Lymphoproliferative Disorders of the Gastrointestinal Tract
OVERVIEW
Introduction
The gastrointestinal (GI) tract contains the largest aggregate of lymphoid tissue aside from lymph nodes, and it is the most frequent site of extranodal lymphoma.1, 2 Surprisingly, the most common site of lymphoma in the GI tract is the stomach, which normally has only rudimentarily organized lymphoid tissue. Advances in molecular genetics have led to a better understanding of the pathogenesis of GI lymphoproliferative disorders and have had a great impact on how we approach these lesions in clinical practice today.
Understanding the organization of normal lymphoid tissue in the gut is essential to understanding its lymphoproliferative disorders. A detailed description of GI lymphoid tissue and its functions is provided in Chapter 5, and only a brief discussion is presented here.3 Aside from the mesenteric lymph nodes, the GI lymphoid tissue is represented by organized mucosa-associated lymphoid tissue (MALT), intraepithelial lymphocytes (IELs), and lamina propria lymphoid cells. Of these, MALT and IELs are unique in many ways.
MALT in the GI tract refers to unencapsulated lymphoid aggregates associated with specialized epithelium, best represented by Peyer’s patches in the terminal ileum and lymphoid tissue of the appendix. However, they are widely distributed throughout the GI tract and vary in size and numbers considerably, not only among different individuals but also in the same individual over time. Similar to lymph nodes, these aggregates have organized B- and T-cell zones along with many accessory cells. The B-cell zone consists of lymphoid aggregates, which may develop germinal centers when stimulated, each of which is surrounded by an outer mantle and an outermost marginal zone similar to lymph nodes. The marginal zone is a broad area populated by small- to intermediate-sized cells that morphologically resemble germinal center cells (centrocyte-like cells [CLC]) or monocytes (monocytoid B cells). The marginal zone cells extend toward the epithelium and can be seen entering the overlying epithelium constituting “lymphoepithelium,” which is the defining feature of MALT. These lymphocytes are IgM-positive and IgD-negative or weakly positive, as compared to mantle zone cells that are positive for both IgM and IgD. The follicles are flanked on the lateral as well as the basal aspects by a T-cell area similar to the paracortical T-cell zone of the lymph nodes.
The lamina propria throughout the gut is populated by a mixture of plasma cells, lymphocytes (B and T cells), mast cells, eosinophils, and macrophages. The composition and the density of this population vary between different GI segments among individuals and even within an individual over a period of time. The plasma cells secrete predominantly IgA but also IgM, IgG, and IgE. The CD4:CD8 ratio of the T-cell population is approximately 4:1. About 50% of these cells express CD103, which represents integrin α4β7 that plays a role in the adhesion of these cells to the epithelium and lymphocyte homing to the gut.
IELs away from MALT areas are largely T cells of a heterogeneous phenotype. They are widely present throughout the GI tract, including the squamous mucosa. The predominant phenotype is the cytotoxic T-cell expressing αβ T-cell receptors (TCRs), which are CD3+, CD8+, CD103+, CD4−, and CD5−. A smaller population (10%-15%) consists of T cells expressing γδ TCRs that are negative for both CD4 and CD8. A third population of CD56+ IELs is also recognized that are virtually undetectable in normal mucosa. They T-cytotoxic and natural killer (NK) properties.
Studies, largely from experimental animals, show that lymphocytes from MALT have receptors that recognize specific cellular adhesion molecules on high endothelial venules that regulate their circulation and homing. This applies to both B and T cells. The MALT obviously functions as the host’s immune response to various luminal organisms and allergens. IELs are known to increase in response to infections or food-induced enteropathies and are also likely to be an important component of the host’s immune response; however, their specific function is poorly understood, although as predominantly CD8+ cells they likely downregulate any immune response.
