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Lymphoid Tissue and Gastric Lymphomas

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Lymphoid Tissue and Gastric Lymphomas Continuing medical education Lymphoid tissue and gastric lymphomas Rocío del Pilar López P, MD,1 Rafael Enrique Andrade P, MD.2 1 Pathologist at the Hospital Universitario Fundación Abstract Santa Fé de Bogotá. Professor at the Universidad de Los Andes in Bogotá, Colombia. In this review we describe various aspects of the primary gastric lymphomas, the classification, and the 2 Pathologist, Chief of the Pathology Department and most important clinico-pathological aspects, with emphasis in mucosa associated lymphoma (MALT) and the Laboratories at the Fundación Santa Fe de Bogotá. Helicobacter pylori infection. Professor at the Universidad de Los Andes and at the Universidad Nacional de Colombia in Bogotá, Colombia. Key words ......................................... Lymphomas of the stomach, extra nodal lymphomas, primary gastric lymphoma, Mucosa associated lymphoid Received: 13-09-10 tissue, lymphoma MALT, Marginal zone lymphoma, Primary gastric diffuse large B cell Lymphoma, follicular Accepted: 05-10-10 lymphoma, Helicobacter pylori. Lymphoid Tissue in The GAsTric mucosA aggregates of the mucous membrane with germinal cen- ters, mantle zones, and a crown of peripheral lymphocytes Lymphoid tissue is dispersed throughout the whole of the called “marginal zone” lymphocytes. The second includes gastrointestinal tract; however, only in the upper aerodiges- the lymphoid tissue dispersed throughout the lamina pro- tive tract and in the terminal ileum is it organized in struc- pria, and the third includes the intraepithelial lymphocytes. tures similar to those present in other secondary lymphoid The immunological response of the mucous membranes organs such as the spleen and the lymph nodes. Waldeyer’s is very similar to that of lymph nodes. The cellular compo- Ring, in the oropharynx, is composed of this tissue, as are nent in the lamina propria is very heterogeneous, with the Peyer’s patches in the terminal ileum. Under normal condi- presence of macrophages, dendritic cells, plasmatic cells, tions there are rarely any lymphoid follicles established in helper T lymphocytes and a small number of eosinophils. the esophagus or stomach. Most likely lymphoid organiza- In a certain manner this resembles the interfollicular zones tion in these functional structures is unnecessary because of lymph nodes. The intraepithelial lymphocytes are mainly intestinal transit is rapid and the environment is hostile to suppressor/cytotoxic T lymphocytes which are more noti- microorganisms. When inflammation, infection, or tumors ceably present in the small intestine. The humoral immune are present, it is possible for persistent antigenic stimulus to response is amplified in the lymphoid follicles where it is favor the development of lymphoid tissue organized in such particularly committed to the production of immunoglo- a way that it resembles mucosa-associated tissue present in bulin A (1). other locations. In normal conditions, this lymphoid tissue Throughout the gastrointestinal tract, different con- can be observed in the cecal appendix. ditions may be found that alter the normal structure of There are three types of cellular present in the lymphoid lymphoid tissue. On one hand, there are processes such as tissue of these organs. The first consists of true lymphoid hyperplastic phenomena related to inflammatory processes © 2010 Asociaciones Colombianas de Gastroenterología, Endoscopia digestiva, Coloproctología y Hepatología 401 which lead to the enlargement of normally present lym- of the lymphoma should always be conducted to exclude phoid tissue. There are also conditions which increase the secondary compromise from nodal lymphomas, some- T lymphocyte population. These include certain immuno- thing that occurs in up to 25% of cases and which entails logical processes and Helicobacter pylori infections in the different prognoses and treatments (5). stomach. Finally, under certain conditions such as endu- ring stomach infection by Helicobacter pylori neoformation epidemiology of an organized lymphoid system occurs and results in the formation of true lymphoid follicles (2). About 40% of non-Hodgkin lymphomas (NHLs) originate Moreover, it is possible to find neoplastic proliferation in extranodal locations, the gastrointestinal tract being of any lymphoid component, whether naturally present one the more frequent locations. In the Western World or acquired, in the gastrointestinal tract. These processes incidence between 2% and 18% occur there, while in the constitute lymphoma, which may be a primary condition Middle East, close to 25% originate there. (extranodal lymphoma), or represent the penetration of Lymphomas are relatively rare in the stomach. They the