Gastrointestinal Lymphomas

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CHAPTER 29 Gastrointestinal Lymphomas

Lymphomas are solid malignancies of the lymphoid system and are subdivided into Hodgkin’s and non-Hodgkin’s lymphomas (NHLs). It was estimated that in 2008, there would be 8,220 and 66,120 new diagnoses of Hodgkin’s and NHL, respectively, in the United States.1 The gastrointestinal tract is very rarely involved with Hodgkin’s lymphoma and will not be discussed in this chapter. There are 0.8 to 1.2 new cases of primary gastrointestinal NHL/100,000 persons/year.2 This accounts for 30% to 50% of all extranodal NHLs, making the gastrointestinal (GI) tract the most common site of extranodal NHL. Lymphomas that involve the GI tract but have the bulk of the disease in nodal areas are managed in a similar fashion to those that do not involve the GI tract. This chapter deals with primary gastrointestinal lymphoma, which is usually defined as “a lymphoma that has presented with the main bulk of disease in the GI tract, with or without involvement of the contiguous lymph nodes, necessitating direction of treatment to that site.”3

BACKGROUND

Lymphomas are malignancies of the immune system. In broad terms, the immune system can be thought of as a highly structured and tightly regulated interaction between lymphoid and nonlymphoid tissues aimed at protecting the host from harmful agents.4 Lymphoid cells are produced in the bone marrow and thymus and then arrayed in the lymphoid tissues, which include the lymph nodes, spleen, Waldeyer’s ring, and mucosa-associated lymphoid tissue (MALT; see Chapter 2). The GI tract lymphoid tissue is MALT, typified by the Peyer patches of the terminal ileum. MALT contains B cells at various stages of differentiation, organized into different zones (Fig. 29-1A). B cells that have encountered antigen diffusing across the mucosa enter the germinal center of MALT and undergo repeated immunoglobulin gene mutations (somatic mutations)5; the resultant B cell subclones whose immunoglobulins are highly specific for antigen have a survival advantage over B cells whose immunoglobulins are less specific. These more specific B cells then leave the germinal center, enter the circulation, differentiate into memory B cells or antibody-producing plasma cells, and return to the intestinal mucosa. Memory B cells reside in the marginal zone of MALT. Some marginal zone B cells occupy the epithelial tissue that covers the Peyer patches; these cells are called intraepithelial marginal zone B cells. B cells that have not encountered antigen make up the mantle zone of MALT. T cells play a role in the coordination and delivery of the immune system and thus are also found in MALT (see Fig. 29-1A). Therefore, MALT is composed of B and T cells at various stages of differentiation; immune cells at a given stage of differentiation have characteristic histologic, immunophenotypic, and genetic features. Malignant transformation may occur in a cell at any one of these particular stages of differentiation, leading to a malignancy with distinct clinical pathologic features (see Fig. 29-1B). This way of understanding lymphomas has led to the World Health Organization (WHO) lymphoma system, which recognizes at least 28 different clinical pathologic entities.6

Most lymphomas of the GI tract are B cell lymphomas, with most of these resulting from transformation of marginal zone B cells, classified by the WHO system as extranodal marginal zone B cell lymphomas. However, B cell lymphomas can also arise from other cells of MALT, such as centrocytes of the germinal center (follicular lymphomas) or cells of the mantle zone (mantle cell lymphoma). The precise histogenesis of large B cell lymphomas likely varies from case to case. T cell lymphomas of the GI tract are less common and usually involve malignant transformation of intraepithelial T cells in patients with celiac disease (see Chapter 104).

GI lymphomas most commonly involve the stomach or small intestine, although the oral pharynx, esophagus, colon, or rectum may be involved uncommonly. In developed countries, the stomach is the most common site of involvement (approximately 60% of cases), but in the Middle East, the small intestine is the most common site of GI involvement. Table 29-1 lists the GI lymphomas discussed in this chapter. Clinicians dealing with GI lymphoma are faced with a specific pathologic diagnosis of a lymphoma occurring in a specific site and, in some cases, modified by important patient characteristics, such as human immunodeficiency virus (HIV) infection. This chapter discusses the main clinicopathologic entities that a clinician may encounter. Certain of these GI lymphomas have particular features that warrant more extensive discussion; these include gastric extranodal marginal zone B cell lymphoma of MALT type, gastric diffuse large B cell lymphoma, immunoproliferative small intestinal disease, and enteropathy-type intestinal T cell lymphoma. The other lymphomas that may occur in the GI tract are covered in less detail. Before proceeding to discussion of each entity, we briefly review certain general principles that apply to all subtypes.7

Table 29-1 Gastrointestinal Lymphomas

Gastric Lymphomas

Small Intestinal Lymphomas Other Sites Immunodeficiency-Related Lymphoma

HIV, human immunodeficiency virus; IPSID, immunoproliferative small intestinal disease; MALT, mucosa-associated lymphoid tissue.

