1. GENERAL INFORMATION
In early 1990s, the term marginal zone lymphoma (MZL) was proposed in the REAL classification (Harris 1994) 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 B-cell 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 become clear, and each is now considered a unique lymphoma subtype in the World Health Organization (WHO) classification (Isaacson 2001a;Isaacson 2001b; Isaacson 2001c). 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 (Liliemark 1998; Tierens 1998). 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 (Banks 1992; Lennert 1978). 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 MALT (mucosa-associated lymphoid tissue) 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 (Harris 1999). The term high-grade MALT lymphoma, initially used to define a large B-cell lymphoma arising at MALT sites, should no longer be used (Isaacson 2001a).
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 (Wotherspoon 1994). In the stomach, this has been linked to the presence of Helicobacter pylori infection (Wotherspoon 1996); a causal relationship was suggested (Wotherspoon 1996), and later experimentally reproduced (Hussell 1993). Helicobacter 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 some cases, the eradication of Helicobacter pylori infection by using specific antibiotic combinations leads to histological regression of the lymphoma (Parsonnet 1994;Wotherspoon 1993). 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 (Garbe 1991; Roggero 2000). The micro-organism 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 (Ferreri 2004), and clinical responses have been observed after appropriate antibiotic therapy (Ferreri 2005). The entity known as immunoproliferative small intestine disease (IPSID; also known as a chain disease) (Lecuit 2004; Al-Saleem 2005) is now considered an extranodal MZL associated with Campylobacter jejuni infection. This disorder is more frequent in the Middle East, especially the Mediterranean 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 (Lecuit 2004). 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 Sjögren’s syndrome, Hashimoto’s thyroiditis and lymphoid interstitial pneumopathy (Hyjek 1988a) (Isaacson 1992), respectively. A main role for hepatitis C viral infection in pathogenesis of marginal zone lymphomas has been also hypothesized (Luppi 1997). 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 (Du 1996a). 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 (Du 1996b). Thus, in early stages of gastric lymphoma development, antigen-driven T cells specific for the Helicobacter pylori may favor neoplastic growth (Hussell 1993) and the 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
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 (Harris 1999). 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 grading according to the number of large cells has been suggested (Harris 1999). 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 (Isaacson 2001a).
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 (Harris 1994).
2.3 Genetic features
Marginal zone lymphomas are usually not associated with bcl-1, bcl-2, bcl-3, and bcl-6 rearrangements (Pan 1989). 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%) (Ye 2005a). 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 (Wotherspoon 1995). Less frequently, trisomy of chromosomes 7, 12 and 18 as well as structural aberrations of chromosome 1 have been observed non-randomly (Dierlamm 1996a; Wotherspoon 1990; Wotherspoon 1995). 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 (Dierlamm 1996a). 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 (Peng 1996). Other common karyotypic alterations that characterize MALT 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-kB) pathway. The t(11;18)(q21;q21) is the most common chromosomal abnormality associated with MALT lymphomas (13% – 35% of cases) (Auer 1997). 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 zinc-binding 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 Helicobacter pylori eradication (Ye 2003; Liu 2001a; Liu 2001b). 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) (Ye 2003; Liu 2001a; Liu 2001b). In gastric MALT lymphoma, the t(11;18) translocation has been shown to be significantly associated with infection of CagA-positive strains of Helicobacter pylori, which are more likely to be associated with inflammatory responses and the induction of potent neutrophil activation (Ye 2003). 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 (Ye 2003). The t(1;14)(p22;q32) and variant t(1;2)(p22;p12) occur in 1% to 2% of MALT lymphomas, in the stomach, lung and skin (Ye 2005b; Streubel 2004a;Wotherspoon 1990; Achuthan 2000). Thus, 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 over-expression 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-kB 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 (Ye 2000). The t(14;18) translocation occurring in 15% to 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-?ÛB pathway (Sanchez-Izquierdo 2003). This translocation occurs more frequently in nongastrointestinal MALT lymphomas (liver, lung, and ocular adnexa) (Remstein 2004). 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 (Streubel 2005). 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 N-terminal zinc finger and leucine zipper domains (Coffer 2004). 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) (Streubel 2005). Cases with the translocation show overexpression of FOXP1 protein. FOXP1 protein is also over-expressed 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 (Barrans 2004; Banham 2005) but its role in MALT lymphoma is still unclear (Farinha 2005).
