Marginal Zone B-cell Lymphoma 

Updated: Jun 09, 2014
  • Author: Hala El-Zimaity, MD; Chief Editor: Mamoun Younes, MD  more...
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Definition

Marginal zone lymphomas are indolent lymphomas that arise from memory B cells in the marginal zone of lymphoid tissue. [1] They include splenic marginal zone lymphoma, nodal marginal zone lymphoma, and extranodal marginal zone lymphoma. Extranodal marginal zone lymphomas occur outside lymph nodes (eg, in the gastrointestinal tract, thyroid, orbit, leptomeninges, spinal cord, or skin). [2, 3] MALT (mucosa-associated lymphoid tissue) lymphoma (MALToma) is the term traditionally used for extranodal marginal zone lymphoma of MALT. [4] This review focuses on gastric marginal zone lymphoma.

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Epidemiology

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 of MALT (MALT lymphoma) is the most common indolent subtype and represents 7% of all non-Hodgkin lymphomas. [5, 6, 7] The stomach is the most common extranodal site (incidence rate [IR] = 3.8), followed by eye/adnexa (IR = 1.4), lung, skin, and salivary glands (IRs = 0.9–1). [3]

Nearly all patients with gastric MALT lymphoma are infected with Helicobacter pylori. [8] Further, histological and endoscopic improvement commonly follows H pylori eradication. [9]

The true incidence of gastric MALT lymphoma worldwide remains unclear because presenting symptoms are nonspecific and endoscopy findings often mimic gastritis. Nonetheless, H pylori prevalence can be loosely applied as a surrogate for gastric MALT lymphoma worldwide prevalence, bearing in mind that most people infected with H pylori do not become ill from the bacteria.

H pylori prevalence varies from 7-33% [10, 11] in Europe, 48-78% in South America, [12, 13] 87% in a South African population from the Eastern Cape province, [14] and 37.5-66% in Asian countries. [12, 15] Though nongastrointestinal marginal zone lymphoma is most commonly seen in women, [16] the incidence rate of gastric marginal zone lymphoma is nearly equal among men and women, except at older ages when incidence is higher among males (male:female IR ratio = 1.27). [3]

H pylori infection continues to decline worldwide, [15, 17] causing a marked decrease in the incidence of associated diseases, including gastric MALT lymphoma.

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Etiology

Marginal zone lymphoma of MALT 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. [18] Similar to carcinomas, epidemiology and molecular studies support a multistage theory. [19, 20] Though the molecular mechanism is not fully understood, it is believed to involve the stimulation of antigen receptor by autoantigen 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. [21]

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Location

Extranodal marginal zone lymphoma develops from 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, and thyroid gland) is more likely to spread, with gastric involvement reported in up to 30% of patients. [16, 22] Patients with primary marginal zone lymphoma of the aerodigestive mucosal/glandular sites, specifically the parotid gland, are more likely to have gastric involvement. [16] This may reflect the marginal zone lymphoma cells’ homing mechanism, which predisposes them to spread to other regions within the aerodigestive tract. [22, 23]

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Clinical Features and Imaging

The clinical presentation of lymphomas depends largely on its 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. [24] As the endoscopic appearance rarely suggests the diagnosis, [24] an extensive biopsy protocol with biopsies from normal and abnormal areas should be performed at a follow-up esophagogastroduodenoscopy. The histopathologic evaluation of gastric biopsy specimens establishes the diagnosis, reveals the possibility of secondary transformation into a diffuse large B-cell lymphoma, and excludes the presence of other preneoplastic lesions. [25]

Once the diagnosis of gastric marginal zone lymphoma is established, possible etiologies such as H pylori gastritis and autoimmune diseases should be excluded. [26] If the presence of active H pylori infection is not proved by histochemistry, serology can increase the diagnostic yield. [27] The presence of autoimmune diseases should not be excluded to the organ involved by MALT lymphoma.

Gastric MALT lymphomas occur in Sjögren disease and may also be associated with a chronic H pylori infection. [26] MALT lymphomas can occur simultaneously at several sites, including the thyroid and parotid glands and the conjunctiva. Bone marrow involvement is rare in gastric and other MALT-type marginal zone lymphomas. [22]

Regional staging is best performed with endoscopic ultrasound. [28] A multiorgan extensive staging program includes colonoscopy with biopsy and MRI of salivary and lacrimal glands. [22]

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 marginal zone lymphomas of MALT-type requires multiorgan staging programs.

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Microscopic Findings

Florid reactive lymphoid follicles have three compartments: marginal zone, mantle zone, and follicle center. Reactive B cells of the marginal zone have medium-sized nuclei that resemble the nuclei of small cleaved follicular center cells (centrocytes). In marginal zone lymphoma, centrocytelike tumor cells that often show monocytoid or plasmacytoid differentiation selectively invade gut epithelium, forming characteristic lymphoepithelial lesions. Later, they invade follicles, sometimes giving a follicular pattern. See the images below.

