Marginal-zone lymphoma

Critical Reviews in Oncology/Hematology 63 (2007) 245–256

Marginal-zone lymphoma Andr´es J.M. Ferreri a,∗ , Emanuele Zucca b a

Medical Oncology Unit, Department of Oncology, San Raffaele Scientific Institute, Milan, Italy b Lymphoma Unit, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland Accepted 11 April 2007

Contents 1.

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General Information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1. Definition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2. Incidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.3. Risk factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pathology and biology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Morphology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Immunophenotype . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Genetic features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diagnosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Clinical presentations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Diagnostic criteria. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Staging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Staging procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Staging system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. Molecular analysis of minimal residual disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4. Restaging procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Natural history . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. Prognostic factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1. Treatment of limited disease (stage I–II) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2. Treatment of advanced disease (stage III–IV) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3. Treatment of relapsed or refractory disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.4. New active drugs and therapeutic options . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biographies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Abstract The term marginal-zone lymphoma (MZL) encompasses three closely related lymphoma subtypes, namely the “low-grade B-cell lymphoma of MALT type” currently named MALT lymphoma, the “nodal marginal-zone B-cell lymphoma” and a provisional entity in the REAL classification named “primary splenic MZL with or without villous lymphocytes”. These entities display different characteristics, with evident clinical and biological variations according to the organ where the lymphoma arises. Marginal-zone B-cells are functionally heterogeneous and may differ with respect to the pattern of somatic hypermutation in their Ig variable genes. Sequence and mutation analysis of the rearranged Ig heavy chain variable genes and that somatic mutations pattern indicate that MZL may arise from different subsets of marginal-zone B-cells. Pathogenesis of these groups of lymphomas is correlated to chronic infections, like Helicobacter pylori, hepatitis C virus, Campylobacter ∗

Corresponding author. Tel.: +39 02 2643 7649; fax: +39 02 2643 7603. E-mail address: [email protected] (A.J.M. Ferreri).

1040-8428/$ – see front matter © 2007 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.critrevonc.2007.04.009

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jejuni, Chlamydia psittaci and Borrelia burgdorferi. Several therapeutic strategies against these malignancies exist. Surgical resection, radiotherapy and alkylating agent-based chemotherapy constitute standard approaches, while antimicrobial therapies, anti-CD20 therapy and new forms of immunotherapy constitute interesting experimental approaches. However, prospective trials on these malignancies are rare and universally accepted therapeutic guidelines do not exist. MZLs constitute an exciting investigational setting both from molecular and clinical points of view. © 2007 Elsevier Ireland Ltd. All rights reserved. Keywords: MALT; Helicobacter pylori; Borrelia burgdorferi; Chlamydia psittaci; Hepatitis C virus

1. General Information 1.1. Definition In early 1990s, the term marginal-zone lymphoma (MZL) was proposed in the REAL classification [1] to encompass two apparently closely related lymphoma subtypes, namely the “low-grade B-cell lymphoma of MALT type” currently named MALT lymphoma and the “nodal marginal-zone Bcell lymphoma”, also known as “monocytoid lymphoma”. A third MZL subtype, with similar immunophenotype, but distinct clinical features was also provisionally included in the REAL classification, i.e., the “primary splenic MZL with or without villous lymphocytes”. In the following years, the distinctiveness of these lymphoid neoplasms becomes clear, and each is now considered a unique lymphoma subtype in the World Health Organization (WHO) classification [2–4]. Marginal-zone lymphomas have been postulated as arising from a marginal-zone B-cell presenting in lymph nodes and extranodal tissues with capacity to differentiate into plasma cell and home to certain tissue compartments. Marginal-zone B-cells are functionally heterogeneous and may differ with respect to the pattern of somatic hypermutation in their Ig variable genes. Sequence and mutation analysis of the rearranged Ig heavy chain variable genes (VH) demonstrated that marginal-zone lymphomas preferentially rearrange the VH4, VH3 and VH1 family genes, without preference for any particular VH gene, and that somatic mutations are extremely frequent. These data indicate that marginal-zone lymphomas may arise from different subsets of marginal-zone B-cells. In addition, lymphomagenesis may not be triggered by antigen in all cases of marginal-zone cell lymphoma [5,6]. Marginal-zone lymphomas were not included in the Working Formulation; they mostly correspond to cases of small lymphocytic lymphoma, small cleaved or mixed small and large, diffuse or nodular, lymphomas, according to that classification. Many cases would have been formerly recognized as monocytoid B-cell lymphoma, immunocytoma, centroblastic/centrocytic or centrocytic in the Kiel classification [7,8]. MALT lymphoma was first recognized as a separate clinical pathological entity by Isaacson and Wright in 1983. At present, the term extranodal marginal-zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) or MALT-type lymphoma should be applied only to a lymphoma predominantly composed of small cells (previously defined “low-grade MALT lymphoma”) and not to a large cell

