Abstract: The term marginal-zone lymphoma (MZL) encompasses three closely related indolent B-cell non-Hodgkin's lymphoma subtypes, namely extranodal MZL or MALT lymphoma, nodal MZL, and splenic MZL. Although these neoplasms may share a common cell of origin, being the marginal zone B-cell, they display different characteristics with evident clinical and biological variations according to the organ where the lymphoma arises. The past 2 decades have spawned an avalanche of new data that encompasses the genetic aberrations and pathogenic mechanisms leading to these diseases. This article briefly addresses each of the MZL.
Marginal zone B-cell lymphomas (MZL) are a group of indolent B-cell non-Hodgkin’s lymphomas that arise from the marginal zone of lymphoid tissues. The latter is a distinct micro-anatomic compartment of the B-follicle, well developed in those lymphoid organs where an abundant influx of antigens is known to occur (spleen, mesenteric lymph nodes, and mucosa-associated lymphoid tissue or MALT). MZL account for approximately 10% of all non-Hodgkin’s lymphomas, being the third most frequent subtype after diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma. They are subdivided into three entities by the World Health Organization (WHO): splenic MZL, nodal MZL, and MALT lymphoma (or extranodal MZL) (Jaffe et al., 2008). Despite histologic and genetic similarities, clinical differences were the main reason to consider these 3 MZL subtypes as distinct clinicopathological entities. MALT lymphoma is relatively common, encompassing about 8% of all non-Hodgkin’s lymphomas, while nodal and splenic MZL are quite rare, each comprising less than 1% of non-Hodgkin’s lymphomas.
MALT lymphoma differs from its splenic and nodal counterparts as it arises in organs that normally lack lymphoid tissue (like stomach, lung, and salivary and lachrymal glands) but have accumulated B-cells in response to either chronic infections or autoimmune processes. Besides inducing an initially polyclonal B-cell proliferation, sustained (auto)antigenic stimulation may also trigger inflammatory responses by attracting neutrophils, which release reactive oxygen species. The latter are genotoxic and cause a wide range of genetic abnormalities. Moreover, prolonged proliferation of B-cells induced by chronic inflammation may also increase the risk of DNA damage, like double-strand DNA breaks and translocations, due to the intrinsic genetic instability of B-cells during somatic hypermutation and class switch recombination. Remarkably, the genes targeted by most of these abnormalities are involved in one and the same pathway leading to the activation of nuclear factor κB (NF-κB). The latter is a key transcription factor in the immune response as it regulates the expression of a number of survival- and proliferation-related genes in B-cells (Siebenlist et al., 2005). As such, its constitutive activation by MALT lymphoma-related genetic abnormalities results in uncontrolled B-cell proliferation and thus subsequent neoplastic transformation of the B-cell clone. In splenic and nodal MZ, the mechanisms determining lymphomagenesis are not yet clear.
Link between chronic inflammation and MZL
Growing evidence indicates that MZL, and MALT lymphomas in particular, are preceded by chronic antigenic stimulation (chronic infection or autoimmune diseases) and involve deregulation of the nuclear factor κB (NF-κB) pathway. Indeed, long-standing (auto)antigenic stimulation explains how lymphoid infiltrates may appear in extranodal sites that are normally devoid of lymphoid tissue (e.g., the stomach, lung, the salivary and lachrymal glands). The list of microbial species associated with MZ lymphoproliferations now comprises at least 6 distinct members: Helicobacter pylori (H. pylori), Helicobacter heilmannii, Campylobacter jejuni, Borrelia burgdorferi, Chlamydia psittaci (C. psittaci), and hepatitis C virus, which have been associated with gastric MALT lymphoma, immunoproliferative small intestinal disease (IPSID), cutaneous MALT lymphoma, orbital MALT lymphoma, and splenic MZL, respectively (Ferreri et al., 2009; Lecuit et al., 2004; Roggero et al., 2000; Zucca et al., 2000; Sagaert et al., 2010).