GENERAL PRINCIPLES OF LYMPHOMA MANAGEMENT

STAGING AND PROGNOSTIC ASSESSMENT

The extent of involvement by NHL is assessed by careful history and physical examination; computed tomography (CT) of the neck, chest, abdomen, and pelvis; positron emission tomography (PET) in cases of high-grade NHL; bone marrow examination; and endoscopic ultrasonography for GI lymphomas.9 Waldeyer’s ring is often involved in gastrointestinal lymphomas, and examination of the upper airway is therefore indicated. The Ann Arbor staging system (Table 29-2),10 which was originally developed for Hodgkin’s lymphoma but is also used for NHL, is deemed by many to be inadequate for staging of GI lymphomas, and several alternative systems have been proposed, two of which are also shown in Table 29-2.11

Prognosis is assessed by defining the distinct lymphoma subtype and evaluating clinical features, including tumor stage, age of the patient, performance status, and serum lactate dehydrogenase (LDH) level. The International Prognostic Index, a model used to predict outcome in patients with aggressive NHL,12 can also be used to assess the prognosis of patients with diffuse large B cell lymphoma of the stomach.13

GASTRIC LYMPHOMAS

Primary gastric lymphomas account for 5% of gastric neoplasms, with an increasing worldwide trend.14 The stomach is the most common extranodal site of lymphoma in developed countries.15 Most of these lymphomas are classified as marginal zone B cell lymphoma of the MALT type16 or as diffuse large B cell lymphoma.

GASTRIC MARGINAL ZONE B CELL LYMPHOMA OF MUCOSA-ASSOCIATED LYMPHOID TISSUE

Extranodal marginal zone B cell lymphoma of MALT, also known as MALT lymphoma, comprises about 8% of all NHLs.17 These lymphomas arise from malignant transformation of B cells from the marginal zone of MALT.18 They may arise from MALT that exists under normal physiologic circumstances (e.g., in Peyer’s patches of the gut) or from MALT that has been acquired in sites of inflammation associated with infection or an autoimmune process. For example, gastric tissue normally does not contain MALT but may acquire it in response to chronic Helicobacter pylori infection (see Chapters 50 and 51).19 Malignant transformation occurs in a small percentage of patients with acquired gastric MALT and results in a lymphoma with generally indolent behavior. The malignant process appears to be driven to a large degree by chronic H. pylori infection, because eradication of the infection leads to regression of the lymphoma in most cases.20

Epidemiology

Gastric marginal zone B cell lymphoma of MALT represents approximately 40% of gastric lymphomas.15 The incidence varies according to the incidence of H. pylori in the population being assessed; the incidence in northeastern Italy, where the rate of H. pylori infection is very high, is roughly 13 times the incidence in the United Kingdom.21 The incidence in H. pylori–infected individuals is from 1 in 30,000 to 1 in 80,000.22 The median age at diagnosis is approximately 60 years, with a wide age range. The male-to-female ratio is equal.

Cause and Pathogenesis

Helicobacter pylori Infection

Several lines of evidence support the key role of H. pylori in the development of gastric MALT lymphoma (see Chapter 50). Infection by H. pylori is present in approximately 90% of cases of gastric MALT lymphoma examined histologically23 and in 98% of cases studied by serology.24,25 The epidemiologic studies cited earlier have shown a close correlation between the prevalence of H. pylori infection and gastric lymphoma in a given population,22 and case-control studies have shown an association between previous H. pylori infection and subsequent development of gastric lymphoma.26 In vitro studies have shown that gastric MALT lymphoma tissue contains T cells that are specifically reactive to H. pylori.27 These H. pylori–reactive T cells support the proliferation of neoplastic B cells.28,29 Many groups have documented the regression of gastric MALT lymphoma after eradication of H. pylori.20,3033 Of interest, responses of small intestinal and rectal lymphoma to H. pylori eradication have been reported,34,35 although a consistent role of the organism at these nongastric sites is not clear. Lymphomas have also been reported in patients with Helicobacter heilmannii infections, with resolution after eradication of the infection.36