lymphoma in a MALT site [9]. The term high-grade MALT lymphoma, initially used to define a large B-cell lymphoma arising at MALT sites, should no longer be used [2]. 1.2. Incidence Extranodal marginal-zone lymphoma of MALT type is relatively common, encompassing 5–8% of all NHL. The nodal and splenic marginal-zone lymphomas are quite rare, each comprising less than 1% of NHL. 1.3. Risk factors Some risk factors have been clearly identified in extranodal marginal-zone lymphomas. These malignancies have been related to the acquisition of mucosa-associated lymphoid tissue (MALT) in organs that normally contain no organized lymphoid tissue, such as stomach, salivary gland, thyroid, conjunctiva, skin and others. Acquisition of MALT is induced by autoimmune diseases or chronic inflammatory disorders [10]. In the stomach, this has been linked to the presence of Helicobacter pylori infection [11]; a causal relationship was suggested [11], and later experimentally reproduced [12]. H. pylori antigens elicit a T-cell-specific response, which induces a B-cell proliferation, which may evolve into a neoplastic marginal-zone B-cell proliferation. In most cases, the eradication of H. pylori infection by using specific antibiotic combinations leads to histological regression of the lymphoma [13,14]. A growing list of other infectious organisms has recently been shown to be associated with MALT lymphomas at other anatomic sites. Borrelia burgdorferi, the spirochete responsible for Lyme disease, may be implicated in the pathogenesis of at least a subset of cutaneous marginal-zone B-cell lymphomas [15,16]. The microorganism has been cultured or its DNA amplified from skin extranodal MZL, and complete remission of lymphoma has been achieved with antibiotics therapy aimed to the spirochete. The presence of Chlamydia psittaci has been shown in up to 80% of ocular adnexa lymphomas [17], and clinical responses have been observed after appropriate antibiotic therapy [18]. The entity known as immunoproliferative small intestine disease (IPSID; also known as ␣ chain disease) [19,20] is now considered an extranodal MZL associated with Campylobacter jejuni infection. This disorder is more frequent in the Middle East, especially the Mediter-

A.J.M. Ferreri, E. Zucca / Critical Reviews in Oncology/Hematology 63 (2007) 245–256

ranean area, where it was established in the 1970s that cases of early IPSID respond to antibiotic treatment. More recently, Lecuit et al. demonstrated the presence of a specific pathogen in five of seven patients, linking this extranodal MZL to C. jejuni [19]. Other extranodal marginal-zone lymphomas have been found associated with a continuous antigenic triggering mechanism based on auto-antigens. A higher incidence of lymphomas of salivary or lachrymal glands, thyroid and lung has been observed in patients affected by Sj¨ogren’s syndrome, Hashimoto’s thyroiditis and lymphoid interstitial pneumopathy [21,22], respectively. A main role for hepatitis C viral infection in pathogenesis of marginal-zone lymphomas has been also hypothesized [23]. A role for antigen-driven clonal expansion is supported by the evidence of ongoing somatic mutation in the analysis of immunoglobulin heavy chain genes in lymphoma cells [24]. The involvement of antigen is further supported by evidence of clonal evolution within the tumor, suggesting pressure to increase affinity of the surface immunoglobulin for antigen [25]. Thus, in early stages of gastric lymphoma development, antigen-driven Tcells specific for the H. pylori may favor neoplastic growth [12] and the lymphoma regression following eradication of this infection with antibiotics is consistent with this postulate. Much less is known about the role of the host immune response in pathogenesis, as demonstrated by the fact that only a small proportion of infected patients ever develop gastric lymphoma. Differences in MALT lymphoma incidence may correlate with different inflammatory cytokines and HLA polymorphisms. Chronic inflammation induced by persistent infection or autoimmune disorders may result in organized lymphoid tissue and a microenvironment that facilitates lymphomagenesis. Important determinants of risk may relate to the etiology of the inflammation and/or the specific nature of the host immune response. One or both of these may be required for the acquisition of initial genetic aberrations, which allow irreversible progression to MALT lymphoma.

