eMedicine - Mucosa-Associated Lymphoid Tissue : Article by Sara Grethlein, MD

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Mucosa-Associated Lymphoid Tissue

Last Updated: May 17, 2006

Synonyms and related keywords: lymphoid tissue, lymph node, mucus membrane, mucus, mucosal tissue, tonsils, Peyer patches, Peyer's patches, vermiform appendix, non-Hodgkin lymphoma, non-Hodgkin's lymphoma, NHL, lymphoma, malignancy, malignancies, cancer, Hashimoto thyroiditis, Hashimoto's thyroiditis, Crohn disease, Crohn's disease, celiac disease, Sjögren syndrome, Helicobacter pylori, H pylori, MALT, gut-associated lymphoid tissue, GALT, bronchial/tracheal-associated lymphoid tissue, BALT, nose-associated lymphoid tissue, NALT, vulvovaginal-associated lymphoid tissue, VALT, MALToma, MALT lymphoma, gastric MALT lymphoma, nongastric MALT lymphoma, gastric MALToma, nongastric MALToma, human mucosa

AUTHOR INFORMATION Section 1 of 10

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Author: Sara Grethlein, MD, Associate Dean for Graduate Medical Education, Associate Professor, Department of Internal Medicine, Division of Hematology and Oncology, State University of New York at Upstate
Coauthor(s): Jose A Perez, Jr, MD, MSEd, Director of Medical Education, Residency Program Director, Associate Professor, Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, Kern Medical Center

Sara Grethlein, MD, is a member of the following medical societies: American Society of Clinical Oncology, and American Society of Hematology

Editor(s): Karen Seiter, MD, Professor, Department of Internal Medicine, Division of Oncology/Hematology, New York Medical College; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Troy H Guthrie, Jr, MD, Director of Cancer Institute, Baptist Medical Center; Rajalaxmi McKenna, MD, FACP, Consulting Staff, Department of Medicine, Southwest Medical Consultants, SC, Good Samaritan Hospital, Advocate Health Systems; and Emmanuel C Besa, MD, Professor, Department of Medicine, Division of Hematologic Malignancies, Thomas Jefferson University, Jefferson Medical College

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INTRODUCTION

Section 2 of 10

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Background: A significant quantity of lymphoid tissue is associated with human mucosa. Mucosa-associated lymphoid tissue (MALT) is scattered along mucosal linings, measuring roughly 400 m². These surfaces protect the body from an enormous quantity and variety of antigens. The tonsils, Peyer patches within the small intestine, and the vermiform appendix are examples of MALT. The nomenclature incorporates location; therefore, MALT includes 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.

MALT may consist of a collection of lymphoid cells or 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 lymphocytes 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, thus blocking entry to the subepithelial layers of the intestine.

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

Under these M cells and in close proximity, B lymphocytes, CD4⁺ T lymphocytes, and APCs are found, of which dendritic follicular cells (DFCs) are one type. This group of cells together 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.

Another APC is the DFC, which activates some clones of type 1 THCs, although less potently than B lymphocytes. Stimulation of CD28 on type 1 THCs by B7 co-stimulatory molecules results in the secretion of interleukin 2 and gamma-interferon by type 1 THCs. Regulation of the immune response involves the suppression of type 2 THCs (involved in humoral immunity) by gamma-interferon and production of interleukin 10 by type 2 THCs, which inhibits type 1 THCs. Tolerance to antigens results from the lack of a T-lymphocyte response. Often, this is due to failed involvement of B-lymphocyte co-stimulatory 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 lymphocytes known as founder cells concentrate in the germinal center, forming the dark zone, where rapid division of these cells occurs.

Selection of B lymphocytes for participation in the immune response occurs based on their interaction with antigen-antibody complexes on the surface of DFCs. This involves a series of steps resulting in expression of complexes of major histocompatibility complex II and peptides resulting from processed antigens. This then begins a process of somatic hypermutation in the dark zone and, later, 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 also depends on the adequate function of IgA. Individuals with selective IgA deficiency are prone to infections along mucosal surfaces in the respiratory, gastrointestinal, and genitourinary tracts. Adequate function of IgA depends on the production and acquisition of a joining (J) chain. This glycoprotein is produced by plasma cells and is important in the formation of IgA dimers and IgM pentamers. It has been shown that in children who have recurrent tonsillitis, B lymphocytes in tonsillar crypts do not produce the J chain. The J chain is key in permitting secretory IgA and IgM to function as the first line of defense in mucosal epithelium.

Pathophysiology: In selective IgA deficiency, 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.

Malignancies that occur in MALT are called MALT lymphomas or MALTomas. MALTomas are extranodal manifestations of marginal-zone lymphomas. Most MALTomas are of low grade, although a minority either manifest initially as intermediate-grade non-Hodgkin lymphoma (NHL) or evolve from the low-grade form. Most of the MALTomas occur in the stomach, and roughly 70% of gastric MALTomas are associated with Helicobacter pylori infection. Several cytogenetic abnormalities have been identified, the most common being trisomy 3 or 11:18 translocation. 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, although both BCL2 and TP53 have been reported.