Evidence for Antigen-Driven B Cell Proliferation

As noted, the B cell immunoglobulin variable region (V) genes undergo somatic hypermutation during the T cell–dependent B cell response to antigen5; this leads to the production of new antigen receptors with altered antigen-binding affinity. Resultant B cell clones that express higher affinity antigen receptors have a survival advantage over B cell clones containing receptors with lower affinity. Thus, somatic mutation is a marker for antigen-driven selection of B cell clones. Sequence analysis of malignant B cells from gastric MALT lymphoma shows that the immunoglobulin genes have undergone somatic mutation.3739

As discussed in Chapter 2, helper T cells support the proliferation of various B cells through cytokines and cell-to-cell interactions.40 These B cells may be specific for the same antigen as the T cells or may be reactive with other antigens. As noted, CD4+ T cells within gastric MALT lymphoma tissue are reactive with H. pylori antigens. The malignant B cells in gastric MALT lymphoma may be reactive with non–H. pylori antigens and, in fact, may be self-reactive. One study has shown that idiotypic immunoglobulins isolated from gastric MALT lymphoma react with a variety of autoantigens.27 Another study has shown that the immunoglobulin genes from gastric MALT lymphoma are derived from germline genes commonly used in the formation of autoantibodies.38 One study has suggested the presence of selecting antigens common to different patients. Analysis of the DNA and amino acid sequences of the antigen-binding region of tumor-derived immunoglobulin from two separate patients showed that although the DNA sequences differed, the resultant amino acid sequences were almost identical.39

Genetic Studies

There are four main chromosomal translocations in extranodal marginal zone lymphomas: t(11;18)(q21;q21), t(14;18)(q32;q21), t(1;14)(p22;q32), and t(3;14)(p14.1;q32). The most common translocation is t(11;18)(q21;q21). Overall, it is found in 30% of cases, but its incidence varies with disease site: it is more common in cases involving the lung and stomach, but rare in other sites.41 The t(11;18) translocation results in the reciprocal fusion of the API-2 and MALT-1 genes. API-2 is an apoptosis inhibitor, and MALT-1 is involved in nuclear factor κB (NF-κB) activation. MALT lymphomas with this translocation do not respond as well to antibiotic therapy aimed at eradicating H. pylori infection as lymphomas without this infection.42 However, they are also less likely to have other chromosomal translocations or transform to more aggressive large cell lymphomas.43,44

The t(14;18)(q32;q21) variant results in the translocation of the MALT-1 gene on chromosome 18q21 to the immunoglobulin gene heavy chain enhancer region, leading to its overexpression, thus differing from the t(14;18) translocation of follicular lymphoma, which involves the bcl-2 gene. This occurs in about 20% of MALT lymphomas overall, although the incidence varies according to the disease site; it is more common in lymphomas occurring in the salivary glands and ocular adnexa, but rare in the GI tract.45,46

Approximately 5% of gastric MALT lymphomas have a t(1;14)(p22;q32) translocation.47 In this translocation, the bcl-10 gene is brought under the control of the immunoglobulin heavy-chain gene enhancer, deregulating its expression. This translocation has been detected only in patients with MALT lymphomas, but those with it often have concurrent trisomies of chromosomes 3, 12, and 18. It is more commonly found in advanced-stage cases, which are less likely to respond to H. pylori eradication.41

The t(3;14)(p14.1;q32) is the latest translocation to be described and results in the juxtaposition of the transcription factor FOXP1 on 3p14.1, next to the immunoglobulin gene heavy (IGH) chain enhancer region.46 The oncogenic role of the IGH-FOXP1 fusion protein is not yet known.

