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Chronic inflammation and extra-nodal marginal-zone lymphomas of MALT-type

Seminars in Cancer Biology, pages 33 - 42

Abstract

Extranodal marginal zone lymphoma of mucosa associated lymphoid tissue (MALT) is an indolent B-cell non-Hodgkin lymphoma (NHL) arising in lymphoid populations that are induced by chronic inflammation in extra nodal sites. The stomach is the most commonly affected organ, and MALT lymphoma is clearly associated with a gastroduodenitis induced by a microbial pathogen, Helicobacter pylori, thus gastric MALT lymphoma represents a paradigm for evaluating inflammatory-associated lymphomagenesis. Variable levels of evidence have indicated a possible association between other microorganisms and non-gastric MALT lymphomas. In addition to infectious etiology, chronic inflammation arising as a result of autoimmune diseases such as Sjogren's syndrome or Hashimoto thyroiditis, poses a significant risk factor for developing NHL. Recently, genetic alterations affecting the NF-κB pathway, a major signaling pathway involved in many cancers, have been identified in MALT lymphoma. This review will present MALT lymphoma as an example of the close pathogenetic link between chronic microenvironmental inflammation and tumor development, showing how these observations can be integrated into daily clinical practice, also in terms of therapeutic implications, with particular focus on the NF-κB pathway.

Keywords: MALT lymphoma, Chronic inflammation, Marginal zone, Microbial pathogen autoimmune disease.

1. Introduction

The marginal zone of B-cell follicles is especially well developed in lymphoid organs that are continuously exposed to antigenic stimulation [1] . The marginal zone is easily observed in the spleen and to a lesser extent, in mucosa-associated lymphoid tissues (MALT), whereas it is scarcely identifiable in lymph nodes [1] . In the spleen, the marginal zone has a crucial role in T-cell-independent responses to various antigens, including polysaccharides derived from encapsulated bacteria, such as Streptococcus pneumoniae, Neisseria meningitides, and Haemophilus infuenzae [1] . In addition, marginal zone B-cells are per se primed for involvement in the immune response, since they are a source of natural antibodies (mostly IgM), which are available even in the absence of antigenic challenge and show polyreactivity against self and exogenous antigens [1] and [2].

Lymphomas arising from the marginal zone, termed marginal zone lymphomas (MZL), account for 5–17% of all non-Hodgkin lymphomas [3] . According to the sites involved, three subtypes of MZL are distinguished in the last WHO classification: (1) the extra nodal marginal zone of mucosa-associated lymphoid tissue or MALT lymphoma; (2) the splenic MZL (SMZL); (3) and the nodal MZL [4] .

MALT lymphoma differs from SMZL and nodal MZL as it arises in organs that normally lack lymphoid tissue, such as the stomach, lung, ocular adnexa, or salivary glands, but accumulate B-cells in response to chronic inflammation. This chronic inflammation may be due to either chronic infection or autoimmune processes [5] . Sustained antigenic or auto antigenic stimulation not only triggers polyclonal B-cell proliferation, but also recruits a series of inflammatory cells, including T-lymphocytes, macrophages and neutrophils, to the site of inflammation. Additional microenvironmental components, such as endothelia, contribute to the pathogenesis of these lymphomas as well. The inflammatory components may promote the growth of neoplastic B-lymphocytes by either one of two mechanisms: (i) a direct one, where, for instance, neutrophils release reactive oxygen species (ROS), which cause a wide range of genetic aberrations [6] ; (ii) an indirect one, where chronic inflammation sustains and prolongs proliferation of B-cells, with the consequent increased risk of double-stranded DNA breaks and translocations, owing to the inherent genetic instability of B-cells during somatic hypermutation and class-switching recombination [7] . Several genetic aberrations have been identified in MALT lymphomas, such as trisomy of chromosomes 3 and 18, and characteristic, mostly exclusive, translocations. Many of these recurrent chromosomal translocations and unbalanced genomic aberrations disrupt genes and related protein products involved in multiple and diverse levels of the nuclear factor κB (NF-κB) pathway [8] . The constitutive activation of NF-κB may therefore result in uncontrolled B-cell proliferation that eventually favors the development of overt lymphoma [9] .

The present review aims to link the available data on the intrinsic properties of MZL B-cells to the mechanisms orchestrated by the microenvironmental inflammatory milieu, which in turn may substantially contribute to the development of these lymphomas.