2. Pathology and biology 2.1. Morphology At present, the term extranodal marginal-zone B-cell lymphoma of MALT (mucosa-associated lymphoid tissue) or MALT-type lymphoma should be applied only to a lymphoma composed of small cells and not to large cell lymphoma in MALT site [9]. Marginal-zone lymphoma is characterized by cellular heterogeneity, including centrocyte-like cells, monocytoid B-cells, small lymphocytes and plasma cells. Centrocyte-like cells are small atypical cells resembling small-cleaved follicular center cells or centrocytes, but with more abundant cytoplasm, similar to Peyer’s patch, mesenteric nodal or splenic marginal-zone cells. Occasional large cells are present in most cases. An increased number of large cells may be of prognostic importance, and tumor

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grading according to the number of large cells has been suggested [9]. In any way, this issue is now considered a major research question. Reactive follicles are usually present, with the neoplastic cells occupying the marginal-zone and the interfollicular region. Occasional follicles may contain an excess of marginal-zone or monocytoid cells, giving them a neoplastic appearance (follicular colonization). In lymph nodes, neoplastic cells dispose in perisinusoidal, parafollicular or marginal zone patterns. In extranodal sites, mainly mucosal tissues, the marginal-zone cells typically infiltrate the epithelium, forming so-called lymphoepithelial lesions. Some degree of plasma cell differentiation is also often seen [2]. 2.2. Immunophenotype The cells of marginal-zone lymphoma express monotypic surface immunoglobulin, more frequently sIgM+ than IgG+ or IgA, but not IgD, and are cIg+ in 40% of cases. They express the B-cell-associated antigen (CD19, CD20, CD22, CD79a and CD79b), and are CD5−, CD43−/+, CD3−, CD23−, CD11c−/+ and CD10−. CD5 negativity is useful in differential diagnosis with chronic lymphocytic leukemia, mantle cell and follicular lymphomas, while CD10 negativity is useful to distinguish marginal-zone lymphoma from follicular lymphomas. Marginal-zone lymphoma does not express bcl-1 nor bcl-2 proteins [1]. 2.3. Genetic features Marginal-zone lymphomas are usually not associated with bcl-1, bcl-2, bcl-3 and bcl-6 rearrangements [26]. However, a recent study of a large number of MALT lymphomas from several organs, using an interphase fluorescence in situ hybridization (FISH) technique, has suggested that 3q27 translocations, involving the BCL6 gene, may be found in a small number of cases (<2%) [27]. In some cases, the translocation partner was the IGH gene at chromosome 14q32. The presence of the translocation appeared to correlate with BCL6 protein expression. Anatomical sites of MALT lymphomas with BCL6 translocations included the stomach, salivary gland, lung, skin and thyroid. These preliminary data will need to be substantiated before implicating the BCL6 oncogene in MALT lymphomagenesis. Trisomy 3 and t(11;18) have been reported in cases arisen in extranodal sites [28]. Less frequently, trisomy of chromosomes 7, 12 and 18 as well as structural aberrations of chromosome 1 have been observed non-randomly [28–30]. Some of these features occur with a similar frequency in nodal, extranodal and splenic marginal-zone lymphomas, supporting the hypothesis of a common histogenesis of these neoplasms [29]. Molecular analysis has demonstrated the presence of RER+ phenotype, c-myc rearrangements and complete or partial inactivation of p53 in extranodal MALT lymphomas displaying histological progression [31]. Other common karyotypic alterations that characterize MALT

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lymphomas include the translocations t(11;18)(q21;q21), t(1;14)(p22;q32), t(14;18)(q32;q21), t(3;14)(q27;q32) and the recently described, t(3;14)(p14.1;q32). This apparent complexity of cytogenetic alterations that have now been implicated in the pathogenesis of extranodal MALT lymphoma serves as a paradigm for molecular cross-talk in neoplastic disease. Recent data have shown that at least three of the disparate translocations affect a common signaling mechanism, and thus unify all three under a common pathogenesis, resulting in the constitutive activation of the nuclear factor kappa B (NF-␬B) pathway. The t(11;18)(q21;q21) is the most common chromosomal abnormality associated with MALT lymphomas (13–35% of cases) [32]. It has been found in MALT lymphomas arising in the lung, stomach, intestine and less commonly, the skin, orbit and salivary gland. It is restricted to MALT lymphomas and has not been detected in nodal or splenic MZLs. The t(11;18) represents the fusion of the API2 (apoptosis inhibitor-2) gene on chromosome 11 and the MALT1 (MALT lymphoma-associated translocation) gene on chromosome 18. API2, which is expressed highly in lymphoid cells, is a member of the inhibitors of apoptosis (IAPs) gene family. IAP genes contain one to three copies of a BIR (baculovirus inhibitor of apoptosis repeat) motif, a caspase recruitment domain (CARD) and a C-terminal zincbinding really interesting new gene (RING) finger domain. In most cases, t(11;18)(q21;q21) is the sole chromosomal aberration and only exceptionally has it been detected in de novo diffuse large B-cell lymphomas (DLBCL) arising at mucosal sites. The t(11;18) translocation is seen more frequently in cases with lymph node or systemic dissemination, and it has been associated with cases that do not respond to H. pylori eradication [33–35]. In the stomach, the detection of the translocation identified 70% of cases that were unresponsive to antibiotic therapy alone, including 60% of those confined to the stomach (stage IE) [33–35]. In gastric MALT lymphoma, the t(11;18) translocation has been shown to be significantly associated with infection of CagA-positive strains of H. pylori, which are more likely to be associated with inflammatory responses and the induction of potent neutrophil activation [33]. This neutrophil response leads to the production of reactive oxygen species that are known to cause a wide range of DNA damage. It has been hypothesized that B-cell DNA damage due to these free radicals released by neutrophils in the context of the inflammatory response in the pre-malignant lesions associated with MALT lymphoma, such as H. pylori gastritis, may have a relevant role in the lymphomagenesis process [33]. The t(1;14)(p22;q32) and variant t(1;2)(p22;p12) occur in 1–2% of MALT lymphomas, in the stomach, lung and skin [30,36–38]. As a result of these translocations, the entire coding region of the BCL10 gene on chromosome 1 is relocated to chromosome 14, thereby bringing BCL10 gene under control of the IGH enhancer region (or IGL region in the case of variant translocations). The t(1;14) results in overexpression of nuclear BCL10 protein. BCL10 is an intracellular protein that is essential for both the development and function of