Common Molecular Pathway for MALT Lymphoma Chromosomal Translocations

The first three translocations listed earlier all activate nuclear factor-κB (NF-κB), a transcription factor that increases cell activation, proliferation, and survival.47 In unstimulated B and T lymphocytes, NF-κB is sequestered in the cytoplasm because it is bound to IκB, an inhibitory protein. Phosphorylation of IκB targets it for ubiquitination and degradation, thus releasing NF-κB, which then translocates to the nucleus to function as a transcription factor. The pathways through which IκB is phosphorylated are tightly regulated and involve BCL-10 and MALT-1. Excessive BCL-10 or MALT-1 activity occurring as a consequence of t(11;18), t(14;18), or t(1;14) leads to constitutive NF-κB activation.47,48

Model for Pathogenesis of Gastric MALT Lymphoma

A model for the pathogenesis of gastric MALT lymphoma suggests that the evolution of the disease is a multistage process, comprising the sequential development of H. pylori gastritis, low-grade B cell lymphoma, and then high-grade B cell lymphoma.47,49 This model is supported by gastric biopsies obtained from patients with chronic gastritis taken years before the onset of lymphoma showing B-lymphocytic clones that later gave rise to a clinically evident lymphoma. In this model, H. pylori infection elicits an immune response in which T and B cells are recruited to the gastric mucosa, where MALT is then formed. H. pylori–specific T cells provide growth help to abnormal B cell clones. The abnormal B cells may not be H. pylori–specific and may even be autoreactive. However, their continued proliferation, initially, depends on T cell help. The pivotal role of H. pylori–reactive T cells in driving B cell proliferation may explain why tumor cells tend to remain localized and why the tumor regresses after eradication of H. pylori. However, continued B cell proliferation eventually leads to accumulation of additional genetic abnormalities, resulting in autonomous growth and more aggressive clinical behavior.

Because only a small percentage of H. pylori–infected individuals develops lymphoma, additional currently unknown environmental, microbial, or genetic factors must play a contributory role. H. pylori strains expressing certain proteins such as CagA have been suggested to play a role in the development of gastric lymphoma, but studies have yielded conflicting results.50,51

Pathology

Histology

The key histologic feature of low-grade MALT lymphoma is the presence of lymphoepithelial lesions (Fig. 29-2).52,53 These lesions are defined as the unequivocal invasion and partial destruction of gastric glands or crypts by tumor cell aggregates. It should be noted, however, that these lesions can sometimes be seen in cases of florid chronic gastritis. Tumor cells are small to medium-sized lymphocytes, with irregularly shaped nuclei and moderately abundant cytoplasm. The morphology of these cells can vary from small lymphoplasmacytoid cells to monocytoid cells that have abundant pale cytoplasm and well-defined borders. Scattered larger cells or transformed blasts may also be seen. The lymphoma cells infiltrate the lamina propria diffusely and grow around reactive follicles; the germinal centers may be invaded, a phenomenon termed follicular colonization. Because there is a continuous spectrum from the transition of gastritis to lymphoma, diagnosis of borderline cases can be difficult. Various parameters may assist in the distinction, such as the prominence of lymphoepithelial lesions, degree of cytologic atypia, and presence of plasma cells with Dutcher bodies (periodic acid–Schiff [PAS]–positive intranuclear pseudoinclusions).

The presence of large cells can add further complexity to the diagnosis.14 The low-grade MALT lymphoma may have scattered large cells, but the tumor is composed predominantly of small cells. At the other end of the spectrum, gastric lymphomas that contain only large cells or only small areas of small cell MALT-like lymphoma should be classified as diffuse large B cell lymphomas (see later).6 In between the ends of this spectrum are low-grade lymphomas in the process of evolving into more aggressive lymphoma, with increasing numbers of large cells being observed with transformation. Some investigators have proposed histologic grading systems to take this into account; these systems appear to be able to assess prognosis on the basis of large cell percentages and clusters, but it is unclear how reproducible the systems are.20,54

Immunophenotype

Gastric MALT lymphoma cells have the typical immunophenotype of marginal zone B cells. They express pan-B antigens (CD19, CD20, and CD79a) and lack expression of CD5, CD10, CD23, and cyclin D1.55 Further immunostaining by experienced pathologists can aid in identifying lymphoepithelial lesions (see Fig. 29-2) and in distinguishing follicular colonization from follicular lymphoma (a rare occurrence in the stomach; see later).

