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Gastric Mucosa-Associated Lymphoid Tissue Lymphoma and Helicobacter Pylori Infection: a Review of Current Diagnosis and Manageme

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Gastric Mucosa-Associated Lymphoid Tissue Lymphoma and Helicobacter Pylori Infection: a Review of Current Diagnosis and Manageme Hu et al. Biomarker Research (2016) 4:15 DOI 10.1186/s40364-016-0068-1 REVIEW Open Access Gastric mucosa-associated lymphoid tissue lymphoma and Helicobacter pylori infection: a review of current diagnosis and management Qinglong Hu1* , Yizhuo Zhang2, Xiaoyan Zhang3 and Kai Fu3 Abstract Helicobacter pylori (H. pylori)-associated gastritis is one of the most common infectious diseases in the United States, China and worldwide. Gastric mucosa-associated tissue lymphoma (MALT lymphoma) is a rare mature B-cell neoplasm associated with H. pylori infection that is curable by antibiotics therapy alone. The pathological diagnosis of gastric MALT lymphoma can be reached by histological examination, immunohistochemical staining and B-cell clonality analysis. H. pylori eradication is the choice of therapy for early-stage gastric MALT lymphoma. High response rates and long-term survival have been reported in refractory and localized diseases treated with low-dose radiation therapy. Systemic chemotherapy is recommended for advanced-stage gastric MALT lymphoma and cases with large B-cell lymphoma transformation. Recent advances in the pathological diagnosis and management of gastric MALT lymphoma are reviewed in this article. Keywords: Gastric MALT, Helicobacter pylori Background for gastric MALT lymphoma. Since the discovery of the Helicobacter pylori (H. pylori) infection of the stomach association of H. pylori gastritis with gastric MALT is one of the most common diseases worldwide. Accord- lymphoma [6], extensive basic studies and clinical trials ing to the World Health Organization, H. pylori infec- have been performed worldwide, and treatment guide- tion contributes to approximately 75 % of stomach lines have been recommended for H. pylori-associated cancers and 5.5 % of all cancers worldwide [1]. The in- gastritis and gastric MALT lymphoma [7–11]. Gastric fection rate varies in different countries of the world and MALT lymphoma is a rare disease. The estimated inci- also in different regions of China, from 55 to 80 % in the dence of gastric lymphoma was approximately 0.3–0.8 mainland to 15 % in Hong Kong and 40 % in Taiwan per 100,000 people in Europe [8]. The incidence of [2–4]. The infection rate is higher in rural areas than in gastric MALT lymphoma was approximately 0.38 per cities [4]. Gastric mucosa-associated lymphoid tissue 100,000 people in the United States, according to a re- (MALT) lymphoma is a clonal B-cell neoplasm arising cent study. The incidence rates increased with age [12]. from post-germinal center B-cells in the marginal zone No population-based studies have been reported in the of the lymphoid follicles. H. pylori was identified from Chinese literature, and the incidence of gastric MALT the gastric mucosa of patients with active chronic gastri- lymphoma is unknown in China. We searched literature tis more than 30 years ago by Marshall and Warren [5]. of studies of H. pylori gastritis and gastric MALT lymph- H. pylori infection of the stomach is considered a major oma in English and Chinese and reviewed the recent cause of chronic active gastritis and a major risk factor advances in the diagnosis and management of these two closely related diseases. Current issues in the diagnosis * Correspondence: [email protected] and management of the disease are also discussed. 1Tucson Pathology Associates, PC Carondelet Saint Joseph Hospital, 351 North Wilmot Road, Tucson, AZ 85711, USA Full list of author information is available at the end of the article © 2016 The Author(s). Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Hu et al. Biomarker Research (2016) 4:15 Page 2 of 9 Diagnosis of gastric MALT lymphoma marginal zones. Aberrant expression of CD43 by the B- The diagnosis of gastric MALT lymphoma relies on clin- cells may be identified, which is a supporting evidence ical symptoms, endoscopic features and pathohistological for gastric MALT lymphoma. The diagnosis of gastric examination of gastric biopsy tissue, as well as noninvasive lymphoma can be established by morphologic examin- tests for H. pylori infection, such as the 13C-urea breath ation and immunohistochemical evaluation. However, a test and the monoclonal stool antigen test. The clinical majority of the cases may require clonality analysis of presentation of patients with gastric MALT lymphoma is the B-cells by in situ hybridization for kappa and lambda nonspecific. The symptoms include dyspepsia, vague epi- light chains with formalin-fixed tissue sections. The ex- gastric pain, bloating and heartburn; more severe and pression of kappa/lambda light chain may be weak, and alarming symptoms are anemia, melena, hematemesis, they often cannot be detected by in situ hybridization. vomiting and weight loss. Negative expression of the light chains cannot rule out Endoscopic examination with biopsy and histopatho- the diagnosis of lymphoma. If the result of in situ logic examination is a standard practice in the diagnosis hybridization is inconclusive, further molecular studies, of gastric MALT lymphoma in the United States and the such as polymerase chain reaction (PCR), for immuno- Western world. The macroscopic changes of the gastric globulin heavy chain (IgH) gene rearrangement may be mucosa in MALT lymphoma are nonspecific, including beneficial. A definitive diagnosis of gastric MALT thickening of the mucosal folds, irregular nodules, lymphoma is supported if clonal IgH gene rearrange- polypoid lesions, petechiae, edema, erosion and ulcers. ment is demonstrated by a PCR study. However, this The distribution of the lesions is usually patchy, with result is not a prerequisite for the diagnosis of gastric multiple foci. Therefore, sampling at different anatomic MALT lymphoma [14]. A report of “atypical lymphoid sites is recommended during gastric endoscopic examin- proliferation, suspicious for MALT lymphoma” may be ation and biopsy. Biopsies should be taken from abnor- issued for ambiguous cases. Clinical follow-up and re- mal and normal areas, including the antrum, the greater peat biopsy may finally lead to a definitive diagnosis. and lesser curvatures, and the fundus. At least two biop- Wotherspoon and colleagues [15] observed a spectrum sies should be taken from each site of the stomach, and of histological changes between normal gastric mucosa, the tissue from each biopsy site should be fixed in separ- chronic active gastritis and gastric MALT lymphoma, as ate containers with 10 % buffered formalin [13]. Sam- shown in Table 1. This histological grading is helpful in pling from multiple sites may be difficult in practice as it differential diagnosis. Histopathologic changes of Types increases risk of complications, such as acute gastric 3 and 4 requires immunohistologic staining and/or mo- bleeding, especially in patients on anticoagulant therapy. lecular investigation to reach a definitive diagnosis. The H. pylori-associated chronic active gastritis is present in biopsy tissues taken by endoscopy are usually small, and the majority of patients with gastric MALT lymphoma. the layer of muscularis propria may not be observed in most of the biopsies. The depth of invasion of the gastric Histopathologic features of gastric MALT wall by the lymphoma cells is important for disease sta- lymphoma ging, and it should be evaluated and documented if Under microscopic examination, the biopsy tissue usu- identified under a microscope. Monotonous and dense ally shows dense lymphoid infiltration with monotonous lymphoid infiltration in the gastric mucosa may raise the features. Germinal centers may be observed with the suspicion of gastric MALT lymphoma. This requires the expansion of the marginal zone. The lymphoma cells are pathologist’s experience and may be affected by the typically small and monotonous with monocytoid fea- adequacy of tissue processing, the thickness of the tissue tures, with small, round nuclei and a scant to moderate sectioning, and the quality of histologic staining. Immuno- amount of pink to clear cytoplasm. Some cases may histochemical staining may show expansion of the B-cell show prominent plasmacytoid differentiation mixed with compartment with sheets of B-cells. The thickness of the small lymphocytes. The lymphocytes may infiltrate the tissue sections can significantly affect the interpretation of glandular epithelium, resulting in the destruction of the compartment expansion of B-cells or T-cells. The tissue glands, forming so-called “lymphoepithelial lesions”. The sections of the gastric biopsy should not be more than lymphocytes in the glands are B-cells, which may be 3 μm in thickness. A false impression of mixed B-cell and identified by immunohistochemical staining for B-cell T-cell proliferation may be obtained due to inadequate and epithelial markers such as CD20 and pan- thickness of the tissue sections during immunostaining. cytokeratin. However, these stains are not used routinely. Gastric MALT lymphoma is a type of low-grade B-cell Common immunohistochemical stains may include the lymphoma with tissue infiltration by small lymphocytes. B-cell markers CD20 and CD79a and the T-cell markers High-grade transformation to large B-cell lymphoma is CD3 and CD5. Staining for CD21 may be helpful to uncommon. If high-grade lymphoma is present, the infil- highlight residual lymphoid follicles and expanding tration of large lymphoma cells may be a predominant Hu et al. Biomarker Research (2016) 4:15 Page 3 of 9 Table 1 Wotherspoon scale of confidence of histological diagnosis of lymphoma [15] Grade Description Histological features 0 Normal Scattered plasma cells in the lamina propria. No lymphoid follicles. 1 Chronic active gastritis Small clusters of lymphocytes in the lamina propria.
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