This image depicts typical lymphocytic infiltrate This image depicts typical lymphocytic infiltrate in marginal zone B-cell lymphoma.
B-cell centrocyte-like cells are shown in this ima B-cell centrocyte-like cells are shown in this image.
Lymphoepithelial lesions (LELs) can be seen in thi Lymphoepithelial lesions (LELs) can be seen in this image.

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. [29]

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Immunohistochemistry

Wide-spectrum keratin immunostain such as AE1/AE3 or low-molecular-weight cytokeratins CK8 or Cam 5.2 can highlight the presence of destructive lymphoepithelial lesions. [30]

As marginal zone lymphomas arise from B cells, B-cell markers (eg, CD20, CD79a, CD10, CD23, and bcl-2) are expressed. Frequently, a coexpression of T-cell marker CD43 suggests a neoplastic proliferation. In some cases, light-chain restriction can be demonstrated with kappa and lambda light-chain antibodies. In neoplastic proliferations, there is an excess of kappa-positive, exceeding 10:1 of lambda-positive, cells.

See the images below.

This image depicts marginal zone lymphoma cells ex This image depicts marginal zone lymphoma cells expressing CD20.
This image depicts marginal zone lymphoma cells ex This image depicts marginal zone lymphoma cells expressing CD3.
This image depicts marginal zone lymphoma cells ex This image depicts marginal zone lymphoma cells expressing CD5.
Epithelial destruction is highlighted in this imag Epithelial destruction is highlighted in this image with the use of broad-spectrum keratin AE1/AE3 reagent.
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Molecular/Genetics

Translocation t(11;18)(q21;q21) API2-MALT1 is found in around 30% of MALT lymphomas. Two other known genetic alterations include translocation t(14;18)(q32;q21)/IGH-MALT1 found in roughly 10% of MALT lymphomas and t(1;14)(p22;q32)/BCL10-IGH. [21] Lymphomas harboring these translocations commonly activate the nuclear factor (NF)-kappaB pathway and usually do not respond to H pylori eradication. [21] In contrast, most of gastric lymphomas without such translocation can be cured by antibiotics.

Scientists continue to uncover other molecular changes. For example, recently, evidence has indicated a role for FOXP1 on band 3p13. [31] In a subset of diffuse large B-cell lymphomas, this subset has been linked to marginal zone lymphoma of MALT [31] and perhaps occasionally representing transformation of the latter. [32]

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Tumor Spread and Staging

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 lymphoma. [33, 34, 35, 36] The classic Ann Arbor staging system as modified for extranodal disease [33] and the Lugano staging system [37, 34, 36] have been widely used in the past two decades. The newer Paris staging system describes more accurately the depth of gastric wall involvement, [35] 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. [38]

In overall, early staging procedures should include a gastroduodenal endoscopy (or endosonography), with multiple biopsies taken from each region of the stomach, duodenum, gastroesophageal junction, and any abnormal-appearing site. [37] Endoscopic ultrasound is recommended to evaluate regional lymph nodes and gastric wall infiltration. [37] In marginal zone lymphoma of MALT-type, attention to other MALT sites and autoimmune diseases is necessary. [24] As in other lymphomas, staging procedures should include CT-scanning, laboratory studies, and bone marrow examination. [24]

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Prognosis and Predictive Factors

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 natural history and organ-specific management strategies. [39]

Early low-grade gastric MALT rarely transforms into secondary diffuse large B-cell lymphoma or progresses beyond the stomach. Gastric 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. [37] H pylori eradication therapy with antibiotics can cure about 70% of gastric MALT lymphoma.

Lymphomas that are positive for the (11;18) translocation, however, or with nuclear expression of NF kappa B, are unresponsive. [21] Further, t(11;18) was 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. [40] Responders compared with nonresponders often produce a higher number FOXP3 T-regulatory cells among CD4 T cells (FOXP3:CD4). [41] The presence of involved perigastric lymph nodes on endoscopic ultrasonography is a negative predictive factor of tumoral response to anti– H pylori treatment. [42]

Differential Diagnoses

Surprisingly, the most common differential is the distinction between florid lymphoid hyperplasia associated with H pylori gastritis with lymphoid hyperplasia and incipient marginal zone lymphoma. Morphologic features that favor MALT lymphoma include extensive infiltrates, B-cell lymphocytic infiltrates (rather than plasma cells) found between glands, and destructive lymphoepithelial lesions in which intraepithelial lymphocytes express CD20 (B cells). [30]

The morphologic examination is essential in selecting cases for further workup. It is also important to keep unusual presentations, such as Burkitt lymphoma and mantle cell lymphoma, as part of the lymphoma differential in evaluating gastric biopsies and follow antibody panels as previously suggested. [30]

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