomas are treated with combination chemotherapy (usually CHOP [cyclophosphamide, doxorubicin, vincristine, prednisone]), with or without rituximab.

Antineoplastics

Class Summary

Antineoplastics interrupt proliferative activity and induce programmed cell death in proliferating B cells of MALTomas.

Cyclophosphamide

Cyclophosphamide is transformed primarily in the liver to active alkylating metabolites. These metabolites interfere with the growth of susceptible rapidly proliferating malignant cells. The mechanism of action is thought to involve cross-linking of tumor cell DNA.

Doxorubicin (Adriamycin)

Doxorubicin results in a conformational change of DNA and interferes with RNA polymerase, causing inhibition of protein synthesis.

Vincristine (Vincasar)

Vincristine is a vinca alkaloid extracted from the plant Catharanthus rosea. It is cell cycle specific (M phase). The mitotic apparatus is arrested in metaphase via disruption of the microtubules. Absorption of vincristine through the GI tract is variable; therefore, administer the drug intravenously. It is metabolized extensively in the liver and excreted primarily via bile. Neurotoxicity is the limiting factor during therapy. Peripheral neuropathy is vincristine's most common adverse effect at usual doses.

Corticosteroids

Class Summary

Corticosteroids have anti-inflammatory properties and cause profound and varied metabolic effects. These agents modify the body's immune response to diverse stimuli.

Prednisone

Prednisone is metabolized by the liver to the active metabolite prednisolone. This binds extensively to albumin and transcortin. The unbound portion crosses cell membranes and binds to specific cytoplasmic receptors, inducing a response by modifying transcription and, ultimately, protein synthesis. Prednisolone is further metabolized to inactive compounds. It is used as a component of the CHOP combination chemotherapy regimen.

Antineoplastic Agents

Class Summary

These agents inhibit cell growth and proliferation. Some agents may also suppress immune cells involved in MALTomas.

Fludarabine (Fludara)

Fludarabine is a nucleotide analogue of vidarabine that is converted to 2-fluoro-ara-A, which enters the cell and is phosphorylated to form the active metabolite 2-fluoro-ara-ATP, which inhibits DNA synthesis.

Etoposide (Toposar)

Etoposide inhibits topoisomerase II and causes DNA strand breakage, causing cell proliferation to arrest in the late S or early G2 portion of the cell cycle.

Mitoxantrone

Mitoxantrone inhibits cell proliferation by intercalating DNA and inhibiting topoisomerase II.

Bleomycin

Bleomycin is a glycopeptide antibiotic that inhibits DNA synthesis. It is used for palliative purposes in the management of several neoplasms.

Chlorambucil (Leukeran)

Chlorambucil alkylates and cross-links strands of DNA, inhibiting DNA replication and RNA transcription.

Monoclonal Antibodies

Class Summary

Monoclonal antibodies are genetically engineered chimeric murine-human immunoglobulins directed against proteins involved in cell cycle initiation.

Rituximab (Rituxan)

Rituximab is a genetically engineered chimeric murine-human monoclonal antibody that is directed against the CD20 antigen found on the surface of normal and malignant B cells. The antibody is an immunoglobulin G1 (IgG1)-kappa containing murine light- and heavy-chain variable region sequences and human constant region sequences.

Antibiotics

Class Summary

Antibiotics are the mainstay of therapy aimed at eradicating H pylori, the major etiologic agent of gastric MALToma.

Clarithromycin (Biaxin, Biaxin XL)

Clarithromycin inhibits bacterial growth, possibly by blocking the dissociation of peptidyl transfer RNA (tRNA) from ribosomes, causing RNA-dependent protein synthesis to arrest.

Metronidazole (Flagyl)

Metronidazole is an imidazole ring-based antibiotic that is active against various anaerobic bacteria and protozoa. It is used in combination with other antimicrobial agents (except for Clostridium difficile enterocolitis).

Amoxicillin (Moxatag)

Amoxicillin is an acid-stable semisynthetic penicillin. Its antimicrobial activity is pH-dependent, with the minimal inhibitory concentration (MIC) decreasing as the pH increases.

Proton Pump Inhibitors

Class Summary

Proton pump inhibitors (PPIs) are used in combination with antibiotics for eradication of H pylori.

Omeprazole (Prilosec)

Omeprazole decreases gastric acid secretion by inhibiting the parietal cell proton pump (hydrogen/potassium adenosine triphosphatase [H+/K+ ATPase]).

Lansoprazole (Prevacid)

Lansoprazole suppresses gastric acid secretion by specific inhibition of the H+/K+-adenosine triphosphatase (ATPase) enzyme system (ie, proton pump) at the secretory surface of the gastric parietal cell. The drug blocks the final step of acid production, inhibiting basal and stimulated gastric acid secretion and therefore increasing gastric pH. Lansoprazole's effect is dose related. The drug is easy to administer to children because it is available as a capsule or an oral disintegrating tablet or in granular form for use in an oral suspension.

Esomeprazole (Nexium)

Esomeprazole is an (S)-isomer of omeprazole. It inhibits gastric acid secretion by inhibiting the H+/K+-ATPase enzyme system at the secretory surface of the gastric parietal cells.

Dexlansoprazole (Dexilant)

Dexlansoprazole suppresses gastric acid secretion by specifically inhibiting the H+/K+-ATPase enzyme system at the secretory surface of gastric parietal cells.

Rabeprazole sodium (AcipHex)

Rabeprazole sodium suppresses gastric acid secretion by specifically inhibiting the H+/K+-ATPase enzyme system at the secretory surface of gastric parietal cells.

Pantoprazole (Protonix)

Pantoprazole suppresses gastric acid secretion by specifically inhibiting the H+/K+-ATPase enzyme system at the secretory surface of gastric parietal cells.