Frequency:

In the US: MALTomas account for approximately 5% of NHLs diagnosed annually. NHL represents only 4% of non–skin cancer malignancies.

Internationally: NHL accounts for 2-3% of all malignancies, and MALTomas comprise approximately 5% of all NHLs. Although extensive studies have not been performed, no particular ethnic group or geographic area shows a strong predilection for MALTomas.

Mortality/Morbidity:

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.

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

Race: No significant racial differences of MALT distribution are known; however, some epidemiologic studies indicate a slight increase in MALTomas in whites over African Americans.

Sex: Although no sex differences are known regarding MALT distribution, males usually have a more extensive distribution of lymphoid tissue. However, according to some epidemiologic studies, MALTomas are slightly more common in females than in males.

Age: 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.

CLINICAL

Section 3 of 10

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History: The median age of onset of 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 African Americans.

Symptoms of MALTomas are nonspecific and are related to the organs involved.

Gastric MALToma symptoms may mimic peptic ulcer or gastritis.

Chronic fatigue, low-grade fevers, nausea, constipation, tarry stool, epigastric pain, weight loss, anemia, and shortness of breath are some of the more nonspecific symptoms that may occur in patients with gastric MALTomas.

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.

Physical: Most patients with MALTomas have no physical findings; lymphadenopathy is rare.

Causes: Although the cause of MALTomas and most other tumors is still unknown, accumulated evidence indicates a strong association between autoimmune diseases and MALTomas. A clear causal association exists between H pylori infection and gastric 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.

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 weaker etiologic associations, infection with H pylori has been definitively established as a cause of MALTomas. H pylori gastritis is common in individuals who develop gastric lymphomas.

DIFFERENTIALS

Section 4 of 10

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Helicobacter Pylori Infection
Lymphoma, B-Cell
Lymphoma, Diffuse Large Cell
Lymphoma, Non-Hodgkin

Other Problems to be Considered:

Extranodal lymphoma
Gastric lymphoma
Low-grade NHL

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WORKUP

Section 5 of 10

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Lab Studies:

Complete blood cell counts 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 that is similar to marginal-zone lymphomas.

MALTomas are almost always negative for CD10, CD5, and CD23, but they do express CD20. They also express surface immunoglobulin that is restricted to one 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, translocation 11;18, and, less frequently, translocation 1;4.

Imaging Studies:

Staging MALTomas can be a challenge. Imaging studies are not helpful for visualizing normal MALT, but they may be useful in diagnosing and staging MALTomas.

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

CT scan 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.

Procedures:

Endoscopy may reveal mucosal rigidity and hyperplasia in patients with MALTomas. Diagnosis requires a biopsy. Endoscopic ultrasonography can be performed for gastrointestinal tract lesions, but 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 digestive, genitourinary, and respiratory mucosae contains an outer, dense-staining region that contains small T lymphocytes (dark zone) and a lighter-staining region that contains large cells (B lymphocytes and plasma cells). Together, these areas constitute the germinal center, consisting of a mesh of follicular dendritic cells 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, and pseudostratified and ciliated columnar epithelium is 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 theme in MALTomas is the production of a diffuse infiltrate that invades epithelial structures and disrupts epithelium, resulting in 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 the B-cell antigens CD19 and CD20 and monotypic surface immunoglobulin (usually IgM without immunoglobulin D). The CD23 marker, which is negative in almost all MALTomas, is useful for distinguishing 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-Helicobacter 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 of MALTomas uses the same definitions as other NHLs; MALTomas are, by definition, extranodal in origin.

Stage IE: Lymphoma is present in only one area or organ outside the lymph nodes.

Stage IIE: Lymphoma is present in only one area or organ outside the lymph nodes and in the lymph nodes around it. Other lymph nodes on the same side of the diaphragm also may be involved.

Stage IIIE: Lymphoma is present on both sides of the diaphragm. It also may have spread to an area or organ near the lymph nodes and/or the spleen.

Stage IV: Lymphoma is widespread to several organs, with or without lymph node involvement.

TREATMENT

Section 6 of 10

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Medical Care: MALTomas have recently been reclassified as extranodal marginal-zone lymphomas of MALT-type. Management is different for gastric and nongastric MALTomas.

Nongastric MALTomas are most common in the head and neck, lung, and orbit. These nongastric MALTomas are not associated with H pylori and are treated using standard modalities that include radiation, chemotherapy, and monoclonal antibodies.

Gastric MALTomas are the most common and well-studied MALTomas. These neoplasms are intimately associated with H pylori, with the organism being present in more than 90% of pathologic specimens of MALTomas.