The best-studied association involves Helicobacter pylori (Hp) and gastric MALT with a prevalence of the bacterium in up to 90% of cases [10] . The second most studied association is Chlamydophila psittaci (Cp) in ocular adnexal lymphomas (OAL), which exhibits geographic variability: the prevalence of Cp in OAL ranges from 47% to 80% in Italy, Austria, Germany and Korea, while the percentages are much lower in other countries, including the United States [10] . A similar geographical variation is observed for the association between Borrelia burdgorferi (Bb) and cutaneous MALT lymphoma. Although generally less frequent, this association varies between 10 and 42% in Europe [10] , and is almost absent in non-endemic areas [11] . Finally, less robust data support the association between Campylobacter jejuni infection and Immunoproliferative small intestinal disease, due to the low frequency of reported cases and the modest levels of evidence [10] .

2.1. Autoimmunity and MALT lymphomas

Patients with Sjogren Syndrome (SS) display a 1000-fold increased risk of developing a MALT lymphoma of the parotid gland. In addition, the risk of developing MALT lymphoma increases by 2.7-fold in Systemic Lupus Erythematous [12] . From a pathogenetic standpoint, it has been hypothesized that, in the case of SS, a local chronic antigen-driving stimulation triggers the development of organized lymphoid tissue. In this context, the overexpression of B-cell activating factor (BAFF) leads to excessive immunoglobulin production and reduced apoptosis, providing a stimulus for sustained proliferation of B-cells, which eventually become autoantibody-producing plasma cells [13] .

2.2. Pathological features of extra nodal marginal zone lymphomas

In most instances, these lymphomas are often multifocal, with small, often microscopic clonally identical foci of lymphoma scattered throughout the involved organ [14] . MALT lymphoma is composed of heterogeneous B-cells, including medium-sized centrocytic-like cells, small lymphocytes with round nuclei and clumped chromatin, and monocytoid cells ( Fig. 1 ). One or more cytological features can predominate, or the different types of cells can coexist to various degrees within the same case. In some cases, plasma cell differentiation may occur and shares with the lymphocytic component the same light chain restriction by immunohistochemistry. Scattered and rare (usually less than 15–20%) large cells (immunoblastic- and centroblastic-like) may occur within the lymphoid population. Very rarely blast cells form solid or sheet-like proliferations; in such instances, a separate diagnosis of a diffuse large B-cell lymphoma should be made [15] . Neoplastic B-cells can infiltrate and disrupt the mucosal crypts and glands, forming lymphoepithelial lesions, although these structures are not pathognomonic and diagnostic for MALT lymphoma, since they can also occur in some reactive conditions [16] and in other lymphoma subtypes. Along with lymphomatous cells, reactive T lymphocytes [15] ( Fig. 2 ), neutrophils, monocytes/macrophages, and vessels ( Fig. 3 ) can be recognized. Histopathological examination remains the gold standard for diagnosis and the detection of monoclonality by polymerase chain reaction (PCR) represents a useful aid, keeping into mind that it can be observed in benign inflammations, such as chronic gastritis [17] , and conversely, cannot be detected in up to 15% of cases of overt MALT lymphomas [18] .

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Fig. 1 A case of conjunctival marginal zone B-cell lymphoma showing replacement of lamina propria by dense infiltrate made by medium-sized lymphocytes (Hematoxylin–Eosin, 100×, original magnification).

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Fig. 2 Neoplastic lymphocytes are infiltrated by a variable amount of reactive T-cells (CD3, 200×, original magnification).

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Fig. 3 The lymphomatous population is admixed with small- and medium-sized vessels (Hematoxylin–Eosin, 400×, original magnification).

The tumor cells typically express IgM, less often IgA or IgG; they are positive for CD20, CD79a, CD21, and CD35, and they are negative for CD5, CD23, CD10, and cyclinD1, recapitulating the immunophenotype of normal marginal zone B-cells. These data show that, until recently, there were not specific immunohistochemical markers for MALT lymphoma. However, two interesting molecules have been recently reported: myeloid cell nuclear differentiation antigen (MDNA) [19] has been preferentially, although not exclusively, described in MZL and the immunoglobulin receptor translocation associated-1 (IRTA-1) has been described as highly characteristic for MALT and nodal MZL, in contrast to SMZL [20] .