3.1 Clinical presentations
There are two major clinical presentations of marginal zone 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 Sjögren’s syndrome or Hashimoto’s thyroiditis, or of Helicobacter 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 (Cogliatti 1991; Hyjek 1988a; Hyjek 1988b; Li 1990; Mattia 1993; Medeiros 1989; Sundeen 1992; Zukerberg 1990). 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 (Berger 1994). The gastrointestinal tract is the most frequently involved extranodal site (66% of all MALT lymphomas). MALT lymphomas represent the 40% – 50% of primary gastric lymphomas (Cogliatti 1991). 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% (Montalban 1995; Pinotti 1997). 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 bad-defined margins and air broncogram. Atelectases and pleural effusion are rare (Cordier 1993). 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 nongastrointestinal MALT lymphomas, in which about one fourth of cases have been reported to present with involvement of multiple mucosal sites or nonmucosal sites such as bone marrow (Zucca 2003). Bone marrow involvement has been reported in up to 10% of cases, with peripheral blood dissemination in some cases (Carbone 1989). 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 (Ngan 1991; Nizze 1991; Sheibani 1988). These cases are today considered a separate entity, namely the nodal marginal zone lymphoma (Isaacson 2001b).
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 Sjögren’s syndrome or Hashimoto’s thyroiditis, or of Helicobacter pylori infection. These patients often have no adverse prognostic factors(Berger 1994). Localized extranodal disease (stage I-II), involving the stomach, salivary glands, thyroid gland, intestine, conjunctiva, lachrymal gland, skin and others (Cogliatti 1991; Hyjek 1988a;Hyjek 1988b; Li 1990; Mattia 1993; Medeiros 1989; Sundeen 1992; Zukerberg 1990). In cases with gastrointestinal involvement, symptoms are usually dyspepsia, with or without signs of chronic bleeding, and less frequently abdominal pain and weight loss (Cogliatti 1991). 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 bad-defined margins and air broncogram. Atelectasia and pleural effusion are rare (Cordier 1993). In many cases, diagnosis requires 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) marginal zone 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 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. 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 (Harris 1994). Marginal zone lymphoma is not associated with bcl-1, bcl-2, bcl-3, and bcl-6 rearrangements (Pan 1989). Trisomy 3 and t(11;18) have been reported in cases arisen in extranodal sites (Wotherspoon 1995). Less frequently, trisomy of chromosomes 7, 12 and 18 as well as structural aberrations of chromosome 1 have been observed non-randomly (Dierlamm 1996; Wotherspoon 1990; Wotherspoon 1995). 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 (Dierlamm 1996). 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 (Peng 1996). 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 burdorferi 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 of lymph node involvement, and a lower response rate with antibiotic therapy alone (Sackmann 1997; Steinbach 1999).
4.1 Staging procedures
The finding that patients presenting with extranodal MZL lymphoma disseminated at multiple mucosal sites may have a favourable outcome with survival curves similar 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 (Musshoff 1977); nevertheless, the staging system to be used for extranodal MZL is still controversial (De Jong 1999). A modified Blackledge staging system (known as the “Lugano staging system”) has been recommended for the cases presenting in the stomach (Rohatiner 1994). 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 (Ruskone-Fourmestraux 2003). 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 are 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 of potential hepatic or splenic involvement in marginal zone lymphomas should follow the general statements for all NHL.
4.2 Staging system
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 (Carbone 1971). 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:
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 (Rohatiner 1994).
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 (Wotherspoon 2004). 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 (Bertoni 2002; Thiede 2001; Fischbach 2002).
4.4 Restaging procedures
Restaging should include all diagnostic procedures positive at time of diagnosis and initial staging.
