Organized lymphoid nodules are distributed throughout the small intestine, the appendix, and the colorectum. These nodules concentrate in the terminal ileum, where they collectively form the Peyer patches, the generic term applied to this compartment of MALT. Peyer patches are unencapsulated aggregates of lymphoid cells that bear a certain resemblance to lymph nodes (Fig. 18.1). Each Peyer patch nodule consists of B- and T-cell areas and associated accessory cells. The B-cell area is composed of a germinal center surrounded by a mantle zone of small B lymphocytes, which is broadest at the mucosal aspect of the follicle. Surrounding the mantle zone is a broad marginal zone in which most of the cells are small to intermediate-sized B lymphocytes with moderately abundant, pale-staining cytoplasm and nuclei with a slightly irregular outline leading to a resemblance to centrocytes. The marginal zone extends toward the mucosal surface and some marginal zone B cells enter the overlying dome epithelium, where they form the lymphoepithelium, which is a defining feature of MALT (Fig. 18.2). Immunohistochemical studies of Peyer patches (25,26,27) have shown that the B-cell follicles are identical to those of lymph nodes. In contrast to the IgM- and IgD-positive mantle zone, the peripheral marginal zone cells are IgM positive but IgD negative. Lateral to the deep aspect of the B-cell follicle, there is a T-cell zone in which high endothelial venules are prominent, equivalent to the paracortical T zone of the lymph node.

MALT lymphoma comprises 7% to 8% of all B-cell lymphomas and at least 50% of primary gastric lymphomas
(28,29). Most cases occur in adults with a median age of 61 years and a slight female predominance. There is a higher incidence of gastric MALT lymphoma in northeastern Italy, probably related to a high prevalence of Helicobacter pylori–associated gastritis in that region (6). Histologically, identical intestinal (30,31) and esophageal lymphomas also occur, but they are distinctly infrequent in comparison. A special subtype of small intestinal MALT lymphomas known as immunoproliferative small intestinal disease occurs in the Middle East, parts of the Indian subcontinent, and the Cape region of South Africa (14).

MALT lymphomas only rarely arise from native MALT; they more usually arise from MALT that has been acquired as a result of a chronic inflammatory disorder at sites normally devoid of MALT, including the stomach (Fig. 18.3). Here MALT is commonly acquired almost always as a result of the reaction to infection with H. pylori, which precedes development of most cases of gastric MALT lymphoma (Fig. 18.4) (32). A similar relationship has been proposed between intestinal infection with Campylobacter jejuni and IPSID (33). The functional characteristics of acquired MALT and the degree to which it resembles normal MALT have not been investigated. Likewise, the factors that, in a small number of cases, result in transformation of this reactive MALT into a lymphoma that recapitulates many of its normal morphologic and functional properties remain speculative.

Macroscopically, MALT lymphomas, although sometimes forming obviously tumorous masses, frequently are indistinguishable from the inflammatory lesion that underlies the acquisition of MALT from which the lymphoma arises. Gastric MALT lymphoma, for example, may form a single dominant mass but often results in only slightly raised congested mucosa with superficial erosions easily confused at endoscopy with chronic gastritis (Fig. 18.6). MALT lymphomas are typically multifocal with small, even microscopic foci of lymphoma scattered throughout the organ involved. Each of these foci is clonally identical (45).

Although there are some differences determined by the site of origin, the histology of MALT lymphoma is essentially stereotyped in that, like acquired MALT, the lymphomas, especially in their early stages, recapitulate the histology of Peyer patches (46). The neoplastic B lymphocytes infiltrate around reactive B-cell follicles, external to a preserved follicular mantle, in a marginal zone distribution and spread out to form larger confluent areas, which eventually overrun some or most of the follicles (Fig. 18.7). Like marginal zone B cells, the neoplastic cells have pale cytoplasm with small to medium-sized, slightly irregularly shaped nuclei containing moderately dispersed chromatin and inconspicuous nucleoli. These cells have been called centrocyte-like because of their resemblance to germinal center centrocytes. The accumulation of more abundant pale-staining cytoplasm may lead to a monocytoid appearance of the lymphoma cells, while in some cases the cells more closely resemble small lymphocytes (Fig. 18.8). Scattered large cells resembling centroblasts or immunoblasts are usually present, but are in the minority and do not form confluent clusters or sheets (Fig. 18.9). Plasma cell differentiation is present in up to a third of cases (Fig. 18.10) and, in gastric lymphomas, tends to be maximal beneath the surface gastric epithelium. In a subset of cases there is extreme plasma cell differentiation characterized by a subepithelial band of confluent large eosinophilic plasma cells often accompanied by lakes of extruded immunoglobulin (Fig. 18.11). Small clusters of neoplastic marginal zone cells are present often invading individual gastric glands to form lymphoepithelial lesions (Fig. 18.12). In these lesions, glandular epithelium is invaded and destroyed by discrete aggregates of lymphoma cells (Fig. 18.13). Lymphoepithelial lesions are defined as aggregates of three or more neoplastic marginal zone lymphocytes within glandular epithelium preferably associated with distortion or necrosis of the epithelium. In gastric MALT lymphoma the lesions are often accompanied by eosinophilic degeneration of the epithelium (Fig. 18.13). Lymphoepithelial lesions, although highly characteristic of MALT lymphoma, especially gastric lymphoma, are not pathognomonic. In some MALT lymphomas, such as those of the small and large intestine, they are difficult to find.

