Emerging Role of Infectious Etiologies in the Pathogenesis of Marginal Zone B-cell Lymphomas Emanuele Zucca 1 , Francesco Bertoni 1,2 , Barbara Vannata 1 , and Franco Cavalli 1 Abstract Extranodal marginal zone B-cell lymphomas of the mucosa-associated lymphoid tissue (MALT) arise from lymphoid populations that are induced by chronic inflammation in extranodal sites. The most frequently affected organ is the stomach, where MALT lymphoma is incontrovertibly associated with a chronic gastritis induced by a microbial pathogen, Helicobacter pylori. Gastric MALT lymphoma therefore represents a paradigm for evaluating inflammation-associated lymphomagenesis, which may lead to a deeper understanding of a possible etiologic association between other microorganisms and nongastric marginal zone lymphomas. Besides infectious etiology, chronic inflammation caused by autoimmune diseases, such as Sj € ogren syndrome or Hashimoto thyroiditis, can also carry a significant risk factor for the development of marginal zone lymphoma. In addition to the continuous antigenic drive, additional oncogenic events play a relevant role in lymphoma growth and progression to the point at which the lymphoproliferative process may eventually become independent of antigenic stimulation. Recent studies on MALT lymphomas have in fact demonstrated genetic alterations affecting the NF-kB) pathway, a major signaling pathway involved in many cancers. This review aims to present marginal zone lymphoma as an example of the close pathogenetic link between chronic inflammation and tumor development, with particular attention to the role of infectious agents and the integration of these observations into everyday clinical practice. See all articles in this CCR Focus section, "Paradigm Shifts in Lymphoma." Clin Cancer Res; 20(20); 5207–16. Ó2014 AACR. Introduction A better understanding of the molecular mechanisms of lymphomagenesis is fundamental as it may lead to the deve- lopment of nonchemotherapeutic agents active in specific lymphoma subtypes, as highlighted in three of the articles included in this CCR Focus section (1–3). Furthermore, infectious agents can represent additional therapeutic targets for lymphoma treatment toward chemotherapy-free thera- peutic approaches. While Tsukasaki and Tobinai (4) have reviewed the published data on HTLV-1–associated adult T- cell leukemia–lymphoma, here we summarize the data avail- able on the role of infectious agents in the pathogenesis of marginal zone B-cell lymphomas (MZL). The latter comprise three different entities, namely extranodal MZL of mucosa- associated lymphoid tissue (MALT) type, nodal MZL, and splenic MZL (5). While splenic and nodal MZL are quite rare, each comprising less than 2% of lymphomas, extranodal MZL of MALT type is relatively common, representing around 8% of the total number of non–Hodgkin lymphoma cases. The term "mantle cell lymphoma" is due to the fact that extranodal MZL, nodal MZL, and splenic MZL are believed to derive from B cells normally present in the marginal zone, which is the outer part of the mantle zone of B-cell follicles. MALT lymphoma is composed of morphologically heterogeneous small B cells, including marginal zone (centrocyte-like) cells, monocytoid cells, small lympho- cytes, and scattered (immunoblast- and centroblast-like) large cells; there is a variable degree of plasma cell differentiation. The lymphoma infiltrates the marginal zone of reactive B-cell follicles and extends into the interfollicular region. In epithelial tissues, the neoplastic cells typically penetrate in the epithelium forming lym- phoepithelial lesions (6). The B cells resident in the marginal zone function as innate-like lymphocytes that mount rapid antibody res- ponses to both T-cell–dependent and T-cell–independent antigens (7). Most of the marginal zone lymphocytes are B cells that are involved in the T-cell–independent early immune response and express a restricted immunoglob- ulin (Ig) repertoire. Postgerminal center memory B cells, needed for the T-cell–dependent immune response, are also localized in the marginal zone. MALT lymphoma presents somatically mutated immunoglobulin heavy chain variable (IGHV) genes in nearly all cases. IGHV 1 Lymphoma Unit, Division of Research, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland. 2 Lymphoma and Genomics Research Program, IOR Institute of Oncology Research, Bellinzona, Switzerland. Corresponding Author: Emanuele Zucca, Oncology Institute of Southern Switzerland (IOSI), Ospedale San Giovanni, CH-6500 Bellinzona, Switzer- land. Phone: 419-1811-9040; Fax: 419-1811-9182; E-mail: ielsg@ticino.com doi: 10.1158/1078-0432.CCR-14-0496 Ó2014 American Association for Cancer Research. CCR FOCUS www.aacrjournals.org 5207