mature B- and T-cells, linking antigen-receptor signaling to the NF-␬B pathway. The deregulated expression of wild-type BCL10 resulting from translocation is important in MALT lymphomagenesis. The t(1;14)(p22;q32) and t(1;2)(p22;p12) have been reported exclusively in MALT lymphoma, and these cases typically display additional genomic abnormalities. Similar to cases with t(11;18), patients present with advanced stage and are unlikely to respond to H. pylori eradication [39]. The t(14;18) translocation occurring in 15–20% of MALT lymphomas brings the MALT1 gene under the control of the IGH enhancer on chromosome 14, resulting in deregulated expression of MALT1 and downstream activation of the NF-␬B pathway [40]. This translocation occurs more frequently in non-gastrointestinal MALT lymphomas (liver, lung and ocular adnexa) [41]. MALT lymphomas with t(14;18)(q32;q21) frequently harbor additional genetic aberrations, including trisomies 3 and/or 12 and 18. The recently described t(3;14)(p14.1;q32) brings the FOXP1 gene at 3p14.1 under the control of the IGH gene enhancer and deregulates its expression [42]. FOXP1 (forkhead box protein P1) is a member of the FOXP subfamily (FOXP1-4) of forkhead transcription factors, characterized by a common DNA binding winged-helix or forkhead domain together with Nterminal zinc finger and leucine zipper domains [43]. This novel translocation has been associated with MALT lymphomas involving the thyroid (50%), ocular adnexa (20%) and skin (10%) and distinct from those involving the t(11;18) [42]. Cases with the translocation show overexpression of FOXP1 protein. FOXP1 protein is also overexpressed in cases of MALT lymphoma with trisomy of chromosome 3, suggesting that increased gene copy number may be another mechanism of deregulated gene expression. Overexpression of FOXP1 seems associated with a poorer prognosis in diffuse large cell lymphomas [44,45] but its role in MALT lymphoma is still unclear [46].

3. Diagnosis 3.1. Clinical presentations There are two major clinical presentations of marginalzone lymphomas: the extranodal and the nodal forms. The extranodal form is the most frequent one, usually presenting in adults, slightly more common in females, with a history of autoimmune disorders, such as Sj¨ogren’s syndrome or Hashimoto’s thyroiditis, or of H. pylori infection. The majority of patients present with localized extranodal disease (stage I–II), involving the stomach, salivary glands, thyroid gland, intestine, conjunctiva, lachrymal gland, skin and others [21,47–53]. These patients (median age 57 years, M/F ratio: 1) often have no adverse prognostic factors. The main features are limited stage, small tumor burden, excellent performance status and normal LDH and (2-microglobulin levels [54]. The gastrointestinal tract is the most frequently involved extranodal site (66% of all MALT lymphomas). MALT lym-

