Gastric Marginal Zone B-Cell Lymphoma (Gastric MALT lymphomas, Gastric MALTomas)

Marginal zone lymphomas are indolent lymphomas that arise from memory B cells in the marginal zone of secondary lymphoid follicles. ^{[1, 2]} They include three distinct types: splenic marginal zone lymphoma, nodal marginal zone lymphoma, and extranodal marginal zone lymphoma. ^[3]

Extranodal marginal zone lymphomas occur outside lymph nodes (eg, gastrointestinal tract, ^{[4, 5, 6]} thyroid, orbit, leptomeninges, spinal cord, ^{[7, 8]} liver, or skin) ^{[9, 10, 11]} often in a setting of chronic inflammation or autoimmune disease (eg, Sjogren disease). MALT (mucosa-associated lymphoid tissue) lymphoma (MALToma) is the term traditionally coined for extranodal marginal zone lymphoma of MALT. ^[12]

This review will focus on gastric marginal zone lymphoma.

Marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma; MALToma) is the most common indolent subtype representing 7%-8% of all B-cell lymphomas, and as many as 50% of primary gastric lymphomas. ^{[13, 14, 15, 16, 17]} The stomach is the most common extranodal site, followed by the eye or opticadnexa, lung, skin, and salivary glands. ^[10]

Nearly all patients with gastric MALT lymphoma are infected with Helicobacter pylori. ^[18] Further, histologic and endoscopic improvement commonly follows H pylori eradication. ^[19] The true incidence of gastric MALToma worldwide remains unclear, because the presenting symptoms are nonspecific and endoscopy findings often mimic gastritis. Nonetheless, we can loosely use H pylori prevalence as a surrogate for the worldwide prevalence of gastric MALT lymphoma. Bear in mind that most people infected with H pylori will not become ill from the bacteria.

H pylori prevalence varies from 7% to 33% ^{[20, 21]} in Europe, 48%-78% in South America, ^{[22, 23]} 87% in a South African population from the Eastern Cape province, ^[24] and between 37.5% and 66% in Asian countries. ^{[22, 25]} Though non-gastrointestinal marginal zone lymphoma is most commonly seen in women, ^[26] the incidence of gastric marginal zone lymphoma is nearly equal among men and women—except at older ages in whom the incidence is higher among males (male-to-female incidence rate ratio = 1.27). ^[10]

H pylori infection continues to decline worldwide ^{[25, 27]} causing a marked decrease of associated diseases, including gastric MALT lymphoma.

Extranodal marginal zone lymphomas commonly follow immune system dysregulation from sustained stimulation with chronic infections or autoimmune disorders. Susceptibility is thus influenced by both genetic and environmental factors.

Marginal zone lymphoma or mucosa-associated lymphoid tissue (MALT) lymphoma (MALToma) is acquired secondary to persistent antigenic stimulation with either chronic infectious conditions or autoimmune processes, such as H pylori gastritis, Hashimoto thyroiditis, and Sjögren syndrome. ^[28] Similar to carcinomas, epidemiologic and molecular studies support a multistage theory. ^{[29, 30]}  Although the molecular mechanisms are not fully understood, they are believed to involve stimulation of antigen receptors by autoantigens, and co-stimulatory molecule CD40 by H pylori-specific T cells. MALT lymphoma develops as marginal zone memory B cells undergo somatic mutation and replace the normal B cell population. ^[31]

Extranodal marginal zone lymphoma develops from mucosa-associated lymphoid tissue (MALT) secondary to chronic antigenic stimulation. It usually presents in MALT of the gastrointestinal tract, mainly the stomach, without evidence of a systemic primary tumor. ^[1] In contrast, extranodal marginal zone lymphoma outside the gastrointestinal tract (eg, salivary glands, ocular adnexa, thyroid gland) is more likely to spread, with gastric involvement reported in up to 30% of patients. ^{[26, 32]} Patients with primary marginal zone lymphoma of the aerodigestive mucosal/glandular sites, specifically the parotid gland, are more likely to have gastric involvement. ^[26] This may reflect homing mechanisms of the marginal zone lymphoma cells that predispose them to spread to other regions within the aerodigestive tract. ^{[32, 33]}

The clinical presentation of lymphomas depends largely on their location and is similar to those of other malignancies affecting that specific organ. Unfortunately, the most common presenting symptoms of gastric marginal zone lymphoma are nonspecific upper gastrointestinal complaints such as dyspepsia, abdominal pain, and/or hemorrhage.