Of all MZ lymphomas, the infectious etiology of gastric MALT lymphoma has been documented the most extensively. In healthy individuals, a thick layer of viscous mucus as well as gastric acid limit bacterial colonization of the stomach. However, H. pylori, a Gram-negative bacterium also associated with peptic ulceration and gastric carcinoma, survives in the acid environment by secreting a pH buffering urease, and triggers lymphoid infiltration. There is now compelling evidence that gastric MALT lymphoma is caused by H. pylori infection. First, the prevalence of H. pylori in both the gastric mucosa and serum of gastric MALT lymphoma patients is well above the infection frequency in other populations (Parsonnet et al., 1994). Second, gastric MALT lymphoma has the highest incidence in regions with endemic H. pylori infection (Doglioni et al., 1992). Third, H. pylori triggers T-cell-mediated B-cell growth in vitro by activating the CD40 pathway (Hussell et al., 1993b). Also, H. pylori eradication therapy leads to complete lymphoma regression in about 80% of the cases with early stage disease (Wundisch et al., 2005). Finally, gastric MALT lymphomas can be induced in vivo in mice models by prolonged H. pylori infection (O’Rourke, 2008). Remarkably, despite proliferation of tumor cells after H. pylori stimulation, the gastric MALT lymphoma-derived immunoglobulin recognizes various auto-antigens other than H. pylori (Hussell et al., 1993a). As such, it may be hypothesized that gastric MALT lymphoma arises from H. pylori-stimulated, auto-reactive B-cells.
Outside the stomach, the role of (auto)antigens is less clearly defined. Contrary to H. pylori, none of the other previously mentioned infections linked to MALT lymphoma fulfills the 4 criteria postulated by Koch (namely: Is the bacteria detectable in the host’s tissue in early disease stage? Can the bacteria be cultivated from the affected tissue? Can the bacteria induce the disease in animal models? Can the bacteria be isolated from sick animals?). However, new criteria have been established by recent molecular advances that take into account the host-specificity as well as putative uncultivability of certain microbial organisms (Franco et al., 2004). Also, recent years have witnessed a significant improvement of our understanding of the link between orbital MALT lymphomas and the intracellular bacterium C. psittaci. Not only are monocytes/macrophages that infiltrate orbital MALT lymphomas carriers of C. psittaci (as shown by electron microscopy, PCR, immunohistochemistry, and fluorescence), but moreover, C. psittaci is both viable and infectious in blood and conjunctiva of orbital MALT lymphoma patients (Ponzoni et al., 2008). Furthermore, it is well established that autoimmune diseases increase the risk of developing nongastric MALT lymphomas. Autoreactive B-cells infiltrate the thyroid gland in Hashimoto thyroiditis and the salivary glands in Sjögren syndrome, and progressively organize into a MALT-mimicking lymphoproliferation. Patients with Sjögren syndrome have a 44-fold increased risk of developing a lymphoma and patients with Hashimoto thyroiditis have a 70-fold increased risk of thyroid lymphoma (Derringer et al., 2000; Manganelli et al., 2006).
Trisomies 3 and 18 have been detected at similar frequencies, ranging from 15% to 60%, in extranodal, nodal, and splenic MZL. Other trisomies, such as 7 and 12, are less common.
The chromosomal translocations t(11;18)(q21;q21), t(1;14)(p22;q32), t(14;18)(q32;q21), and t(3;14)(p13;q32) are all known to occur with variable frequencies in MALT lymphomas, resulting in API2-MALT1, IGH-BCL10, IGH-MALT1, and IGH-FOXP1 rearrangements, respectively (Sagaert et al., 2006b; Wlodarska et al., 2005). Recently, some novel translocations in MALT lymphomas were identified, in which the IGH-gene was rearranged with a partner-gene on chromosome arm 1p (CNN3), 5q (ODZ2), or 9p (JMJD2C) (Vinatzer et al., 2008). The t(11;18)(q21;q21) is the most common structural chromosomal abnormality in MALT lymphomas. It is demonstrated in 10-50% of gastric MALT lymphomas, whereas this translocation rarely occurs in nongastric MALT lymphomas, with the exception of pulmonary MALT lymphomas (Streubel et al., 2004). The t(11;18)(q21;q21) fuses the amino-terminus of the API2-gene (located at 11q21) to the carboxyl-terminus of the MALT1-gene (located at 18q21), generating the fusion-protein API2-MALT1. Remarkably, the presence of t(11;18)(q21;q21) in MALT lymphomas correlates with the lack of any further genetic instability or chromosomal imbalances. T(11;18)(q21;q21)-positive gastric MALT lymphomas do not differ from their t(11;18)(q21;q21)-negative counterparts, with respect to morphology and immunophenotype. However, several studies revealed that t(11;18)(q21;q21)-positive gastric MALT lymphomas are more often resistant to Helicobacter pylori eradication treatment (Liu et al., 2001; Sugiyama et al., 2001). Nevertheless, complete lymphoma regression can still be obtained in 20% of these cases after Helicobacter pylori eradication (Sugiyama et al., 2001; Zullo et al., 2010). Also, for a decade, researchers believed that t(11;18)(q21;q21)-positive gastric MALT lymphomas rarely if ever evolved to a more aggressive diffuse large B-cell lymphoma (DLBCL), but new data show that the t(11;18)(q21;q21) can be found in both gastric MALT lymphomas and gastric DLBCLs at approximately equivalent frequencies (Toracchio et al., 2009). Although the presence of t(11;18)(q21;q21) may facilitate and/or confirm the diagnosis of a MALT lymphoma, current guidelines do not recommend a routine screening for the t(11;18)(q21;q21) once the diagnosis of a gastric MALT lymphoma is established (Fischbach et al., 2009).