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phomas represent 40–50% of primary gastric lymphomas [47]. The symptoms are usually dyspepsia, with or without signs of chronic bleeding, and less frequently abdominal pain and weight loss. “B” symptoms are exceedingly uncommon. The endoscopic findings vary from a flat gastritic appearance to one or more ulcers. Stage of disease in gastric forms is IE in 70–80%, IIE in 10–20% and IVE in 5–10% [55,56]. Within the stomach, low-grade MALT lymphoma is often multifocal and this may explain the report of relapses in the gastric stump after surgical excision. The most common extragastric site is the lung. Usually, patients complain cough, dyspnea, hemoptysis and chest pain. Routine chest X-rays are often able to detect lesions that have an alveolar aspect with badly defined margins and air broncogram. Atelectases and pleural effusion are rare [57]. In many cases, diagnosis requires surgical lung biopsy. MALT lymphoma usually remains localized for a prolonged period within the tissue of origin, but dissemination to multiple mucosal sites is not uncommon, especially in non-gastrointestinal MALT lymphomas, in which about one-fourth of cases have been reported to present with involvement of multiple mucosal sites or non-mucosal sites, such as bone marrow [58]. Bone marrow involvement has been reported in up to 10% of cases, with peripheral blood dissemination in some cases [59]. Nodal presentation can reflect a nodal spread of an extranodal marginal-zone lymphoma. However, tumors with identical features to extranodal marginal-zone or monocytoid B-cell lymphomas have been reported with isolated or disseminated lymph nodal involvement, in the absence of extranodal lesions [60–62]. These cases are today considered a separate entity, namely the nodal marginal-zone lymphoma [3]. 3.2. Diagnostic criteria The main diagnostic criteria for the marginal-zone lymphomas include clinical, morphological, immunophenotypic and genetic aspects. The major clinical criterion is the site of presentation. MALT lymphoma seems slightly more common in females and most often presents in adults (median age 57 years) with a history of autoimmune disorders, such as Sj¨ogren’s syndrome or Hashimoto’s thyroiditis or of H. pylori infection. These patients often have no adverse prognostic factors [54]. Localized extranodal disease (stage I–II), involving the stomach, salivary glands, thyroid gland, intestine, conjunctiva, lachrymal gland, skin and others [21,47–53]. In cases with gastrointestinal involvement, symptoms are usually dyspepsia, with or without signs of chronic bleeding, and less frequently abdominal pain and weight loss [47]. The endoscopic findings vary from a flat gastritic appearance to one or more ulcers. The most common extragastric site is the lung. Usually, patients complain cough, dyspnea, hemoptysis and chest pain. Routine chest X-rays are often able to detect lesions that have an alveolar aspect with badly defined margins and air broncogram. Atelectasia and pleural effusion are rare [57]. In many cases, diagnosis requires

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surgical lung biopsy. Nodal presentation may reflect a nodal spread of a primary extranodal marginal-zone lymphoma or be related to the less common nodal (monocytoid) marginalzone lymphoma. Histological features are characterized by a prominent cellular heterogeneity, including centrocyte-like cells, monocytoid B-cells, small lymphocytes and plasma cells. Centrocyte-like cells are small atypical cells resembling small-cleaved follicular center cells or centrocytes, but with more abundant cytoplasm, similar to Peyer’s patch, mesenteric nodal or splenic marginal-zone cells. Occasional large cells are present in most cases. Reactive follicles are usually present, with the neoplastic cells occupying the marginalzone and the interfollicular region. Occasional follicles may contain an excess of marginal-zone or monocytoid cells, giving them a neoplastic appearance (follicular colonization). In lymph nodes, neoplastic cells dispose in perisinusoidal, parafollicular or marginal zone patterns. In extranodal sites, mainly mucosal tissues, the marginal-zone cells typically infiltrate the epithelium, forming so-called lymphoepithelial lesions. A monoclonal proliferation of plasma cells is often distributed in distinct subepithelial or interfollicular zones. The cells of marginal-zone lymphoma express monotypic surface immunoglobulin, more frequently sIgM+ than IgG+ or IgA, but not IgD, and are cIg+ in 40% of cases. They express the B-cell-associated antigen (CD19, CD20, CD22, CD79a and CD79b), and are CD5−, CD43−/+, CD3−, CD23−, CD11c−/+ and CD10−. Marginal-zone lymphoma does not express bcl-1 nor bcl-2 proteins [1]. Marginal-zone lymphoma is not associated with bcl-1, bcl-2, bcl-3 and bcl6 rearrangements [26]. Trisomy 3 and t(11;18) have been reported in cases arisen in extranodal sites [28]. Less frequently, trisomy of chromosomes 7, 12 and 18 as well as structural aberrations of chromosome 1 have been observed non-randomly [28–30]. Some of these features occur with a similar frequency in nodal, extranodal and splenic marginalzone lymphomas, supporting the hypothesis of a common histogenesis of these neoplasms [29]. Molecular analysis has demonstrated the presence of RER+ phenotype, c-myc rearrangements and complete or partial inactivation of p53 in extranodal MALT lymphomas displaying histological progression [31]. The study of other karyotypic alterations could help us to define diagnosis and prognosis of marginal-zone lymphomas. Appropriate investigations must be performed to show the presence of infectious agents. In particular for gastric MALT lymphomas, the presence of active H. pylori infection must be determined by histochemistry (Genta stain or Warthin-Starry stain) and breath test; serology is recommended when the results of histology are negative. For other locations of extranodal MZL, an evaluation for infectious agents may be undertaken as noted in the preceding paragraphs but the clinical consequences of the identification of and treatment for C. psittaci or B. burgdorferi have not been validated. In the stomach, an endoscopic ultrasound is recommended in the initial staging for evaluation of depth of infiltration and presence of perigastric lymph nodes. A deep infiltration of the gastric wall is associated with a higher risk

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of lymph node involvement, and a lower response rate with antibiotic therapy alone [63,64].

of potential hepatic or splenic involvement in marginal-zone lymphomas should follow the general statements for all NHL.