Endoscopy findings often mimic gastritis or erosions, with mass lesions being unusual. ^[34] As the endoscopic appearance rarely suggests the diagnosis, ^[34] an extensive biopsy protocol with biopsies from normal and abnormal areas should be performed at a follow-up esophagogastroduodensocopy (EGD). The histopathologic evaluation of gastric biopsies establishes the diagnosis, the possibility of secondary transformation into a diffuse large B-cell lymphoma (DLBCL), and excludes the presence of other preneoplastic lesions. ^[35]

Once the diagnosis of gastric marginal zone lymphoma is established, possible etiologies such as H pylori gastritis and autoimmune diseases should be excluded. ^[36] If the presence of active H pylori infection is not proved by histochemistry, serology can increase the diagnostic yield. ^[37] The presence of autoimmune diseases should not be excluded to the organ involved by mucosa-associated lymphoid tissue (MALT) lymphoma. Gastric MALT lymphomas occur in Sjogren’s disease and may also be associated with chronic H pylori infection. ^[36] MALT lymphomas can occur simultaneously at several sites, including the thyroid and parotid glands and the conjunctiva. Bone marrow involvement is a rare event in gastric and other MALT-type marginal zone lymphomas. ^[32]

Regional staging is best performed with endoscopic ultrasonography. ^[38]  A multiorgan extensive staging program includes colonoscopy with biopsy and magnetic resonance imaging (MRI) of the salivary and lacrimal glands. ^[32]

In summary, clinical symptoms and signs as well as endoscopic images are often not specific. The diagnosis relies on endoscopic biopsies with a firm pathological subtyping of the lymphoma. Locoregional staging requires endosonography. The multifocal localization and dissemination pattern in MALT-type marginal zone lymphomas requires multiorgan staging programs.

Not surprising, the most common differential diagnosis is distinguishing between florid lymphoid hyperplasia associated with H pylori gastritis and incipient marginal zone lymphoma. Morphologic features that favor mucosa-associated lymphoid tissue (MALT) lymphoma include extensive infiltrates, B-cell lymphocytic infiltrates (rather than plasma cells) found between glands, destructive lymphoepithelial lesions (LELs) in which intraepithelial lymphocytes express CD20 (B cells), the presence of Dutcher bodies, and moderate cytologic atypia. ^{[39, 40, 41]} In contrast to benign reactive hyperplasia, lymphoma cells express immunoglobulin light-chain restriction. ^[42] Morphologic examination is essential in selecting cases for further work-up.

MALT lymphoma with prominent follicular colonization can mimic follicular lymphoma. ^[40] Myeloid cell nuclear differentiation antigen (MNDA) staining may facilitate the differential diagnosis as this nuclear antigen is expressed in 61-75% of MALT lymphomas but less than 10% of follicular lymphomas. ^[43]

Mantle cell lymphoma can resemble extranodal marginal zone lymphoma. ^[44] Mantle cell lymphomas frequently have an enlarged mantle zone, 85% express Bcl-1 and CD 43, and 80% express CD5. It is important to keep unusual presentations, such as Burkitt lymphoma and mantle cell lymphoma, as part of the lymphoma differential diagnosis in evaluating gastric biopsies with appropriate antibody panels, ^[39]  particularly if the clinical course is unusual for MALT lymphoma. ^[44]

Florid reactive lymphoid follicles have three compartments: marginal zone, mantle zone, and follicle center. In marginal zone lymphoma, the lymphoma cells invade the marginal zone external to the preserved mantle zone. Marginal zone lymphoma cells are small- to medium-sized B cells resembling those of centrocytes (centrocyte-like [CCL]), often with abundant pale cytoplasm. The accumulation of more pale-staining cytoplasm may lead to a monocytoid appearance. ^[42]

Gastric marginal zone lymphomas are characterized by the presence of reactive (nonneoplastic) B-cell follicles surrounded by an infiltrate of neoplastic B cells as a monotonous infiltrate of small- to medium-sized lymphoid cells with variable amounts of plasma cells (see the first two images below). ^[45] These CCL tumor cells often show monocytoid or plasmacytoid differentiation that selectively invade gut epithelium, forming characteristic lymphoepithelial lesions (LELs) (see the third image below). Later, the cells invade follicles, sometimes forming a follicular pattern.

 

Wide-spectrum keratin immunostains such as AE1/AE3 or low molecular weight cytokeratins CK8 or Cam 5.2 can highlight the presence of destructive lymphoepithelial lesions (LELs) (see the following image). ^[39]

Nonetheless, LELs, though typical of mucosa associated lymphoid tissue (MALT) lymphoma, are not always present and can be seen in other lymphoma subtypes. ^[46] It is common to see large lymphoid cells resembling centroblasts or immunoblasts, but these cells are in the minority. ^[42] Marginal zone lymphomas with more than 80% blasts should be designated as diffuse large B-cell lymphoma (DLBCL), and the presence of accompanying MALT lymphoma noted. ^[42] The terms “high-grade MALT lymphoma" and "MALT lymphoma” should not be used to label a DLBCL even if it arose in a MALT site or is associated with LELs. ^[42]