The t(1;14)(p22;q32) and t(14;18)(q32;q21) occur in a small minority of almost exclusively non-gastric MALT lymphomas, which typically display additional genomic aberrations and tend to be at the advanced stage of disease at presentation. These translocations are both mediated by the IGH-gene enhancer and result in overexpression of the BCL10-gene (located at 1p22) and MALT1-gene (located at 18q21), respectively. Both BCL10 and MALT1 play a key role in the antigen-receptor signaling to NF-κB (see below). Of interest, t(11;18)(q21;q21)- and (1;14)(p22;q32)-positive MALT lymphomas are marked by a moderate and strong nuclear BCL10 expression, respectively, while t(14;18)(q32;q21)-positive MALT lymphomas are characterized by a perinuclear BCL10 immunohistochemical staining pattern (Sagaert et al., 2006b). More recently, FOXP1 (located at 3p13) was identified as a new translocation partner of IGH at low frequency, not only in MALT lymphomas, but also in DLBCL with mainly extranodal location. Remarkably, a significant number of t(3;14)(p13;q32)-negative MALT lymphomas and DLBCLs harbor strong nuclear FOXP1 expression, suggesting that mechanisms other than underlying FOXP1 rearrangements can upregulate FOXP1 expression. The significance of this nuclear FOXP1 overexpression in MALT lymphomas is still debated; some studies found strong nuclear FOXP1 expression to be confined to MALT lymphomas that are at risk of transforming into a DLBCL with poor clinical outcome (Han et al., 2009; Sagaert et al., 2006a). So far, it is not clear yet how FOXP1 may mediate MALT lymphomagenesis.
Except for trisomies 3 and 18, cytogenetic findings in both splenic and nodal MZL are rather heterogeneous and complex, and no unique abnormalities have been documented so far. Of interest, chromosome 7 is most frequently altered in splenic MZL, with a loss of 7q31-q32 in 40% of cases (Mateo et al., 1999). In addition, cases with 7q loss behave more aggressively and display more frequent tumoral progression (Traverse-Glehen et al., 2005).
Deregulation of NF-κB: The unifying concept for MALT lymphomagenesis?
Mounting evidence links the oncogenic activity of t(11;18)(q12;q21), t(1;14)(p22;q32), and t(14;18)(q32;q21) to aberrant activation of the canonical NF-κB pathway by API2-MALT1, BCL10, and MALT1, respectively. The NF-κB family is composed of five proteins that share a conserved REL homology domain for DNA binding: NF-κB1 (p105/p50), NF-κB2 (p100/p52), RelA (p65), RelB, and c-REL (Siebenlist et al., 2005). In unstimulated B-cells, the NF-κB molecules RelA and p50 are sequestered in the cytoplasm as latent complexes through binding with inhibitory κB (IκB) proteins. However, upon antigen encounter, CARMA1 interacts with the antigen-activated B-cell receptor in the lipid-rafts and induces the oligomerization of its downstream components BCL10 and MALT1 with TNF-receptor associated factor 6 (TRAF6) (Sun et al., 2004). The latter elicits its ubiquitin ligase activity, resulting in polyubiquitination of IκB kinase-γ (IKKγ or NEMO), which in turn phosporylates IκB, hereby targeting IκB for phosphorylation and proteasomal degradation. This allows the RELA/p50 dimers to enter the nucleus and mediate transcription of NF-κB-responsive genes, such as the pro-proliferative gene cyclin D2 and the anti-apoptotic genes BCL-XL and BCL-2 (Bonizzi and Karin, 2004) (Figure 1).