3. Microenvironment

The best-known microenvironmental factor comprises T-lymphocytes. In Hp-dependent gastric MALT lymphoma, infiltrating T-cells can generally act via two mechanisms. The classical one involves the CD40/CD40 ligand axis (expressed on B-cells and CD4+ T-cells, respectively), with the aid of interleukin-4 and/or interleukin-10 cytokines [21] . The other more recently described mechanism involves the recruitment of regulatory T-cells (CD4+, CD25+, FOXP3+) through the secretion of specific chemokines like CCL17 and CCL22 by B-cells [22] ; although the number of regulatory T-cells does not differ between chronic gastritis and MALT lymphoma samples, patients with lymphoma and a higher number of these cells in their biopsies at diagnosis show a better response to anti-Hp antibiotic therapy [23] . The cytotoxic CD8+, granzyme-B+ T-cell population does not seem to play a major role in classical MALT lymphoma, contrary to the increase of these cells in rare cases transforming into high-grade lymphomas [24] .

Another important microenvironmental component in MALT lymphomas is represented by neutrophils. These cells may be recruited by Hp and are a source of reactive oxygen species (ROS) [25] . ROS, which are associated with carcinogenesis, could be generated by NADPH oxidases (NOX); interestingly, one NOX family member, NOX2, appears significantly overexpressed in gastric MALT in comparison with patients with gastritis [26] . It is therefore conceivable that these molecules, possibly produced not only by myeloid cells but also by other constituents of the immune system such as mononuclear cells, may play a pathogenetic role in MALT lymphomagenesis, since a well-known property of ROS is in causing a wide range of genetic aberrations [6] , including translocations. Interestingly, CagA strains of Hp generate a strong inflammatory response characterized by release of interleukin IL-8, a powerful chemokine involved in neutrophil activation and subsequent ROS secretion [27] . Taken together, these data suggest that acquired genetic abnormalities could be related to the increased oxidative stress associated with inflammatory responses in pre-malignant MALT-like lesions, specifically in the mucosa of organs exposed to exogenous antigens.

Along with the above-mentioned cellular constituents, also monocytes/macrophages seem to play an active role in the pathogenesis of MZL. Other than being a source of the costimulatory molecules CD80 and CD86, which are molecules involved in MALT lymphomas [28] , the most exciting novelty in this context is represented by the discovery of lymphoma-associated macrophages releasing a proliferation inducing ligand (APRIL), which sustains Hp-associated MALT lymphoma progression; in particular, a local pool of macrophages, upon Hp infection, may release large amounts of APRIL and this phenomenon could be further amplified and prolonged by the contribution of Hp-specific T-cells [29] . Another pivotal role played by monocytes/macrophages in MZL is to act as selective reservoirs for pathogens, similar to the scenario in Cp-associated MALT lymphomas of ocular adnexa [30] .

Endothelia have been included in the MALT lymphoma-associated microenvironment as well. First of all, high endothelial venules expressing N-acetylglucosamine-6-O-sulfotransferases (GlcNAc6ST-1)-mediated L-selectin ligand carbohydrate and mucosal-addressin cell adhesion molecule 1 (plMAdCAM-1) play a crucial role in chronic gastritis and gastric MALT lymphoma induced by a Candidatus Helicobacter heilmannii strain in a mouse model [31] . Moreover, sialyl Lewis glycans are expressed by these particular types of endothelia and act as ligands for L-selectin, a molecule particularly important for the recruitment of Hp-specific T-cells; importantly, such vessels are greatly reduced in biopsies taken after eradication therapy in patients with MALT lymphoma [32] .

Finally, chemokine receptors are very important players in the MZL milieu. In particular, Hp-related gastric MALT shows up-regulation of CCR7, CXCR3, CXCR7 and CXCL12 as well as loss of CXCR4, in contrast to Hp-associated gastritis. Two exceptions to invariable CXCR3 expression in these lymphomas are represented by cutaneous MALT, which lacks this molecule [33] and Cp-negative MALT lymphomas of ocular adnexa, in which CXCR3 is variably expressed [34] ; these features may point toward different pathogenetic mechanism(s) present in these two forms of extra nodal MZL.

4. Pathogenetic mechanism

The overall pathogenetic multistep process is initiated by chronic inflammatory antigenic stimulation, which favors the assembly of aggregates of polyclonal B-lymphocytes in the sites of chronic inflammation. This antigen-driven polyclonal B-cell proliferation favors, through class-switch recombination and somatic hypermutation mechanisms, the selection of auto-reactive B-cell clones. The hypermutation process associates with genomic instability, which eventually leads to the development and progressive prevalence of a neoplastic monoclonal lymphoproliferation ( Fig. 4 ) [35] and [36].

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Fig. 4 Microbial pathogen infection or auto antigens induce chronic inflammation with the attraction of B-cells, T-cells, neutrophils, macrophages, endothelia, and stromal cells. B-cell proliferation is driven by activated reactive T-cells through CD40-mediated signaling, as well as by Th2 cytokines. The chronic proliferative state of these B-cells, as well as neutrophil-mediated release of reactive oxygen species in areas of chronic inflammation, induces additional oncogenic events that eventually make lymphoproliferation independent of antigenic stimulation.