Proton pump inhibitors and antibiotics

Treatment with a protein pump inhibitor (PPI) and antibiotics to eradicate H pylori is the most important modality used in the therapy of gastric MALTomas, resulting in regression in up to 75% of cases of the low-grade form and some, but a minority, of the intermediate-grade forms of MALToma.
Treatment with a combination of amoxicillin, clarithromycin, and PPIs results in eradication rates of 90%. An alternate regimen of metronidazole, clarithromycin, and PPIs achieves the same result.
The presence of t(11;18)(q21;q21) translocations has been shown to predict a poor response to therapy.
Because most gastric MALTomas are of low grade, they may remain localized and may not progress for several years.
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.
In cases in which no initial response to anti-Helicobacter therapy is observed, an alternative regimen is recommended for use during the second course of treatment.
Locally advanced disease that has infiltrated the muscularis mucosa, serosa, or perigastric lymph nodes has a significantly lower response rate.

Chemotherapy

Chemotherapy for MALTomas has not been studied extensively. Historically, the chemotherapy used for low-grade NHLs has been used.
Several traditional monotherapy regimens have been used, including chlorambucil, cyclophosphamide, or fludarabine. In addition, standard combination regimens such as CHOP (cyclophosphamide, Adriamycin [hydroxydaunomycin], Oncovin [vincristine], and prednisone) 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.
- In patients in whom antibiotic regimens fail, chemotherapy should be used, although it 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 in other NHLs.
- A small nonrandomized study evaluated single agents (chlorambucil and cyclophosphamide) in the treatment of low-grade gastric MALTomas. Complete remissions were achieved in 75% of patients.
- Rituximab, an anti-CD20 monoclonal antibody, has recently been reported to achieve remissions in patients with gastric MALTomas who either were not responsive to anti–H pylori therapy or who were not infected with H pylori.
The large cell, intermediate-grade forms of MALToma require standard chemotherapy similar to that used in other intermediate-grade NHLs (eg, diffuse large B-cell lymphoma).

Radiation therapy

The efficacy of radiation therapy has been demonstrated in several small trials.
Patients 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.
Treatment with radiation therapy has achieved long-term remissions (<8 y in one series) in selected patients with gastric MALToma.
The optimal dose, patient characteristics, and role in the treatment armamentarium for gastric MALToma are not well delineated, but the dose generally recommended is in the range of 3000-3600 cGy.
Radiotherapy may be very effective for orbital soft tissue MALTomas.
Caution is warranted in patients with tumor infiltration into the serosa; successful treatment may lead to gastric perforation, requiring immediate surgical intervention.
Secondary malignancies may occur in a small fraction of patients treated with radiation.

Surgical Care:

Surgery has an important, although limited, role in the treatment of gastric MALTomas. The morbidity associated with a partial or total gastrectomy is considerable, and, in most cases, neither 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 for nongastrointestinal MALToma is predominantly used for 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 curative component of treatment.

Consultations: A gastroenterologist is an integral member of the treatment team for follow-up of the results of therapy.

Diet: No special diet is required for patients with MALTomas.

MEDICATION Section 7 of 10

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In patients with H pylori infection in association with a MALToma, especially gastric MALToma, the first line of therapy is treatment for the H pylori infection. In patients with low-grade MALTomas who are not infected with H pylori or whose MALToma does not respond to H pylori treatment, options in asymptomatic patients include observation versus active intervention. If treatment is required, treatments similar to those used for other low-grade NHLs are used. Examples are single-agent therapy such as chlorambucil, cyclophosphamide, fludarabine, or rituximab. Combinations of chemotherapy agents with or without rituximab also may be used. Patients with large cell MALTomas are treated with combination chemotherapy (usually the CHOP regimen) with or without rituximab.

Further Outpatient Care:

Patients should continue to receive serial examinations at increasing frequencies for several years following the successful completion of therapy.

Prognosis:

Generally, low-grade MALTomas are indolent neoplasms with a fairly good prognosis.

MALTomas that are not eradicated by treatment of H pylori infection are incurable but are associated with a long course.

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 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. Long-term responses to anti–H pylori treatment alone have been reported.

Nongastrointestinal MALTomas are most common in the head and neck, ocular adnexa, and lungs.

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 in advanced stages.

Use of the International Prognostic Index, taking into account age, Ann Arbor stage, LDH levels, number of extranodal sites, and performance status, has better characterized low-, intermediate-, and high-risk groups. Five-year survival rates in these groups are 99%, 85-88%, and 72%, respectively. Patients with early-stage disease may be curable with chemotherapy.

The risks and benefits of surgical or radiation therapy should be considered before use.

MISCELLANEOUS

Section 9 of 10

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Medical/Legal Pitfalls:

Failure to diagnose cancer is one of the most frequent reasons for medical malpractice actions. Suggestive symptoms should be thoroughly investigated.

Failure to diagnose the correct subtype of lymphoma and subsequent use of treatment for another type of lymphoma or other malignancy that is not optimal therapy for MALToma is a medicolegal hazard.

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.

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