In MALT lymphomas, the overexpression of BCL10 and MALT1 induced by fusion with the IGH-enhancer in t(1;14)(p22;q32) and t(14;18)(q32;q32), respectively, hints at a role for NF-κB deregulation in lymphomagenesis. In t(1;14)(p22;q32)-positive MALT lymphomas, in which BCL10 is overexpressed, BCL10 is believed to form oligomers without the need for upstream signaling, triggering MALT1 oligomerization and aberrant NF-κB activation. In t(14;18)(q32;q21)-positive MALT lymphomas, in which MALT1 is overexpressed, the oligomerization of MALT1 with subsequent NF-κB activation is thought to be dependent on BCL10, as MALT1 does not have a structural domain to mediate self-oligomerization, nor does its overexpression alone activate NF-κB in vitro (Lucas et al., 2001; Uren et al., 2000). In t(11;18)(q21;q21)-positive MALT lymphomas, it is believed that the fusion-protein API2-MALT1 activates NF-κB directly by constitutively increased IKKγ polyubiquitination, as shown in vitro and in mice models (Baens et al., 2006; Zhou et al., 2005). Also, the API2-MALT1 fusion protein was reported to reside in the lipid-rafts. This raft association facilitates oligomerization of the API2-MALT1 fusion-protein and/or its interaction with its downstream signaling components (e.g., TRAF6), in this way bypassing the normal antigen requirement for formation of MALT1-TRAF6 oligomers and resulting in constitutive NF-κB activation (Ho et al., 2005).
Recently, another possible mechanism for uncontrolled NF-κB activation in orbital MALT lymphomas was revealed, which is the recurrent, homozygous deletion of the chromosomal band 6q23 with subsequent loss of the tumor necrosis factor alpha-induced protein 3 (TNFAIP3, A20) (Honma et al., 2008). A20 inhibits NF-κB activation by acting as a deubiquitinating enzyme, more precisely by catalyzing the removal of polyubiquitin chains not only from TRAF6 and NEMO, but also from the receptor-interacting protein (RIP), which is a key molecule for TNF-α-induced NEMO activation (Heyninck and Beyaert, 2005). As such, loss of the A20-gene in orbital MALT lymphoma suggests a role for A20 as a tumor suppressor gene in this disease. Other studies have confirmed the inactivation of A20-gene (by genomic deletions and/or somatic mutations) with a frequency of up to 20% in other types of MALT lymphoma with a mainly non-gastric location (as well as in DLBCL and mantle-cell lymphoma) (Honma et al., 2009; Novak et al., 2008). Remarkably, this A20 deletion preferentially occurred in lymphomas that had no evidence of chromosomal translocation, hereby offering a possible explanation for uncontrolled NF-κB activation and thus lymphomagenesis in chromosomal stable MALT lymphomas.
MALT lymphomas mostly present as Ann-Arbor stage IE disease (extranodal disease limited to the site of origin) as bone marrow and peripheral lymph node involvement is rather uncommon. Most commonly affected sites are the stomach, salivary glands, thyroid gland, intestine, conjunctiva, lachrymal gland, and skin. Splenic MZL targets elderly patients and is characterized by an enlarged spleen with peripheral blood and bone marrow involvement. Finally, the typical clinical presentation of nodal MZL, without extranodal involvement, is that of a middle-aged individual with peripheral and para-aortic lymphadenopathy and advanced stage disease with bone marrow involvement. This presentation is similar to other low-grade nodal non-Hodgkin’s lymphomas, such as follicular lymphocytic lymphomas.
