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Novel Developments in the Pathogenesis and Diagnosis of Extranodal Marginal Zone Lymphoma

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Novel Developments in the Pathogenesis and Diagnosis of Extranodal Marginal Zone Lymphoma J Hematopathol DOI 10.1007/s12308-017-0302-2 REVIEW ARTICLE Novel developments in the pathogenesis and diagnosis of extranodal marginal zone lymphoma Max I. Schreuder 1 & Michiel van den Brand1,2 & Konnie M. Hebeda1 & Patricia J. T. A. Groenen1 & J. Han van Krieken1,3 & Blanca Scheijen 1,3 Received: 17 May 2017 /Accepted: 13 September 2017 # The Author(s) 2017. This article is an open access publication Abstract Extranodal marginal zone lymphoma (EMZL), Introduction mostly represented by mucosa-associated lymphoid tissue (MALT) type, also referred to as MALT lymphoma, is a clin- There are three different types of marginal zone lymphomas ically heterogeneous entity within the group of low-grade B (MZLs): (i) extranodal marginal zone lymphoma (EMZL), cell lymphomas that arises in a wide range of different mostly represented of mucosa-associated lymphoid tissue extranodal sites, including the stomach, lung, ocular adnexa, (MALT) type; (ii) splenic MZL (SMZL); and (iii) nodal and skin. It represents the third most common non-Hodgkin MZL (NMZL). EMZL accounts for about 7% of all adult lymphoma in the Western world, and the median age of oc- non-Hodgkin lymphoma (NHL) and 70% of MZL [1]. The currence is around 60 years. One characteristic aspect in a most predominant site for EMZL involves the stomach (70%), subset of EMZL detectable in about 25% of the cases is the but virtually all other organs can be affected, including the presence of specific chromosomal translocations involving the lung, salivary gland, ocular adnexa, skin, and thyroid. genes MALT1 and BCL10, which lead to activation of the Despite their clinical heterogeneous presentation, at least three NF-κB signaling pathway. Another unique aspect is that sev- common variants of chromosomal translocations have been eral infectious agents, such as Helicobacter pylori in the case identified as specific for EMZL, all of which affect the of gastric EMZL, and autoimmune disorders, like Sjögren NF-κB pathway [2]. Moreover, EMZLs are frequently asso- syndrome, have been implicated in the pathogenesis of this ciated with chronic inflammation and infectious agents that cancer. Recent findings as summarized in this review have give rise to chronic infections, such as Helicobacter pylori further improved our understanding of the complex pathobi- in gastric EMZL, Chlamydophila psittaci in ocular adnexa ology of this disease and have been essential to better define EMZL, Campylobacter jejuni in immunoproliferative small novel treatment strategies. In addition, many of these specific intestinal disease (IPSID), and Borrelia burgdorferi in cutane- features are currently being implemented for the diagnosis of ous EMZL [3]. On the other hand, several autoimmune disor- EMZL. ders, including Sjögren syndrome, lymphoepithelial sialadenitis and Hashimoto thyroiditis, predispose to EMZL Keywords Lymphoid malignancies . Chromosomal development. The prevailing view is that continuous immune rearrangements . Infections . MALT . EMZL stimulation resulting from chronic infections and autoinflammatory diseases cooperates with recurrent genetic aberrations resulting in lymphoid transformation. * Blanca Scheijen EMZL, in general, shows a remarkably indolent disease [email protected] course with a median survival of more than 12 years [4]. However, in a small proportion of cases, EMZL can progress 1 Department of Pathology, Radboud University Medical Center, Geert and undergo histological transformation into aggressive high- Grooteplein Zuid 10, 6525 AG Nijmegen, The Netherlands grade tumors, mostly diffuse large B cell lymphoma (DLBCL) 2 Pathology-DNA, Rijnstate Hospital, Arnhem, The Netherlands [5]. A common feature of EMZL is deregulation of the pro- 3 Radboud Institute for Molecular Life Sciences, teolytic activity of the MALT1 protein, which results in con- Nijmegen, The Netherlands stitutive nuclear factor κB(NF-κB) stimulation. Current and J Hematopathol novel therapeutic strategies are aimed to target these specific alterations, which frequently result in activation of the features underlying the molecular pathogenesis of EMZL. In NF-κB pathway, neoplastic transformation can occur, de- this review, novel insight into molecular pathogenesis of creasing the dependency of antigenic stimulation (Fig. 1). EMZL will be described and its impact on diagnosis and ther- Nonetheless, many of the EMZL show regression upon erad- apy of this disease spectrum. ication of the bacterial infections with specific antibiotic treat- ment, which is mainly the case in translocation-negative EMZL. Clinical features of EMZL Bacterial infections EMZL often occurs in organs devoid of prominent organized lymphoid tissue, where as a result of chronic inflammation, Helicobacter pylori H. pylori infection is present in 85–90% outgrowth of a malignant clone progressively replaces the re- of gastric EMZL, and support for its role as an etiologic factor active lymphocyte population. Irrespective of the site of origin, was provided in the early 1990s after demonstration of tumor EMZL is characterized by an indolent presentation and course, regression in the early-stage cases treated with antibiotic ther- mainly occurring in adults with a median age of 60 years. The apy. Although H. pylori infection can be detected in about clinical presentation differs depending on the organ involved. 