Definition
Primary GI lymphomas have been defined as those lymphomas that are present in the GI tract with no evidence of liver, spleen, peripheral lymph nodes, or bone marrow involvement at the time of presentation or when the bulk of the disease is in the gut.4 Also included are those lymphomas originating in the mesenteric lymph nodes. This is because of their similarity in clinical presentation and causal relationship to the prelymphomatous intestinal diseases, such as celiac disease and immunoproliferative small intestinal disease (IPSID) in some cases. However, this definition is somewhat restrictive. Problems arise in those cases that present with GI manifestations but on workup are found to be disseminated. For example, it is now well recognized that about 10% of gastric MALT lymphomas have bone marrow involvement at presentation, and secondary dissemination occurs in roughly 50% of patients.5 Using sensitive techniques, it is possible to detect circulating lymphoma cells in about 21% of cases,6 although the clinical implications of this apparent dissemination are unclear as most of these tumors remain localized. However, these should still be regarded as primary GI lymphomas with dissemination, although it is possible that some cases may represent dissemination of nodal lymphomas. This question should be easily resolved in the near future as advances in the molecular diagnostics may provide tools that could help in better classification and subtyping of lymphoma despite clinical, morphologic, and immunophenotypic overlaps. For example, the presence of t(11;18)(q21;q21) can help to differentiate low-grade B-cell gastric MALT lymphomas from their nodal counterparts (marginal zone lymphomas) that are otherwise identical in their morphology and immunophenotype.7 Such a differentiation is currently not possible with regard to many other forms of GI lymphomas, for example, diffuse large B-cell gastric lymphoma from a nodal diffuse large B-cell lymphoma (DLBCL). From a practical point of view, the question is somewhat moot, as the management of these tumors currently depends on the histologic subtype.
Incidence
The GI tract accounts for about 50% of all primary extranodal lymphomas. In addition, GI involvement occurs in up to 50% of patients with disseminated nodal lymphomas or lymphocytic leukemias, in autopsy studies.8, 9 Nevertheless, in the United States, GI lymphomas are still relatively uncommon compared to other GI tumors, primarily adenocarcinomas. Thus, although more than half of all primary and secondary GI lymphomas in the United States are of gastric origin, they represent only about 5% of all gastric tumors.
It should also be noted that there is a marked geographic variation in the types and the site predilection of GI lymphomas (see Table 4-2). In the United States and Europe, the most frequent site of GI lymphomatous involvement is stomach (50%), followed by the small intestine (37%) (primarily the ileum and the ileocecal region) and anorectal region (3%).2, 10, 11, 12, 13 Involvement of the remainder of the intestinal tract, such as duodenum and mesentery, is uncommon.14 In contrast, in the Middle East and South Africa, the incidence of intestinal lymphomas is much more common than that of gastric lymphomas, ranging from 35% to 75% of all GI lymphomas, due to a relatively higher incidence of Mediterranean lymphoma and α-chain disease.15 Interestingly, the duodenal lymphomas occur most frequently around the ampulla of Vater and consist primarily of follicular lymphomas, which are exceedingly rare in other portions of the GI tract.16
Pathogenesis of GI Lymphoma
The predisposing conditions for GI lymphoma are varied and include infections such as Helicobacter pylori (H. pylori) celiac disease, diffuse and nodular lymphoid hyperplasia (which themselves are likely secondary), immunodeficiency disorders (primary or acquired), and occasionally familial tendency. Lymphoma has also been described in association with ulcerative colitis, Crohn’s disease, and epithelial neoplasms.
Details of the pathogenesis of the common GI lymphomas are unraveling a number of interesting associations.3 While the pathogenesis of the nodal lymphomas remains unclear, primary GI lymphomas have led the way in understanding the “genesis” of lymphoma. The key theme of chronic antigenic stimulation (infectious or noninfectious) and immune dysregulation leading to benign proliferations that may eventually lead to a malignant disease is exemplified by many primary GI lymphomas. This process is in a way similar to the “hyperplasia-adenoma-carcinoma” sequence of epithelial neoplasms, although it is currently difficult to define the concept of “prelym-phoma” or “lymphocytic dysplasia.” Understanding the pathogenic mechanisms has had a great impact not only on the understanding of these disorders but on their management as well. A leading example of this is H. pylori-related gastric MALT lymphoma, where treatment of H. pylori results in disappearance of the lymphoma. As our understanding of H. pylori-induced gastric MALT lymphoma continues to evolve, the search for infectious etiologies of other types of lymphomas has already begun to show promising results. Infectious agents that have been implicated in the etiopathogenesis of other lymphomas include Campylobacter jejuni, Clamydia psittaci, Borrelia burgdoferi, Epstein Barr virus (EBV), and hepatitis B
and C viruses.17, 18, 19, 20 Of these, EBV has already been a subject of interest for many years.