Molecular Tests of Monoclonality

Southern blotting or PCR assay of immunoglobulin heavy chain rearrangement can assist in the documentation of monoclonality. It should be noted that B cell monoclonality may be detected in H. pylori–associated gastritis (see Chapter 50). Although monoclonality may predict for later development of lymphoma, monoclonality alone does not allow a diagnosis of lymphoma; thus, molecular tests should always be considered in the context of histologic findings.56

Clinical Features

Symptoms, Signs, and Laboratory Tests

The most common symptoms are dyspepsia and epigastric pain. Other less common symptoms include anorexia, weight loss, nausea and/or vomiting, and early satiety.15 Gastric bleeding and B symptoms (fevers, night sweats, weight loss) are rare. Serum levels of serum LDH and β2-microglobulin are usually normal.57

Diagnosis and Staging

Patients are evaluated by esophagogastroduodenoscopy (EGD). Endoscopic findings include erythema, erosions, and/or ulcers. Diffuse superficial infiltration is typical for MALT lymphoma, whereas masses are more commonly seen in diffuse large B cell lymphoma (Fig. 29-3), an aggressive NHL.58 The most common sites of involvement in the stomach are the pyloric antrum, corpus, and cardia, but biopsies should be taken from all abnormal areas and randomly from each area of the stomach, as well as the duodenum and gastroesophageal junction, because disease is often multifocal.59 Because some lymphomas infiltrate the submucosa without involving the mucosal membrane, biopsies need to be sufficiently deep and large for histopathologic and immunohistochemical analyses. H. pylori infection should be established by histologic studies, breath test, or fecal antigen testing (see Chapter 50).60 Endoscopic ultrasound (EUS) can determine the depth of infiltration and assess for the presence of enlarged perigastric lymph nodes.6163 Additional staging consists of upper airway examination, CT scans of the chest, abdomen, and pelvis, bone marrow aspiration and biopsy, and measurement of the serum LDH level. PET is not usually helpful in gastric MALT lymphoma because of low uptake of fluorodeoxyglucose (FDG).64,65

Staging System and Prognostic Assessment

In 1994, an international workshop on the staging of GI tract lymphomas proposed the Lugano staging system,11 a modification of the Blackledge system (see Table 29-2). Approximately 75% of gastric MALT lymphomas are confined to the stomach (stage I) at diagnosis66,67 and behave in a clinically indolent fashion; thus, prognosis is good for most patients, with overall survival rates of 80% to 95% at five years. Prognosis is poor in the rare patient with more advanced disease. Additional features associated with a worse prognosis are deep infiltration of the stomach wall, which is associated with a higher likelihood of regional lymph node involvement,68 and high percentages of large cells on histologic evaluation.54

Treatment

Large, randomized clinical trials have not been performed in MALT lymphoma because of the rarity of the disorder. Therefore, treatment recommendations are based on case series and expert opinion. Wotherspoon and colleagues20 first reported that gastric MALT lymphoma could completely regress by endoscopic, histologic, and molecular criteria after eradication of H. pylori. Numerous studies have confirmed these observations,30,33,6971 and antibiotics aimed at eradicating H. pylori (see Chapter 50) have become the mainstay of therapy for low-grade gastric MALT lymphoma. Even patients with advanced stages of disease can regress with eradication of H. pylori.67 However, it is important to recognize that the current literature in this field is less than optimal in several respects: older studies are limited by insufficient staging procedures and outdated classification systems, none of the reports in the literature is a controlled or randomized trial, and longer follow-up is necessary. Nevertheless, the current literature is sufficient to suggest to most experts in the field that early-stage disease is best managed with a trial of antibiotics, reserving more toxic therapies such as radiation, chemotherapy, or surgery for cases without concomitant H. pylori infection or those that do not respond to antibiotics.57,72 Table 29-3 summarizes treatment according to stage, according to the Lugano staging system.

Table 29-3 Treatment of Gastric Marginal Zone B Cell Lymphoma of MALT Type*

LUGANO STAGE TREATMENT
I, with disease limited to mucosa and submucosa Antibiotics
I, with involvement of muscularis propria or serosa; IIE, II Best treatment unknown at this time. Radiation or chemotherapy is probably a better option than surgery (see text).
IV Chemotherapy for symptomatic disease. Local management with radiation or surgery may be indicated in selected cases.

Patients with a high percentage of large cells and more advanced-stage disease should be treated as in Table 29-4 for diffuse large B cell lymphoma.

MALT, mucosa-associated lymphoid tissue.

* According to Lugano staging system.

Patients with Helicobacter pylori infection should be treated with antibiotics to clear the infection, regardless of stage (see Chapter 50).