gastrointestinal tract by a lymphoma originating in a represent less than 15% of all gastric tumors and only 2% lymph node. of total lymphomas. However, it is in the stomach where almost 75% of gastrointestinal tract NHLs originate. GAsTric LymphomA Incidence has been increasing in recent years. According to the World Health Organization (WHO), introduction the most frequent NHLs are diffuse large B-cell lympho- mas (DLBCL), some of which are part of the progression Without doubt, the most frequent type of lymphoma of MALT lymphomas. The next most frequent NHLs are of the mucous membrane or the gastric walls is MALT marginal zone B-cell MALT lymphomas (4). lymphoma, which we shall describe in more detail ahead. Afterwards, other types of gastric lymphoma will be men- subtypes tioned including follicular lymphoma which originates in the lymphocytes of the germinal center: mantle cell lym- Marginal Zone Lymphoma or Mucosa-Associated phoma which originates in the cells of the mantle zone; Lymphoid Tissue (MALT) and diffuse large B-cell lymphoma which originates in the In 1982 Isaacson and Wright were the first to describe a germinal center or in activated cells (and which is the least variant of B-cell lymphoma located outside of the lymph common among T-cell lymphomas). All of these will be, nodes, most commonly within the gastrointestinal tract. to some degree, involved in the differential diagnosis of This location suggested a common histogenesis in the lym- MALT lymphoma and of hyperplastic conditions associa- phoid tissue of the mucosa (6). ted with follicular gastritis (3, 4). The World Health Organization (WHO) divides B-cell lymphomas of the marginal zone into those which are definition nodular and those which are extranodular. Both originate in B-cells of the marginal zone and both share morpholo- In the 1960’s Dawson proposed that a series of diagnostic gical, immunological and phenotypical characteristics, but criteria were necessary for determination of primary lym- extranodular B-cell lymphoma are considered to be a diffe- phoma of the gastrointestinal tract. The most important of rent entity because of their unusual pathogenesis (4). these criteria are absence of peripheral lymphadenopathy, Those which concern us here are the extranodular lym- a leukocyte recount with a normal differential to exclude phomas known as gastric mucosa-associated lymphoid the possibility of leukemia with gastric complications, tissue (MALT) lymphomas. These processes originate in and absence of hepatic or splenic compromise because mucosa which normally lacks organized lymphoid tissue in of the possibility of lymphoproliferative processes. These which chronic secondary inflammatory processes such as criteria are valid, although in some exceptional late cases infections or autoimmune disorders have developed. The of lymphoid neoplasia originating in the gastrointestinal best known of those related to infections are those associa- tract (particularly in the stomach) there may be spreading ted with helicobacter pylori while Sjögren’s syndrome which toward distant lymphoid organs including possible com- occurs in the salivary glands and Hashimoto’s thyroiditis promise of the bone marrow or surrounding cells. are examples of autoimmune disorders associated with Primary gastric lymphoma originates in the stomach, these lymphoma. with or without compromise to contiguous lymph nodes. In 1991 Wotherspoon and his collaborators were the At has been mentioned, tests to determine the extension first to demonstrate the close relation which exists between 402 Rev Col Gastroenterol / 25 (4) 2010 Continuing medical education Helicobacter pylori and MALT lymphomas. They described both by the action of H. pylori and by the host’s cytokines H. pylori’s presence in practically all of the patients they stu- which stimulate the proliferation of tumor B-lymphocytes. died who had MALT lymphomas (7). Two years later they In the first phase the inflammatory reaction results in reac- demonstrated regression of tumors in 5 of the six patients tive lymphoid hyperplasia. If activation of B-lymphocytes they were following after eradication of the bacteria (8). continues, it is possible that a proliferation of monoclonal Following these results it is expected that there should lymphoid cells will follow. Phenotypically these cells may be a higher incidence of lymphomas in countries with hig- resemble centrocytes of the germinal center, but are loca- her incidences of infection. Rates of infection reach nearly ted in the periphery of the lymphoid follicle in the marginal 100% among people with MALT lymphomas and range zone. If the extension continues these cells will penetrate between 50% and 60% among people with lymphomas the lamina propria and invade the epithelial cells produ- which have progressed to diffuse large B-cell
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