4. Staging

4.2. Staging system

4.1. Staging procedures

The standard staging system used for marginal-zone lymphomas is the same as that proposed for Hodgkin’s disease at the Ann Arbor Conference in 1971 [69]. This system is currently used for all non-Hodgkin’s lymphomas, even if other staging systems are used in some extranodal lymphomas with particular biological behavior. The Ann Arbor staging system reflects both the number of sites of involvement and the presence of disease above or below the diaphragm. This staging system considers four stage of disease:

The finding that patients presenting with extranodal MZL lymphoma disseminated at multiple mucosal sites may have a favourable outcome with survival curves similar to those of the patients with localized disease, makes problematic, the usage of the traditional Ann Arbor staging system, which is mainly based on the extension of nodal areas and can be misleading in MALT lymphomas. Specific staging systems for extranodal lymphomas have been proposed already in the 1970s [65]; nevertheless, the staging system to be used for extranodal MZL is still controversial [66]. A modified Blackledge staging system (known as the “Lugano staging system”) has been recommended for the cases presenting in the stomach [67]. However, this system was proposed before the wide use of endoscopic ultrasound and does not accurately describe the depth of infiltration in the gastric wall, a parameter that is highly predictive for the MALT lymphoma response to anti-Helicobacter therapy. But a general consensus has not been achieved and alternative approaches have been also used [68]. Regardless of the presentation site, diagnostic studies should include the standard lymphoma staging procedures with CBCs; basic biochemical studies (including LDH and beta 2-microglobulin); computed tomography of the chest, abdomen and pelvis; and a bone marrow biopsy. The initial staging should include a gastroduodenal endoscopy with multiple biopsies from each region of the stomach, duodenum, gastroesophageal junction and from any site that seems abnormal. Fresh biopsy and washings material should be available for cytogenetic studies in addition to routine histology and immunohistochemistry. Some particular sites frequently involved by marginal-zone lymphomas may require special diagnostic procedures. Ultrasonography and magnetic resonance image are useful to investigate the involvement of thyroid, soft tissue, salivary glands or orbits. Primary bronchial mucosa-associated lymphoid tissue lymphoma requires histological assessment by bronchoscopy. The presence of pulmonary masses or pleural effusions should be histologically verified. As for all other lymphomas, lymphangiography has been completely replaced by abdominal computerized tomography considering the higher sensitivity of tomography to detect mesenteric nodes and its capacity to show a true estimation of nodes size, which usually is underestimated with lymphangiography. Likewise other indolent lymphomas, marginal-zone lymphoma is associated with a high number of false negatives at Gallium-67 scanning. Marginal-zone lymphoma involves bone marrow in less than 10% of cases. Bone marrow assessment in marginal-zone lymphoma should follow the general statements for all NHL. Abdominal staging, with evaluation

Stage I: involvement of a single lymph node region (I) or a single extranodal site (IE). Stage II: involvement of two or more lymph node regions on the same side of the diaphragm (II) or localized involvement of an extralymphatic site (IIE). Stage III: involvement of lymph nodes regions on both sides of the diaphragm (III) or localized involvement of an extralymphatic site (IIIE) or spleen (IIIs) or both (IIIEs). Stage IV: diffuse or disseminated involvement of one or more extralymphatic organs with or without associated lymph node involvement. Localized involvement of liver or bone marrow is also considered stage IV. Patients are divided in two subsets according to the presence (A) or not (B) of systemic symptoms. Fever of no evident cause, night sweats and weight loss of more than 10% of body weight are considered systemic symptoms. Even if a frequent accompanying symptom, itching should not be considered as a systemic symptom. The presence of bulky mass, such as a lesion of 10 cm or more in the longest diameter is signaled as “X”, while the extranodal involvement should be identified by a symbol (O: bone, L: lung, D: skin, etc.). Other systems have been proposed for the primary extranodal presentation of NHL, e.g., the Lugano staging system for primary lymphomas of the gastrointestinal tract [67]. 4.3. Molecular analysis of minimal residual disease No reliable molecular markers are available for monitoring of minimal residual disease in marginal-zone lymphoma. Nevertheless, several studies of post-antibiotic molecular follow-up showed that histological and endoscopic remission does not necessarily mean a cure [70]. The long-term persistence of monoclonal B-cell after histologic regression of the lymphoma has been reported in about half of the cases, suggesting that H. pylori eradication suppresses but does not eradicate the lymphoma clones. The clinical significance of the detection of monoclonal B-cells by molecular methods remains unclear, and histological evaluation of repeated biopsies remains a fundamental follow-up procedure [71–73].