The neoplastic cells of MALT lymphoma express B-cell markers (CD19, CD20, CD79a, PAX5, and Bcl-2), ^{[39, 40]} CD43 positive or negative, but lack CD5, CD10, Bcl-1, and CD23. ^[39] Infrequent cases are CD5 positive, and its expression has been reported with an aggressive clinical behavior in some patients. ^{[47, 48, 49]} Very rare cases are CD10 positive but Bcl-6 negative. ^[42] There is also a prominent population of T cells, predominantly CD4 positive. Importantly, the neoplastic cells of MALT lymphoma show immunoglobulin light chain restriction, and its demonstration is helpful in in the differential diagnosis with reactive hyperplasia. ^[42]

See the images below.

As discussed earlier, mucosa-associated lymphoid tissue (MALT) lymphoma cells show immunoglobulin light chain restriction. Chromosomal translocations including t(11;18)(q21;q21), t(1;14)(p22;q32), and t(3;14) produce a chimeric protein (BIRC3-MALT1) and transcription deregulation of Bcl-10, MALT1, and FOXP1. ^[42] Translocation t (11;18)(q21; q21) API2-MALT1 is found in about 30% of MALT lymphomas and translocation t(14;18)(q32;q21)/IGH-MALT1 is found in roughly 10% of MALT lymphomas. Lymphomas harboring these translocations commonly activate the nuclear factor (NF)-kB pathway and often do not respond to H pylori eradication. ^[31]

In contrast, most gastric lymphomas without such translocation can be cured by antibiotics. Scientists continue to uncover other molecular changes. For example, evidence exists to indicate a role for FOXP1 on chromosome 3p13. ^[50] In a subset of diffuse large B cell lymphomas (DLBCLs), this subset has been linked to marginal zone lymphoma of MALT, ^[50]  perhaps occasionally representing transformation of the latter. ^[51]

Mucosa-associated lymphoid tissue (MALT) lymphomas remain localized to their site of origin for long periods, during which locally directed therapy is effective. Several systems are available for staging gastric marginal zone lymphomas. ^{[52, 53, 54, 55]} The classic Ann Arbor staging system as modified for extranodal disease ^[52] and the Luagano staging system ^{[46, 53, 55]} have been in wide use over the past two decades. The newer Paris staging system more accuratelydescribes  the depth of gastric wall involvement, ^[54] which may predict response to H pylori eradication. In a comparison of the staging systems, only the T stage of the Paris classification showed prognostic significance for overall survival. ^[56]

Overall, early staging procedures should include a gastroduodenal endoscopy (or endosonography) evaluation with multiple biopsies taken from each region of the stomach, duodenum, gastroesophageal junction, and from any abnormal-appearing site. ^[46] Endoscopic ultrasonography is recommended to evaluate regional lymph nodes and gastric wall infiltration. ^[46] In MALT-type marginal zone lymphoma, attention to other MALT-sites and autoimmune diseases is necessary. ^[34] As with other lymphomas, staging procedures should include computed tomography (CT) scanning, laboratory studies, and bone marrow examination. ^[34]

Low-grade marginal zone lymphomas have an indolent clinical course and an impressive response to early therapy. The primary organ of origin is the most significant prognostic factor of the natural history and organ-specific management strategies. ^[57]

Early low-grade gastric MALT rarely transforms into secondary diffuse large B cell lymphoma (DLBCL) or progresses beyond the stomach. Gastric mucosa-associated lymphoid tissue (MALT) lymphoma often remains localized without progression for prolonged periods, even without treatment.

In general, H pylori eradication is the primary treatment for patients with stage I and II disease with low tumor load. If H pylori bacteria cannot be identified in tissue sections, active infection must be ruled out by other means, such as urea breath test or stool antigen test. ^[46]  H pylori eradication therapy with antibiotics can cure about 70% of gastric MALT lymphomas.

Lymphomas that are positive for the (11;18) translocation, however, or with nuclear expression of nuclear factor kappa B (NF-κB) are unresponsive. ^[31]  Furthermore, t(11;18) has been associated with a significantly higher risk of relapse in patients with stage I1E gastric MALT lymphoma who had been successfully treated with H pylori eradication. ^[58]  Compared to nonresponders, responders often produce a higher number of FOXP3 Treg cells among CD4 T cells (FOXP3:CD4). ^[59] The presence or absence of H pylori should be investigated in DLBCLs, as primary DLBCLs may respond to eradication therapy alone. ^[42] The presence of involved perigastric lymph nodes on endoscopic ultrasonography is a negative predictive factor of tumor response to anti–H pylori treatment. ^[60]