Mucosa-Associated Lymphoid Tissue Lymphomas (MALTomas)

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

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.

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.

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. Even with MALTomas that have transformed to diffuse large B-cell histology, the cure rate may be as high as 90% for stage IE disease; the cure rate does decrease to 30-40% for extensive stage IIIE or IVE disease. These outcomes are similar to those with intermediate- to high-grade NHLs of non-MALT origin.

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.