The MALT lymphoma cells sometimes specifically colonize germinal centers of the reactive follicles (47). Usually this imparts a vaguely nodular or follicular pattern to the lymphoma (Fig. 18.14). In some cases the lymphoma cells specifically target germinal centers, where they may undergo blast transformation (Fig. 18.15) or plasma cell differentiation (Fig. 18.16). The presence of transformed blasts confined to pre-existing germinal centers is not considered to be evidence of transformation to a large B-cell lymphoma.

Like other low-grade B-cell lymphomas, MALT lymphoma may undergo transformation to a diffuse large B-cell lymphoma (15). Transformed centroblast or immunoblastlike
cells are present in variable numbers in MALT lymphoma (Fig. 18.9) and there is some evidence that grading of MALT lymphoma according to the number of transformed cells has subtle clinical relevance (48). However, only when solid or sheetlike proliferations of transformed cells are present should the lymphoma be considered to have transformed to diffuse large B-cell lymphoma (Fig. 18.17). This transformation may or may not result in complete overgrowth of the preceding MALT lymphoma. The current recommendation is that such cases are best designated as diffuse large B-cell lymphoma; the presence or absence of concurrent MALT lymphoma and the relative proportions of both should be documented (49).

In small endoscopic biopsies the classic features of MALT lymphoma are not as easily observed as they are in resection
specimens. Reactive follicles are not as easy to define and are particularly affected by crush artefact. Equally, the cytologic appearances of marginal zone cells may not be as clear. A diffuse, dense lymphoid infiltrate in a gastric biopsy (Fig. 18.18A) should always raise suspicion, particularly if it occupies the entire biopsy fragment. Careful evaluation of the cytology of the cells is indicated (Fig. 18.18B) and identification of lymphoepithelial lesions (Fig. 18.18B) is very helpful in establishing the diagnosis.

Approximately 75% of gastric MALT lymphomas will respond to eradication of H. pylori with regression of the tumor over a period of up to 18 months (Fig. 18.19) (39). Repeated endoscopy with biopsy is necessary to determine whether or not the lymphoma is responding. The endoscopic appearances may revert within 6 months of the eradication of H. pylori but may take as long as 2 years. There is often a noticeable change in the histologic appearance of the biopsy within a few weeks with gradual clearance of the lymphoma in following months. Initially, there is disappearance of the inflammatory infiltrate accompanying the lymphoma with an empty-appearing eosinophilic lamina propria that may contain lymphoid aggregates (Fig. 18.20). These aggregates contain small B lymphocytes without transformed blasts and gradually become smaller with time. Immunohistochemistry shows that they contain few accompanying T cells and have a markedly reduced proliferation fraction compared to the original lymphoma. Such aggregates may not disappear altogether and may persist for long periods at the base of the mucosa or in the submucosa. In up to 60% of cases, B-cell monoclonality can still be demonstrated using PCR (50), suggesting that bacterial eradication represses but does not eliminate the lymphoma clone, which
is still presented in the lymphoid aggregates. The fate of these small aggregates is not completely known but it is assumed that they eventually disappear. PCR analysis may reveal persistence of the neoplastic clone after disappearance of morphologic evidence of lymphoma; however, the clinical significance of this finding is not clear. It is important not to make a diagnosis of persisting lymphoma on the basis of molecular analysis alone in the absence of good histologic evidence.

Gastric MALT lymphoma typically disseminates within the stomach to form a multifocal lesion. Indirect evidence for this comes from the observation of recurrent MALT lymphomas in the gastric stump after partial gastrectomy in patients in whom clear resection margins were documented by histologic examination (51). Wotherspoon et al (52) systematically examined gastrectomy specimens of five MALT lymphomas using a “Swiss roll” technique. They showed that numerous small tumor foci with identical immunoglobulin light chain restriction to the main tumor mass were distributed throughout the gastric mucosa, including macroscopically normal regions (Figs. 18.21 and 18.22). A subsequent investigation by sequence analysis of the rearranged immunoglobulin heavy chain genes confirmed the clonal identity of these multiple tumor foci (53). Further studies by
microdissection and clone-specific PCR demonstrated that tumor cells were frequently present in reactive lymphoid tissue that showed no histologic evidence of lymphoma (54,55,56).