The best-evaluated scenario of chronic inflammation leading to MALT acquisition is gastritis induced by Hp. The stomach lacks MALT under physiological conditions, because its low pH prevents the survival of lymphocytes in the gastric mucosa. When infection with either Hp or H. heilmannii establishes, buffering of the gastric pH occurs, due to the secretion of urease by bacteria; this change enables infiltration of lymphocytes and acquisition of MALT. The subsequent clonal B-cell expansion is characterized by the occurrence of somatic hypermutation in the variable regions of IGH genes [37] and [38] and in about 50% of tumors, there is ongoing mutation (intra-clonal variation) with the biased usage of some IGHV segments [39] . Importantly, the IGH genes from MALT lymphoma samples, irrespectively of being associated with bacterial infections, occasionally include sequence variants implicated in autoantibody production [40], [41], [42], and [43]. In fact, it is important to underline that MZL neoplastic B-lymphocytes retain their property as a source of polyreactive antibodies both in gastric MALT [41] and SMZL [44] . The above-reported sequence gastritis-lymphoma is still not completely understood; along with the classic view of antigen-dependent and antigen-independent phases [28] , microRNAs (miR), which play a critical role in posttranscriptional gene regulation have also been implicated. In particular, miR-539 is up-regulated only in gastritis, as opposed to normal gastric mucosa and overt MALT lymphomas, while miR-150, miR-550, miR-124a, miR-518b [45] , mir-142-5p (which is associated with resistance to Hp eradicating therapy), and miR-155 [46] are overexpressed in lymphomas alone, with miR-150 possibly bearing a prognostic impact in cutaneous MZL [47] . In addition, miR-203 and miR-200 have been shown to be down-regulated by epigenetic silencing in gastric MALT lymphomas [48] and conjunctival MALT lymphomas [49] , respectively.

5. Immunogenetics

The vast majority of MALT lymphomas carry somatically mutated IGHV genes [18], [39], [40], [50], [51], [52], [53], [54], [55], [56], [57], [58], [59], [60], [61], [62], [63], and [64], although rare cases, especially if derived from primary lung MALT lymphomas, can have unmutated IGHV[40], [55], [62], and [65]. The frequently reported intra-clonal heterogeneity of the IGHV mutations, the specific pattern of somatically acquired nucleotide substitutions retaining the IGHV framework region, and peculiar use of multiple IGHVD-segments [37], [39], [40], [51], [53], [54], [56], [58], [59], [62], [64], and [66] indicate that the neoplastic cells might undergo a process of maturation and selection for the affinity of their B-cell receptor. There is an apparently biased usage of families of IGHV or of individual IGHV by MALT lymphomas originating in specific anatomical sites or carrying particular clinical or genetic features: IGHVH1-69 in salivary glands, IGHVH3 family (IGHVH3-30 or IGHVH3-23) in the stomach (for MALT lymphomas responsive to Hp eradication and without BIRC3-MALT1 fusion) or thymus, IGHVH3 family (3–30, 3–23, 3–11, 3–07) or IGHVH4-34 in orbital adnexal, IGHV3 and IGHV4 families in the lung, IGHVH1-69 or IGHVH4-59 in the skin [21], [34], [39], [51], [52], [53], [55], [57], [60], [61], [62], [63], [64], [67], [68], [69], [70], [71], and [72]. However, it should be taken into account that the reported frequencies of these associations may be biased by virtue of the different analytical procedures used and the relatively small series.

Importantly, no apparent association has been reported between IGHV usage and Hp or Cp infections [40] and [61]. In addition, the B-cell receptors expressed by MALT lymphoma cells appear to recognize mainly self antigens [for example, the Fc portion of IgG, thus acting as rheumatoid factors (RF)] [52], [62], [68], [43], and [73], although they can behave as polyreactive antibodies binding both self and exogenous antigens [41] .