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Restaging should include all diagnostic procedures positive at time of diagnosis and initial staging.

splenomegaly, elevated LDH and/or 2-beta microglobulin levels, stage of disease and for primary gastric MALT lymphoma, the depth of infiltration of the gastric wall [47,54,63,77,83,84].

5. Prognosis

6. Treatment

5.1. Natural history

6.1. Treatment of limited disease (stage I–II)

Marginal-zone lymphomas are most often very indolent malignancies that usually present with limited stage of disease. Localized disease may be controlled with local treatments [49,51,53], and contrarily to other low-grade lymphomas, a high cure rate is achieved. Gastrointestinal and non-gastrointestinal forms seem to have a similar prognosis [74], with 5-year overall survival higher than 90% and a 10-year survival of 75–80% [57,75]. Recurrences may appear several years after treatment, with a median of 5 years [54,55,75], involving the same organ (60% of cases) or other extranodal sites [75–77]. In extranodal forms, dissemination occurs in 30% of cases, often to other extranodal sites, with a long disease-free interval [50]. When these lymphomas disseminate, they preferentially spread to other mucosal sites without peripheral blood or bone marrow involvement [22]. In the gastric forms, a preferential dissemination to the intestine and spleen has been reported [78]. Disseminated disease is associated with a less favorable survival, and seems to be incurable with available therapy [79]. Transformation to large cell aggressive lymphomas may occur in the first recurrence or in further relapses [62]. The precise frequency of histologic transformation is unclear. The exact mechanisms underlying the transition of low-grade MALT lymphoma to an aggressive lymphoma also remain unclear. A number of genetic alterations have been associated with histologic transformation, including p53 allelic loss and mutation, hypermethylation of p15 and p16 and p16 deletions [24,80]. There is evidence to suggest that aberrant telomerase activity may be involved in some cases of MALT lymphoma showing histologic progression [81]. Both chromosomal gains and losses are often associated with high-grade transformation. Using methylation-specific PCR, a strong association between H. pylori dependence gene methylation has been reported [82]. Importantly, hypermethylation of multiple CpG islands is frequently found in other tumors that have arisen from chronic inflammatory conditions, such as hepatocellular carcinomas with cirrhosis/hepatitis and ulcerative colitis associated with colon carcinoma. These findings support a model of increasing genomic instability from low-grade to high-grade disease, with the accumulation of additional genetic aberrations.

Standard option for patients with stage I–II marginalzone lymphoma has not been yet established because of the paucity of prospective trials and the small number of patients in published studies, the heterogeneity of treatment and the extremely short follow-up [74]. The indolent nature of this disease justifies a conservative approach [56]. Local treatment, such as surgery, radiotherapy or topic interferon and low-aggressive chemotherapy, like chlorambucil alone, showed similar outcome and are suitable for individual clinical use on a type R basis. In fact, these treatment strategies have associated with an 80–100% of complete remission rate and a 5-year survival of 75–80% [56,74,85–87]. The addition of CVP regimen to extended-field radiotherapy 45 Gy did not improve outcome in patients with marginal-zone lymphoma of the parotid gland [88], suggesting that local treatments can be the first choice in these malignancies. The treatment aggressiveness depends of the primary site of disease. While small lesions of the stomach or breast can be treated surgically, marginal-zone lymphomas of thyroid, salivary glands, urinary bladder or lung should be treated with other modalities considering that surgical resection in these districts could result in a too mutilating intervention. Antibiotics to eradicate H. pylori infection and antacids is suitable for individual clinical use on a type 3 level of evidence to treat patients with superficial stage I lesions [89–91]. Indeed, eradication of H. pylori as the sole initial treatment of localized (i.e., confined to the gastric wall) MALT lymphoma is at present the best studied therapeutic approach with more than 20 non-randomized studies reported thus far [92,93]. The relationship between H. pylori infection and marginalzone lymphoma in the stomach has been used to define this new therapeutic approach [10,14]. An excellent survival has been reported with this strategy in very limited lesions, being similar to those reported with gastrectomy, radiotherapy or chemotherapy. Surgery or radiotherapy, however, should include the entire stomach due to the multicentricity of these malignancies [94], having a heavily negative impact on quality of life. Some prognostic factors have been reported to help identifying the patients who can obtain a major clinical benefit from antibiotic therapy. In effect, lesions deeply infiltrating the gastric wall or with a critical large-cell component are often not responsive to antibiotics [95–97]. Endoscopic ultrasound can therefore be useful to predict the lymphoma response to H. pylori eradication. The response rate is highest for the mucosa-confined lymphomas (approximately 70–90%) and decreases progressively for the

4.4. Restaging procedures

5.2. Prognostic factors Commonly reported indicators of a poorer outcome in extranodal marginal-zone lymphomas are advanced age, impaired performance status, systemic symptoms,