Diagnosis of an MZL is always made on a biopsy, and by correlating the clinical data with the morphological (Figure 2), immunophenotypic, and genetic aspects of diagnostic findings. Residual reactive germinal centers are a constant finding in all MZL occurring at any site, although they can be hard to distinguish in the case of neoplastic colonization of the germinal center. The architecture of a lymph node involved by primary nodal MZL is most frequently preserved, with the neoplastic proliferation extending into the interfollicular area and surrounding residual reactive germinal centers as distinct rings. In splenic MZCL, the white pulp is hyperplastic with broad marginal zones and variable invasion into the red pulp, resulting in a massive expansion of the spleen. In MALT lymphomas, the neoplastic cells may invade and destroy the epithelium, resulting in so-called lymphoepithelial lesions. The neoplastic proliferation itself may be predominantly composed of marginal zone B-cells (’centrocyte-like cells’), but is most frequently heterogeneous in cell composition. A polymorphous mixture of centrocyte-like cells, small lymphocytes, plasma cells, and scattered large blast cells may be found in all MZL, regardless of the site. The immunophenotypes of extranodal, nodal, and splenic MZL are almost completely similar and homologous to that of normal MZ B-cells. There is positivity for surface immunoglobulin (IgM >IgA, IgG), pan B-cell markers (CD20, CD19, CD79a), and complement receptors (CD21, CD35). IgD expression may be variable but has been considered by some investigators as an important difference between nodal/extranodal MZL and splenic MZL, as they observed positivity in the latter and no expression in the former. In the differential diagnosis with other small B-cell lymphomas, absence of characteristic markers for those neoplasms is important: lack of CD5 is useful in distinction from mantle cell and small lymphocytic lymphomas, and lack of cyclin D1 in differential diagnosis with mantle cell lymphomas. In the last 2 decades, in addition to morphology and immunophenotyping, molecular techniques such as polymerase chain reaction (PCR) and fluorescence in situ hybridization (FISH) were introduced as new diagnostic tools in hematopathology to further support the diagnosis of an MZL by identifying clonality of B-cells (based on the fact that all lymphoma cells have the same immunoglobulin gene rearrangement) and/or MZL-specific genetic aberrations.
It is presently generally accepted that H. pylori eradication with antibiotics is the first choice of therapy for localized gastric MALT lymphoma. The use of anti-infectious treatment in non-gastric MALT lymphomas is still under investigation, although some reports discourage the use of antibiotics in patients suffering from non-gastric MALT lymphomas (Abramson et al., 2005; Grunberger et al., 2006). In gastric MALT lymphomas that do respond to H. pylori eradication therapy, one has to keep in mind that it may take a couple of weeks up to more than one year before complete remission is obtained. When antibiotic therapy fails or when confronted with a localized, H. pylori-negative gastric MALT lymphoma, modest dose involved-field radiotherapy can be applied with excellent results. Immunotherapy with anti-CD20 monoclonal antibodies (retuximab) and/or chemotherapy is usually indicated for disseminated disease (Zucca and Dreyling, 2008). Surgery only has a role in the treatment of gastric MALT lymphomas if local complications (e.g., perforation) occur.
In the pre-rituximab era, the treatment of choice for splenic MZL patients with symptomatic splenomegaly or threatening cytopenia was splenectomy, since chemotherapy had limited efficacy. Responses to splenectomy occurred in approximately 90% of patients. However, splenic MZL patients are often elderly and pose surgical risks. Presently, treatment of such patients with rituximab (both alone or in combination with chemotherapy) has shown remarkable responses with an overall survival comparable to that reported following splenectomy (Bennett and Schechter, 2010). Rituximab in combination with purine nucleosides may provide further improvement in progression-free survival; however, confirmatory prospective trials are necessary. These results suggest that splenectomy should no longer be considered as an initial therapy for SMZL but rather as a palliative therapy for patients who are not responsive to immunotherapy with or without chemotherapy.
Finally, nodal MZL represents a therapeutic dilemma, since no studies of large series have been published so far. In addition, the 5-year overall survival as well as the failure-free survival of patients with nodal MZL was found to be lower than that of patients with extranodal MZL (56% vs. 81% and 28% vs. 65%, respectively) (Arcaini et al., 2007).
(Corresponding author: Xavier Sagaert, M.D., Ph.D., Senior Clinical Investigator FWO Flanders, Department of Pathology, University Hospitals of K.U.Leuven, Minderbroederstraat 12, B-3000 Leuven, Belgium.)
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[Discovery Medicine; ISSN: 1539-6509; eISSN: 1944-7930. Discov Med 10(50):79-86, July 2010.]