6. Acquisition of genetic abnormalities

In MALT lymphomas, both balanced (chromosomal translocations) and unbalanced (DNA gains or losses) genetic aberrations can be observed. Gains of chromosome 3/3q and of chromosome 18/18q are observed in 20–40% of the MALT lymphomas, a frequency higher than in other lymphomas but similar to that seen in SMZL and nodal MZL [74], [75], [76], and [77]. The pathogenetic role of these two gains affecting large genomic regions is still undefined. A frequently recurrent lesion is the 6q23.3 deletion (15–30% of cases) affecting TNFAIP3 (tumor necrosis factor, alpha-induced protein 3; also known as A20) [76], [78], [79], and [80], a gene whose protein product is involved in limiting the activity of the NF-κB pathway. TNFAIP3 is also a target of inactivating mutations [76] and [79]. Inactivation, by deletions or mutations, of TNFAIP3/A20 also occurs in additional lymphomas, including SMZL [81] and [82]. The frequency of the three most common recurrent unbalanced genomic aberrations appears largely independent of the anatomical site [77] . Less common aberrations are deletion at 17p (targeting the tumor suppressor gene TP53), gains at 8q (maybe affecting the oncogene MYC) and at 6p (no defined affected gene) [76], [77], [83], and [84]. Due to their relatively low frequency, it is not yet known whether these uncommon aberrations have a preferential anatomical distribution [77] . Chromosomal translocations occur at a variable frequency according to the anatomical site of occurrence ( Table 1 ); this heterogeneous distribution may reflect a distinct microenvironmental inflammatory pathogenic agent.

Table 1 Genetic lesions in MALT lymphomas.

Involved genes Genetic lesions Anatomic sites Frequency Clinical relevance Mechanism of action in NF-κB pathway
BIRC3-MALT1 t(11;18)(q21;q21) Stomach, lung 15–40% Antibiotic and alkylating agents resistance Polyubiquitinylation of NEMO
IGH-MALT1 t(14;18)(q32;q21) Lung, salivary gland, skin, ocular adnexa 20%   MALT1 oligomerization (BCL10 dependent)
IGH-BCL10 t(1;14)(p22;q32) Stomach, lung <5% Antibiotic resistance MALT oligomerization
IGH-FOXP1 t(3;14)(p13;q32)   <5%   Unknown
+3/3q Equal distribution 20–40%    
+18/18q Equal distribution 20–40%    
TNFAIP3 −6q23 Ocular adnexa, thyroid, salivary glands 15–30%   Deletion of physiological inactivation of IKKbeta through deubiquitination
MYD88 Somatic mutation Equal distribution 5–10%   Activation of the pathway after stimulation with Toll-like, interleukin-1 and interleukin-18 receptors

The most common chromosomal translocations are represented by t(11;18)(q21;q21), t(1;14)(p22;q32), t(14;18)(q32;q21) and t(3;14)(p13;q32), which result in BIRC3–MALT1, IGH–BCL10, IGH–MALT1 and IGH–FOXP1 rearrangements, respectively. These translocations are well known to occur with variable frequencies in gastric and non-gastric MALT lymphomas [27], [76], [85], [86], [87], [88], [89], [90], [91], [92], [93], [94], [95], and [96] and almost all of them are capable of inducing a deregulation of the NF-κB pathway ( Table 1 ).

The translocation t(11;18)(q21;q21) is the most common structural chromosomal abnormality in MALT lymphomas, accounting for 13%-50% of cases, and is more often encountered in gastric MALT lymphomas but rare in non-gastric sites, with the exception of pulmonary MALT [8], [27], and [97]. Remarkably, this translocation is not found in other MZL and is mutually exclusive with any further genetic aberrations [98] . Furthermore, in gastric MALT lymphomas, it is also strongly associated with infection by Hp CagA-positive strains [27] and [99]. The t(11;18)(q21;q21)-positive MALT lymphomas are more often resistant to Hp eradication treatment than MALT lymphomas lacking this translocation [100] and [101], but complete lymphoma regression can still be obtained in 20% of these positive cases after Hp eradication as well. In contrast to previous data [100] and [101], recent papers have shown that t(11;18)(q21;q21) can be found at approximately equivalent frequencies in both gastric MALT lymphoma and gastric DLBCL [102] , suggesting therefore that the presence of this translocation in gastric MALT lymphoma does not exclude progression to DLBCL. All breakpoints of the t(11;18)(q21;q21) result in BIRC3 fusion in-frame to MALT1. BIRC3 is a member of the inhibitor of apoptosis (IAP) family and inhibits the biological activity of certain caspases [103] . MALT1 is a key mediator of the antigen-receptor signaling pathway that leads to NFκB activation [104] . The t(11;18)(q21;q21) finally deregulates MALT1/paracaspase ubiquitin ligase activity via NEMO ubiquitination, causing constitutive activation of NF-κB and promoting tumourigenesis [105] .