Patients with a high percentage of large cells and disease limited to the mucosa may respond to antibiotics alone, although further study of this issue is necessary.

Stage I Disease

Most patients fall into this category and can be treated with antibiotic therapy aimed at eradication of H. pylori. Any one of the treatment regimens discussed in Chapter 50 may be used. Follow-up endoscopy with multiple biopsies should be done six to eight weeks after completion of therapy to document clearance of infection and to assess disease regression. Regression of lymphoma, but not necessarily complete regression, is usually evident at this examination. Patients with persistence of infection should be treated with a second-line antibiotic regimen (see Chapter 50).73 Histopathology at this examination can predict ultimate response, with biopsies showing only small foci of lymphoma being predictive of subsequent complete regression and biopsies showing diffuse persistent disease predicting a low likelihood of subsequent complete regression.74 Patients are then followed with endoscopy approximately every six months for two years and then yearly. Overall, approximately 75% of patients with stage I disease confined to the mucosa and submucosa will achieve complete remission. The median time to remission is five months, with remission usually occurring within 12 months; however, time to remission has been reported to be as long as 45 months.30,72,75 Of patients in clinical remission, 50% have tumor clones detected by PCR.76 With continued follow-up of these patients, the malignant clone decreases; current studies have suggested that a positive PCR at histologic remission does not predict for subsequent relapse, but longer follow-up of this issue is necessary.71 Approximately 90% of patients who had a complete clinical remission to H. pylori eradication remain in remission, with a median follow-up of three years; however late relapses can occur. Relapse may occur in association with H. pylori reinfection and can be cured by eradicating the organism again.77 In the absence of H. pylori reinfection, relapse is frequently transient.78

Approximately 25% of patients do not respond to H. pylori eradication. Lack of response is more common in patients with t(11;18) translocation; in one study, 67% of nonresponders harbored this abnormality, whereas only 4% of responders did.42 Lack of response to H. pylori eradication is also seen in patients with translocations t(1;14) and t(1;2)72; lymphomas bearing these translocations can be detected by immunohistochemical staining for nuclear BCL-10.79 Lack of response to H. pylori eradication may also indicate higher grade lesions or more extensive disease (i.e., involving the gastric wall and regional lymph nodes).

The optimal management of disease unresponsive to H. pylori eradication is not certain. Options include surgical resection, chemotherapy, and radiation. These options are discussed in the section on treatment of stage IIE disease (see later).

The management of patients with localized disease but a significant percentage of large cells is also uncertain. More recent studies have documented remission to H. pylori eradication,80,81 in contrast to earlier studies. For example, in one study of 16 patients with stage IE disease with high-grade histology, 10 of the patients had disease regression with H. pylori eradication and were free of lymphoma with a median follow-up of 43 months.80 Five of the 6 remaining patients responded to multiagent chemotherapy. If this approach is taken, the patient should be followed closely and, if the response is suboptimal, treated with one of the approaches discussed in the following section.

Occasional cases of gastric MALT lymphoma are H. pylori–negative. As would be expected, these patients are much less likely to respond to antibiotic treatment30; however, optimal management remains undefined.

Locally Advanced Disease—Stage I with Involvement of Muscularis or Serosa or Poor Response to H. pylori Eradication (Stage IIE).

Patients with more advanced-stage disease who are H. pylori–positive should also receive antibiotic therapy against H. pylori, but antibiotic therapy alone is usually not sufficient to eradicate the lymphoma. There is currently no consensus regarding the optimal management of this group of patients. Total gastrectomy can cure more than 80% of patients with stage IIE disease but diminishes patients’ quality of life and has not been shown to achieve superior results when compared with more conservative approaches.82,83 Involved field radiation therapy (30 to 40 Gy delivered in four weeks to the stomach and perigastric nodes) produces excellent results with a complete remission rate of 90% to 100% and a five-year disease-free survival of approximately 80%.8486 Radiation therapy is usually well tolerated and preserves gastric function. Thus, it has become the preferred therapy for patients with advanced-stage disease, those who are negative for H. pylori, and those with persistent disease despite H. pylori treatment.72 Other treatment options in this group include chemotherapy, immunotherapy, or combined chemoimmunotherapy. Single-agent oral chemotherapy using cyclophosphamide87 or chlorambucil has activity,88 as does treatment with purine analogs.89 Immunotherapy with rituximab, a monoclonal antibody against CD20, is also highly efficacious,90,91 although rituximab given with chemotherapy, a common combination in the treatment of aggressive lymphomas, has not been widely tested in low-grade gastric NHLs. The International Extranodal Lymphoma Study Group is currently evaluating the efficacy of this combination in marginal zone lymphomas.