50% of the general population giving rise to chronic active Patients with gastric EMZL often present with symptoms that gastritis or even peptic ulcer disease, only ~ 1% of the infected mimic those of peptic ulcer disease or gastritis (nausea, dys- subjects will develop gastric adenocarcinoma or lymphoma. A pepsia, and chronic fatigue), while recurrent respiratory infec- population-based study has demonstrated a declined incidence tions, chest pain, and dyspnea are observed in patients with of gastric EMZL after specific intervention for H. pylori in- pulmonary EMZL. Patients with conjunctival EMZL may fections in patients with acid peptic disease symptoms [12]. present with blurry vision or other visual field defects. The More direct support for the role of H. pylori in the patho- majority of the patients with EMZL display localized stage I genesis of gastric EMZL derives from studies that have shown or II extranodal disease (Ann Arbor staging system), involving that gastric EMZL cell growth could be stimulated in culture epithelial tissues at specific sites, including the gastrointestinal by H. pylori-specific T cells [13]. An additional effect of tract. In about 30% of the cases, these lymphomas disseminate H. pylori on the microenvironment is the release of the to other MALT sites, predominantly lymph nodes and in very proliferation-inducing ligand (APRIL) by lymphoma- rare cases to the bone marrow, but the peripheral blood is associated macrophages [14]. Furthermore, the H. pylori usually not involved [6]. The outcome of patients with cytotoxin-associated gene A (CagA) protein has direct onco- EMZL is good with a 5-year overall survival between 86 and genic properties both for gastric epithelial cells and B lympho- 95%, without any significant differences between the site of cytes [15, 16]. The CagA protein can enter B cells via type IV the EMZL, localized or disseminated disease [7]. secretion system in an ATP-dependent manner [17], where it undergoes tyrosine phosphorylation by SRC or ABL kinases in the C-terminal region [18, 19]. Phosphorylated CagA interacts Pathogenesis of EMZL with Grb2 and tyrosine phosphatase SHP-2 leading to ERK activation [20], which promotes phosphorylation of the pro- The term Bmarginal zone lymphoma^ refers to the fact that apoptotic protein BAD and upregulation of the anti-apoptotic these lymphoma cells are derived from post-germinal center molecules BCL2 and BCL-XL[17, 21]. Detection of CagA, memory B cells normally present in the marginal zone of phospho-SHP2, and phospho-ERK predicts involvement and lymphoid organs. In nearly all cases, EMZL displays fully dependence of H. pylori in the pathogenesis of gastric EMZL rearranged immunoglobulin heavy chain variable (IGHV) [22]. Alternatively, CagA can block cell cycle progression and and light chain genes, which show somatic hypermutation inhibits B lymphocyte apoptosis by impairing the JAK/STAT and class switching [8, 9]. In many cases, EMZL has been and p53 pathway [23, 24]. Furthermore, H. pylori activates the shown to be associated with chronic immune reactions driven NF-κB pathway in lymphocytes through both the canonical by bacterial, viral, or autoimmune stimuli (Table 1). This latter and non-canonical pathways [25]. These findings provide fur- aspect correlates with the observation that patients with auto- ther evidence that gastric EMZL follows a multistage progres- immune disorders harbor an increased risk for the develop- sion from chronic gastritis to gastric lymphoma that starts with ment of lymphomas [10, 11]. These findings have led to the H. pylori infection. hypothesis that this type of indolent lymphoma follows a mul- tistage development that starts with an infection combined Helicobacter heilmannii Additional non-H. pylori species with (auto-)antigenic stimulation or other direct effects on B have been identified in human gastric mucosa, now cells, like the presence of free radicals in an inflammatory reclassified as Helicobacter heilmannii sensu lato surrounding. With the subsequent accumulation of genetic (H. heilmannii s.l.) without specific sequence information; J Hematopathol Table 1 Summary on the main characteristics of
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