The t(14;18)(q32;q21) translocation occurs in 15% to 20% of MALT lymphomas and brings the intact MALT1 gene under the control of the IGH enhancer, resulting in deregulated expression of MALT1 and downstream activation of the NF-κB pathway [86] . The t(14;18)(q32;21) translocation is frequently associated with additional genetic aberrations, including trisomies 3, and/or 12 and 18. This translocation occurs more frequently in non-gastrointestinal MALT lymphomas, such as those arising in the lung and ocular adnexa [86] and [106].

The t(1;14)(p22;q32) and its variant t(1;p2)(p22;p12) [107] occur in 1% to 2% of MALT lymphomas. As a result of the translocation, the entire coding region of the BCL10 gene is juxtaposed next to the IGH enhancer region (or the IGLk region in the case of a variant translocation). This gene encodes a CARD-containing protein that has a key role in antigen-receptor signaling to the NF-κB pathway [108] , by virtue of its ‘adaptor protein’ role implicated in surface receptor signaling. The subsequent high nuclear expression of BCL10 protein is thus important in MALT lymphomagenesis.

The t(3;14)(p13;q32) translocation juxtaposes the FOXP1 gene to the IGH gene, and is present not only in MALT lymphomas but also in DLBCL [89] . A high expression of FOXP1 seems to correlate with poor outcome of both MALT lymphomas and DLBCL [109] and [110]. How FOXP1 mediates signaling in the mature, peripheral B-cell pool and how this protein could contribute to MALT lymphoma pathogenesis remain unclear.

7. NF-κB involvement in marginal zone B-cell lymphomas

It is well known that B-cells are sustained by interactions with the microenvironment [111] and that antigenic stimulation, through engagement of the B-cell receptor, plays a critical role in this context.

Since the NF-κB pathway appears so instrumental for the development of MALT lymphomas, it should be clarified how the previously mentioned genetic defects interact in this context. In normal B-cells, NF-κB activation is one of the most important downstream effects of the stimulation of receptors such as the B-cell receptor, BAFF receptor or Toll-like receptors [112], [113], [114], [115], [116], and [117]. In the absence of stimuli, NF-κB molecules are kept inactive in the cytoplasm, when complexed to Inhibitory B (IκB) proteins. The IκBα protein can be phosphorylated by the IκB kinase (IKK) heterodimer: this phosphorylation leads to ubiquitylation and subsequent degradation of IκBα, therefore allowing the NF-κB protein to reach the nucleus, where it acts as a transcription factor by targeting genes involved in critical cellular functions. The IKK complex comprises two catalytically active kinases (IKKα and IKKβ) and a regulatory component (IKKγ/NEMO).

MALT1, BCL10 and BIRC3, the three genes involved in the t(11;18), in the t(14;18) and in the t(1;14) translocations, respectively, all act upstream of the IKK complex [108], [118], [119], [120], [121], [122], and [123]. After receptor stimulation, CARD11/CARMA1 recruits BCL10, MALT1 and TRAF6 and the IKK heterodimer. The complex CARD11-BCL10-MALT1-TRAF6 induces IKKγ degradation and activates NF-κB [108], [119], [120], [121], [122], [124], and [125]. BIRC3 and the BIRC3-MALT1 fusion proteins localize to lipid rafts via their BIR domains. MALT1 and the fusion product BIRC3-MALT1 can directly bind to TRAF6 via the Ig-like domains of MALT1 and this leads to the direct activation of TRAF6, which subsequently activates NF-κB [125] . Wild-type BIRC3 represents a physiologic regulator of this process [123] . Similar to other IAPs [126] , the BIRC3 RING domain has ubiquitin ligase (E3) activity [123] . By means of BIR-mediated binding, BIRC3 leads to BCL10 ubiquitylation thus regulating BCL10 response after antigen receptor stimulation [123] . The BIRC3-MALT1 fusion protein created by the t (11; 18) translocation retains the BIR domains, while it always lacks the BIRC3 RING domain, thus suggesting that BIRC3-MALT1 binds BCL10 but can no longer ubiquitinate the molecule [123] . BIRC3-MALT1 can also mediate the proteolytic cleavage of NIK, a kinase that then phosphorylates and activates IKKα, thereby triggering also the non-canonical NF-κB pathway [127] . In activated B-cell-type diffuse large B-cell lymphomas (ABC-DLBCL), somatic mutations of CARD11 and more upstream molecules, such as CD79B or CD79A, frequently activate the NF-κB pathway, which is also constitutively activated by mutated MYD88, a protein that also acts on the JAK/STAT pathway. While activating mutations of CARD11 or CD79A/B have not been reported in MALT lymphomas [128] , MYD88 is affected by mutations, which can be detected in 5–10% of cases [129], [130], and [131]. In addition, the NF-κB negative regulator TNFAIP3/A20, which is a deubiquitinating enzyme able to inactivate IKKβ, is recurrently inactivated in MALT lymphomas (6q23 loss and/or somatic mutations) [76], [78], [79], and [80], thus leaving the pathway active.