DIFFUSE LARGE B CELL LYMPHOMA OF THE STOMACH

Cause and Pathogenesis

The pathogenesis of gastric diffuse large B cell lymphoma is poorly understood.95 Many large cell tumors have components of low-grade MALT tissue and are assumed to have evolved through transformation of low-grade lesions. Frequently, these bear identical rearranged immunoglobulin genes. According to the WHO classification, this is now referred to as diffuse large B cell lymphoma with areas of marginal zone–MALT-type lymphoma.96 However, other DLBCLs have no evidence of associated low-grade MALT tissue. It is unclear whether de novo gastric DLBCL has a worse prognosis than DLBCL with areas of marginal zone–MALT-type lymphoma.68,97 Most studies have suggested this to be the case, but it is unclear what percentage of large cells confers a poorer prognosis.

If the large cell lesions commonly arise from progression of low-grade lesions, then conceivably H. pylori may have a role in the initial pathogenesis. One study has suggested that H. pylori infection is more common in patients whose large cell lesions had a low-grade component.97 As outlined earlier in the discussion of tentative models for H. pylori–induced lymphoma, large cell transformation resulting from genetic events, including loss of p53 and p16, may lead to loss of tumor cells losing their dependence on H. pylori for growth.98 A high incidence of somatic mutations in rearranged immunoglobulin heavy-chain variable genes in one study of diffuse large B cell lymphoma of the stomach has implicated antigen selection in the genesis of the lymphoma. Finally, observation of a response of early-stage large cell lymphomas to H. pylori eradication has suggested a role for the organism, at least in some cases.80,81

Pathology

Diffuse large B cell lymphoma may appear grossly as large ulcers, protruded tumors, or multiple shallow ulcers.99 The most common sites of involvement are the body and antrum of the stomach. Tumors with a low-grade component are more likely to be multifocal than tumors with no low-grade component. Large cell lymphomas typically invade the muscularis propria layer or even more deeply.

Microscopic examination reveals compact clusters, confluent aggregates, or sheets of large cells that resemble immunoblasts or centroblasts, most often with a mixture of the two.99 From 25% to 40% of cases show evidence of derivation from MALT, including dense infiltration of centrocyte-like cells in the lamina propria and typical lymphoepithelial lesions.97

Immunophenotypic analysis shows expression of one or more B cell antigens (CD19, CD20, CD22, CD79a) and CD45.100 Lesions with evidence of low-grade MALT tissue do not express CD10, consistent with their having evolved from the CD10-negative marginal zone low-grade lesions. Lesions without evidence of MALT may or may not express CD10. Genetic analysis reveals monoclonal immunoglobulin gene rearrangements. Bcl-6 is frequently mutated or rearranged.101

It is worth discussing the evolution in terminology regarding diffuse large B cell lymphomas of the stomach. Many pathologists have referred to lymphomas arising in MALT with high-grade features (with or without a component of low-grade disease) as high-grade gastric MALT lymphomas. However, those involved in the development of the WHO classification were concerned that many clinicians had come to regard the term gastric MALT lymphoma as synonymous with a lesion that responds to antibiotics. This is usually not the case with high-grade lesions arising in MALT. Therefore, those involved in formulating the WHO classification96 agreed to use the term extranodal marginal zone B cell lymphoma of MALT type for low-grade lesions, and the term diffuse large B cell lymphoma for high-grade lesions, leaving out the term MALT. Low-grade lesions involving MALT often contain varying proportions of large cells, with a worse prognosis in relation to increased percentage of large cells. However, at this point, a precise grading system for this situation has not been devised and remains a goal of ongoing research.

Clinical Features

Patients present with epigastric pain (70%) or dyspepsia (30%), symptoms similar to those patients with gastric adenocarcinoma.102,103 Large tumors may cause obstruction. Ulcerating lesions may be associated with GI bleeding. B symptoms (fevers, night sweats, weight loss) and elevated serum LDH concentrations are uncommon.

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