Most gastric MALT lymphomas are at stage I when they present; between 4% and 17% have disseminated to regional lymph nodes, and approximately 10% have already disseminated to the bone marrow at the time of diagnosis (44,57). Gastric MALT lymphomas have a tendency to disseminate to other sites where MALT lymphomas occur, including the small intestine, salivary gland, and lung.

When MALT lymphomas disseminate to lymphoid tissue, including lymph nodes and spleen, they specifically invade the marginal zone (Fig. 18.23). This can lead to a deceptively benign or reactive appearance, especially in mesenteric lymph nodes, in which a marginal zone is normally present. Immunohistochemistry for immunoglobulin light chains can be very helpful in discriminating a normal marginal zone from disseminated MALT lymphoma (Fig. 18.24). Subsequently, the lymphoma in the marginal zones expands to form more obvious sheets of interfollicular lymphoma. Occasionally, follicular colonization in involved lymph nodes can lead to an appearance that simulates follicular lymphoma (Fig. 18.25).

The immunophenotype of MALT lymphoma essentially recapitulates that of marginal zone cells (Table 18.2). The B cells are CD20, CD79a, CD21, and CD35 positive and CD5, CD23, and CD10 negative. CD43, indicative of a neoplastic phenotype, is expressed in approximately 50% of cases. The tumor cells typically express IgM and less often IgA or IgG, are IgD negative, and show immunoglobulin light chain restriction (Fig. 18.26). A significant intratumoral population of CD3-positive, predominantly CD4-positive T cells is characteristic. Expanded meshworks of follicular dendritic cells are typically detected with antibodies CD21 and CD23, corresponding to follicles that have been overrun or specifically colonized by lymphoma cells. Variable numbers of CD10- and Bcl6-positive germinal center cells may be seen in
these areas, but the neoplastic MALT lymphoma cells are negative for these antigens.

The architectural features of MALT lymphoma, particularly in early cases, show quite clearly that the neoplastic cells are infiltrating the marginal zone around B-cell follicles (Figs. 18.7 and 18.29). In non-neoplastic lymphoid tissue a prominent marginal zone is present only in the spleen, Peyer patches,
and mesenteric lymph nodes. This allows a comparison of the cytology and immunophenotype of normal marginal zone cells with those of MALT lymphoma. Cytologically, MALT lymphoma cells bear a close resemblance to marginal zone cells. Both are slightly larger than small lymphocytes, have a slightly irregular nuclear outline, and moderate amounts of pale-staining cytoplasm. Interestingly, in Peyer patches collections of marginal zone cells are found within the dome epithelium. The immunophenotype of cells of the marginal zone and MALT lymphoma is virtually identical, both expressing CD20 and other pan B-cell antigens, CD21, CD35, and IgM, but not IgD.

MALT lymphomas are among the most indolent of all lymphomas and have a good prognosis overall regardless of stage. Five- and 10-year overall survival rates of over 80% are the rule, although progression-free survival may be somewhat lower (73). Cases in which transformation to diffuse large B-cell lymphoma has occurred have a significantly lower survival of approximately 50% at 5 years (48).

The treatment of gastric MALT lymphoma has attracted considerable attention since the initial publication showing that the lymphoma may regress following eradication of H. pylori with antibiotics. The follow-up of MALT lymphoma patients following eradication of H. pylori is rather complex, requiring repeated gastroscopy with biopsy (see above), and

it would be extremely useful to be able to identify the approximately 25% of cases of gastric MALT lymphoma that do not respond to eradication of H. pylori. Studies using endoscopic ultrasound have suggested that if the tumor has invaded beyond the submucosa, it is less likely to respond (74,75). Equally, cases that have transformed to large B-cell lymphoma are unlikely to respond, although there are reports of complete regression in such cases (76,77). Following the cloning of t(1;14) and t(11;18) breakpoints, these translocations have been shown to have a bearing on the response to H. pylori eradication. T(11;18)(q21;q21), present in up to 25% of cases, is strongly associated with failure to respond to eradication of H. pylori (78). Interestingly, both t(1;14) and t(11;18) are associated with nuclear expression of BCL10 protein that is particularly intense in t(1;14)-positive cases. Moreover, the frequency of both t(11;18)(q21;q21) and nuclear BCL10 expression is significantly higher in tumors that have invaded or disseminated beyond the stomach (78% and 93%, respectively) than those confined to the stomach (10% and 38%, respectively) (79). These findings in part explain the results based on the use of endoscopic ultrasound and suggest that both t(11;18)(q21;q21) and BCL10 nuclear expression are associated with failure to respond to H. pylori eradication and with more advanced stage MALT lymphoma. Therefore, before embarking on H. pylori eradication as definitive therapy, the pertinent genotypic and/or immunohistochemical investigations should be carried out.