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tumors infiltrating the submucosa, the muscularis propria and the serosa. In the cases with documented nodal involvement, the response is very unlikely [64,83,98,99]. The presence of the t(11;18) translocation predict a poor therapeutic response of gastric MALT lymphoma to H. pylori eradication [100] but not necessarily to other therapeutic approaches [101,102]. After a long interval, some patients undergo a self-limited recurrence that support the hypothesis that antibiotic therapy suppresses but does not necessarily eradicate the neoplastic clone [97]. Relapse of H. pylori infection after a successful eradication is observed in less than 2% of cases. This may be accompanied by recurrence of lymphoma [103]. No definite guidelines exist for the management of the subset of H. pylori-negative cases, for patients who fail antibiotic therapy, and for non-gastric locations. A choice can be made between conventional therapeutic modalities but there are no published randomized studies for evidence-based decisionmaking [93]. In two retrospective series of patients with gastric low-grade MALT lymphoma, no statistically significant difference was apparent in survival between patients who received different initial treatments [56,104]. Radiotherapy is suitable for individual clinical use in patients with H. pylorinegative lymphomas on a type 3 level of evidence [105]. Doses between 30 Gy and 43.5 Gy delivered in 1.5 Gy fractions obtained a 2-year event-free survival of 100%, with an excellent tolerance and without important acute side effects. 6.2. Treatment of advanced disease (stage III–IV) Standard therapeutic option for patients with stage III–IV disease is conventional-dose systemic chemotherapy. Monochemotherapy with alkylating agents is suitable for individual clinical use on a type R basis [86,99]. Anecdotal cases of long-term remissions with interferon alpha2a injected s.c. at 9 × 106 U, 3 days a week for 1 year have been reported [106]. Other phase II studies demonstrated the antitumor activity of the purine analogs fludarabine [107] and cladribine [108], which however may be associated with an increased risk of secondary myelodysplastic syndrome [109]. A balance between the usually indolent nature of these malignancies and the severity of the purine analogs adverse effects should be taken into account when planning the treatment. The combination regimen of chlorambucil, mitoxantrone and prednisone has also been reported to be active with acceptable toxicity [110]. The anti-CD20 monoclonal antibody rituximab is effective in MZL with a reported response rate of about 70%, representing an additional option for the treatment of systemic disease [101,111]. 6.3. Treatment of relapsed or refractory disease Standard therapeutic option for patients with stage relapsed disease has not been yet defined. Radiotherapy is suitable for individual clinical use in patients with antibioticresistant lymphomas on a type 3 level of evidence [105]. In these cases with local relapsed or refractory disease, gastrec-

tomy should be also taken into account. Monochemotherapy with alkylating agents is suitable for individual clinical use on a type 3 level of evidence in patients with low-grade disseminated relapse [86]. Standard therapeutic option for patients with high-grade transformation has not been yet defined. Like for aggressive de novo lymphomas, anthracycline-containing chemotherapy is suitable for individual clinical use on a type R basis. High-dose chemotherapy remains an investigational alternative in these cases. 6.4. New active drugs and therapeutic options A potentially active class of anti-cancer agents drugs are those targeted to the inhibition the NF-␬B pathway, the common target of the recurrent translocations. An example of this class is bortezomib that is currently being tested in clinical trials specifically designed for patients with MALT lymphoma. The use of eradicating therapy with specific antibiotics is an investigational approach in patients with non-gastric marginal-zone lymphoma associated with a well-documented concomitant infection. For example, some cases of tumor regression after eradicating antimicrobial therapy have been reported in B. burgdorferi-associated cutaneous MALT lymphomas [16,112], C. jejuni-associated immunoproliferative small intestinal disease [19] and C. psittaci-associated ocular adnexal MALT lymphomas [18]. Anti-chlamydial therapy with doxycycline has been associated with an overall response rate of 62% in C. psittaci-positive ocular adnexa MALT lymphoma in a multicentre prospective trial [113]. The use of antiviral therapy (interferon plus ribavirin) is an investigational approach in patients with (splenic) marginal-zone lymphoma associated with a chronic infection of hepatitis C virus (HCV). Encouraging results obtained with this therapy in small series of HCV-related indolent lymphomas [114] deserve to be assessed in HCV-positive patients with nodal and extranodal marginal-zone lymphomas. Even if molecular remission of clonal IgH rearrangement and bcl-2 translocation is rarely achieved, more than 70% of patients with HCV-related lymphomas display virology response and lymphoma regression, which seems to be unrelated to HCV genotype [114].

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Biographies Andr´es J.M. Ferreri is coordinator of the Unit of Lymphoid Malignancies and vice director of the Medical Oncology Unit, San Raffaele Scientific Institute, Milan, Italy. Emanuele Zucca is the head of the Lymphoma Unit at the Oncology Institute of Southern Switzerland, Bellinzona.

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