The important role of BIRC3-MALT1 fusion protein, MALT1 and BCL10 in MALT lymphoma is further supported at the experimental level by mouse models bearing constitutively expressed transgenes. In fact, BIRC3-MALT1 fusion gene transgenic mice display an expansion of splenic MZL cells [109] and [124]. MALT1 gene transgenic mice develop MALT lymphomas and ABC-DLBCL [132] , while BCL10 transgenic mice have an expansion of marginal zone B-cells [133] .

Finally, epigenetic abnormalities have been described in MALT lymphomas. CpG island hypermethylation of genes such as CDKN2A, DAPK1, APBA1, APBA2 and MINT31 has been reported in gastric MALT lymphomas [134] and [135].

8. Clinical features of extra nodal marginal zone lymphomas

Most MALT lymphomas present as extra nodal disease, usually limited to the site of origin. The presenting symptoms are essentially related to the primary location.

Markedly and irrespectively of the site of origin, gastric and non-gastric MALT lymphomas share an indolent presentation [136], [137], and [138]. The median age is about 60 years. A slightly higher proportion of females than males are affected. Very few patients present with elevated lactate dehydrogenase (LDH) or beta-2 microglobulin levels. Constitutional B-symptoms are extremely uncommon. Dissemination of MALT lymphoma to multiple sites is not uncommon, with either synchronous or metachronous involvement of multiple mucosal sites or non-mucosal sites such as bone marrow, spleen, or liver [139] and [140]. Regional lymph nodes can also be involved. The stomach is the most common site of localization in MALT lymphoma, accounting for about one-third of cases. Other typical presentation sites include the ocular adnexa, the lung, the skin, the salivary glands, and the thyroid.

The outcome of patients with MALT lymphoma is good with a long overall survival (5-year overall survival reported between 86% and 95%), without any significant difference between gastrointestinal or non-gastrointestinal lymphoma, or between localized and disseminated disease [137], [139], and [141]. Median time-to-progression is estimated at around 5 years and is improved by combined treatment associating rituximab and chlorambucil with a 5-year PFS recently reported at 71% in a large phase III trial [141] . Histological transformation into large cell lymphoma is extremely rare, and occurs independently of dissemination [142] : in such a situation, prospective studies have shown no difference in overall survival between transformed gastric MALT lymphoma and de novo gastric diffuse large B-cell lymphoma [143] and [144].

9. Therapeutics management: present principles and future

How may this comprehensive pathophysiological view of MALT lymphoma help in the therapeutic management of MALT lymphoma? The causative relationship between MALT lymphoma and microbial infection provides a paradigm in the illustration of a causative role of immunological drive in lymphoma pathogenesis [145] . More precisely, most of the data obtained from the analysis of Hp infection in gastric MALT lymphoma show that Hp-generated immune responses will drive MALT lymphoma proliferation via signaling from CD40 and CD86 through bystander - cell help, and direct triggering of Toll-like receptor (TLR) and B-cell receptor by Hp-associated lipopolysaccharides and auto antigen, respectively [145] , in order to activate the NF-κB pathway. When translocations are present, their oncogenic products (BCL10, MALT1, BIRC3-MALT1) are potential activators of the canonical NF-κB pathway. They may further amplify the activity of this pathway by enhanced expression of surface receptors TLR-6 and CCR2 and/or proteolytic cleavage of the negative inhibitor A20 and cooperate with the signaling from BCR, BAFFR and CD40 via the help of bystander T-cells generated in the Hp-mediated reactive component [145] .

These observations enable us to understand why the eradication of infectious agents can cure MALT lymphoma when it is associated with a microbial pathogen [5] . This strategy has been well-reported in gastric MALT lymphoma [146] and [147] and even in gastric DLBCL [148] . A review of 24 studies comprising 780 patients published in 2002, found that complete lymphoma regression after Hp eradication was achieved in 35–100% of patients with MALT lymphoma, depending on the disease stage (stage EI1 confined to mucosa and submucosa vs. stage EI2 beyond submucosa) [149] . More recently, Zullo et al. confirmed this result analyzing data from 32 studies including 1408 patients, with a MALT lymphoma remission rate of 79% [150] . In most patients the response after Hp eradication is quite rapid and can be seen in the first 2–6 months. However, the time between Hp eradication and complete remission of gastric MALT lymphoma can vary and can take even longer than 12 months. Accordingly, most protocols recommend waiting for at least 12 months after successful eradication therapy before a nonresponse is defined and second-line therapy is applied. In non-gastric MALT lymphoma, interesting prospective data have recently been published in patients with Cp-associated ocular adnexa lymphoma, where Cp eradication therapy with doxycycline showed lymphoma regression in 65% of the patients [151] . In the other non-gastrointestinal localizations, only scattered studies are reported, which preclude conclusions being drawn about the benefit of antibiotic therapy in these cases, and may suffer from a publication bias, whereby only positive cases could be reported. On these grounds, antibiotics should presently be regarded as an experimental procedure in patients with non-gastrointestinal MALT lymphomas.