and C viruses.17, 18, 19, 20 Of these, EBV has already been a subject of interest for many years.
Classification of GI Lymphomas
The accurate classification of GI lymphomas is important for identifying specific disease entities and also for determining treatment protocols and assessing prognostic factors. The literature on GI lymphoma suffers from the use of nonuniform classification systems, making it difficult to compare results.
Until fairly recently, the major lymphoma classifications used were the Working Formulation, Rappaport’s classification, WHO modification of the Working Formulation, and Kiel classification, all of which were based primarily on morphologic and immunophenotypic features.21, 22, 23, 24 The problem with the Working Formulation was that the classification was originally developed for the nodal lymphomas, and it was found that many extranodal lymphomas were not variants of nodal lymphomas but were histologically and clinically distinctive. For example, MALT lymphoma, IPSID, and enteropathy-associated T-cell lymphoma (EATL) have histologic features quite distinct from the nodal lymphomas. The Kiel classification was also morphologic based and divided lymphomas primarily into two broad categories, namely, B and T cells, and then classified them on the basis of cytologic morphology and grading. Although the grading frequently predicted the clinical outcome, lymphomas like the mantle cell lymphomas that were morphologically considered low grade are actually aggressive. Other lymphomas, such as the anaplastic large-cell lymphomas, that were considered high grade and to have an aggressive natural history show excellent response to chemotherapy with prolonged disease-free survival.25
Table 4-1 Tumor Site of Gastrointestinal Lymphomas | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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To address these issues, in 1994 a new lymphoma classification was introduced by the International-American Lymphoma Study Group, labeled as the Revised European American Lymphoma (REAL) classification.26 This classification subdivided lymphomas into distinctive entities, based on multiple parameters, including clinical presentation, site of the primary lesion, natural history and clinical course, morphologic appearance, and immunophenotypic and genetic factors. The site of the primary lesion
is important for most extranodal tumors, including many GI lymphomas. This REAL classification was upgraded in 1999 and has now been adopted by the WHO classification.27, 28, 29 While the lymphoma classifications will continue to evolve, disease-specific rather than morphology-centered classification is likely to remain a central theme.
is important for most extranodal tumors, including many GI lymphomas. This REAL classification was upgraded in 1999 and has now been adopted by the WHO classification.27, 28, 29 While the lymphoma classifications will continue to evolve, disease-specific rather than morphology-centered classification is likely to remain a central theme.
The classification of GI lymphomas suggested here is based on the REAL and WHO classifications (Table 4-1). A fair number of distinctive lymphomas occur in the GI tract, although the frequency of the specific types varies greatly from one site to another (Table 4-2).
The vast majority (85%) of GI lymphomas are of B-cell origin, of which most are MALT lymphomas. T-cell lymphomas are rare and occur most often in the small intestine accounting for 34% of cases in one study. The latter are often associated with celiac disease. Since the advent of AIDS and organ transplantation, several new types of lymphomas have been recognized that can involve the GI tract. Only a handful of patients with Hodgkin’s disease and other tumors, such as solitary plasmacytoma, large-cell anaplastic lymphoma, and true histiocytic neoplasms, have been described in the GI tract. The GI tract is also commonly involved secondarily in advanced stages of nodal lymphomas and leukemia. Lastly, a number of lymphomas are impossible to subclassify beyond their lymphoid derivation and are designated as unclassified.
Table 4-2 Classification of GI Lymphomas | |||||
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