In the absence of this microbial association, no standard of treatment exists. In retrospective studies of MALT lymphomas, no significant difference in survival was apparent between patients who received either local therapy including surgery or radiation therapy, or systemic treatment including chemotherapy (alkylating agents with chlorambucil and cyclophosphamide, purine analogs with fludarabine and cladribine) and/or immunotherapy with rituximab [136] . Polychemotherapy (chlorambucil/mitoxantrone/prednisone) has shown antitumor activity [152] . Bendamustine combined with rituximab seems to give similar progression-free survival to R-CHOP (p = 0.3249) [153] . Anthracycline based chemotherapy should be reserved for patients with high tumor burden (bulky mass, high LDH level) [136] . The result of the only prospective randomized trial realized in first-line treatment has shown an advantage in combining rituximab to chlorambucil compared to chlorambucil alone or rituximab alone, with a 5-year event-free survival of 70% with chlorambucil plus rituximab, compared to 52% for chlorambucil and 51% for rituximab [141] and [154].

The unique physiopathology of extra nodal MZL may also lead to novel therapeutic strategies, targeting the microenvironment. In this context, lenalidomide, an agent with a dual antitumor effect, including direct antitumor, anti-angiogenic and immunomodulatory effects, has been tested in untreated patients or in refractory/relapsed patients [155] . The results showed that 61% (11/18) of the patients responded to Lenalidomide. Interestingly, a switch from partial response to complete response (CR) was seen after 9 months arguing for prolonged treatment. In one study comprising 19 untreated MZL patients (out of a total of 75 patients with other lymphoma subtypes), the combination of lenalidomide with rituximab resulted in 90% response, with 66% achieving a CR [156] . The most common grade ≥3 non-hematologic toxicities included rash, muscle pain, thrombosis and infection. Grade ≥3 neutropenia and thrombocytopenia occurred in 27% and 5% patients, respectively. Since there is an important role for BCR signaling in the pathogenesis of extra nodal marginal zone lymphoma in the context of inflammatory reaction, targeting BTK could be an appealing approach. Other agents with direct antitumor activities are under evaluation in MALT lymphoma and include the mTOR inhibitor everolimus, the oral PI3K inhibitor idelalisib (CAL-101), the epigenetic drugs vorinostat and cladribine, and the proteasome inhibitor bortezomib.

In conclusion, MALT lymphomas arise from sites of chronic infection and/or chronic inflammation. It is clear that the tumor microenvironment, which is largely orchestrated by inflammatory cells, is an unavoidable player in the neoplastic process. These insights could foster the use of new anti-inflammatory therapeutic approaches during MALT lymphoma development.

Conflict of interest

The authors declare that there is no conflict of interest.

Acknowledgments

The authors would like to thank our colleague Afua Adjeiwaa Mensah (Bellinzona, Switzerland) for manuscript editing. MP and AJMF are recipients of Special Program in Molecular Clinical Oncology AIRC 5xmille grant number 9965, FB of a grant from Nelia and Amadeo Barletta Foundation.

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Footnotes

a APHP-Hôpital Saint-Louis, Department of Hemato-oncology, Paris Diderot 7 University, INSERM U728, Paris, France

b IOR Institute of Oncology Research, Lymphoma and Genomics Research Program, and Oncology Institute of Southern Switzerland, Lymphoma Unit, Bellinzona, Switzerland

c APHP-Hôpital H. Mondor, Department of Pathology, Creteil, France

d San Raffaele Scientific Institute, Department of Onco-Hematology, Milano, Italy

e San Raffaele Scientific Institute, Unit of Lymphoid Malignancies, Milano, Italy

f San Raffaele Scientific Institute, Pathology Unit, Milano, Italy

lowast Corresponding author at: Pathology Unit, Ospedale San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milano, Italy. Tel.: +39 0226432544; fax: +39 0226437070.

1 Both authors contributed equally.