5.1 Natural history
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 (Li 1990; Medeiros 1989;Zukerberg 1990), and contrarily to other low-grade lymphomas, a high cure rate is achieved. Gastrointestinal and nongastrointestinal forms seem to have a similar prognosis (Thieblemont 1995), with 5-yr overall survival higher than 90% and a 10-yr survival of 75% – 80% (Cordier 1993;Thieblemont 1997). Recurrences may appear several years after treatment, with a median of 5 years (Berger 1994; Montalban 1995; Thieblemont 1997), involving the same organ (60% of cases) or other extranodal sites (Bailey 1996; Radaszkiewicz 1992; Thieblemont 1997). In extranodal forms dissemination occurs in 30% of cases, often to other extranodal sites, with a long disease free interval (Mattia 1993). When these lymphomas disseminate, they preferentially spread to other mucosal sites without peripheral blood or bone marrow involvement (Isaacson 1992). In the gastric forms, a preferential dissemination to the intestine and spleen has been reported (Du 1997). Disseminated disease is associated with a less favorable survival, and seems to be incurable with available therapy (Fisher 1995). Transformation to large cell aggressive lymphomas may occur in the first recurrence or in further relapses (Sheibani 1988). 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 has been associated with histologic transformation including p53 allelic loss and mutation, hypermethylation of p15 and p16, and p16 deletions (Du 1996; Neumeister 1997). There is evidence to suggest that aberrant telomerase activity may be involved in some cases of MALT lymphoma showing histologic progression (Kodera 2000). 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 (Kaneko 2003). 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.
5.2 Prognostic factors
Commonly reported indicators of a poorer outcome in extranodal marginal zone lymphomas are advanced age, impaired performance status, systemic symptoms, 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 (Berger 1994; Cogliatti 1991; Eidt 1994; Radaszkiewicz 1992; Sackmann 1997 ; Tondini 1993).
6.1 Treatment of limited disease (stage I-II)
Standard option for patients with stage I-II marginal zone 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 (Thieblemont 1995). The indolent nature of this disease justifies a conservative approach (Pinotti 1997). 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-yr survival of 75% – 80% (Coiffier 1999; Hammel 1994; Thieblemont 1995; Zinzani 1997; Pinotti 1997). 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 (Aviles 1996), 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 Helicobacter 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 (Bayerdorffer 1995 ; Neubauer 1997; Roggero 1995). 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 (Zucca 2004; Zucca 2000). The relationship between Helicobacter pylori infection and marginal zone lymphoma in the stomach has been used to define this new therapeutic approach (Wotherspoon 1993; Wotherspoon 1994). 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 (Wotherspoon 1992), 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 (de Jong 1997; Hoshida 1997; Isaacson 1999). 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 tumors infiltrating the submucosa, the muscularis propria, and the serosa. In the cases with documented nodal involvement, the response is very unlikely (Ruskone-Fourmestraux 2001; Levy 2002; Eidt 1994; Steinbach 1999). The presence of the t(11;18) translocation predict a poor therapeutic response of gastric MALT lymphoma to H. pylori eradication (Liu 2002) but not necessarily to other therapeutic approaches (Martinelli 2005; Streubel 2004b). 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 (Isaacson 1999). Relapse of Helicobacter pylori infection after a successful eradication is observed in less than 2% of cases. This may be accompanied by recurrence of lymphoma (Tursi 1997). No definite guidelines exist for the management of the subset of H. pylori-negative cases, for patients who fail antibiotic therapy, and for nongastric locations. A choice can be made between conventional therapeutic modalities but there are no published randomized studies for evidence-based decision making (Zucca 2000). 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 (Pinotti 1997; Thieblemont 2003). Radiotherapy is suitable for individual clinical use in patients with Helicobacter pylori-negative lymphomas on a type 3 level of evidence (Schechter 1998). Doses between 30 Gy and 43.5 Gy delivered in 1.5 Gy fractions obtained a 2-yr 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 (Hammel 1994; Levy 2002). Anecdotal cases of long-term remissions with interferon alpha2a injected s.c. at 9×10(6) U, three days a week for one year have been reported (Wollina 1999). Other phase II studies demonstrated the antitumor activity of the purine analogs fludarabine (Zinzani 2004) and cladribine (Jager 2002), which however may be associated with an increased risk of secondary myelodysplastic syndrome (Jager 2004), 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 (Wohrer 2003). 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 (Conconi 2003; Martinelli 2005).
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 antibiotic-resistant lymphomas on a type 3 level of evidence (Schechter 1998). In these cases with local relapsed or refractory disease, gastrectomy should be also take 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 (Hammel 1994). 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-êB 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 Borrelia burgdorferi?associated cutaneous MALT lymphomas (Roggero 2000; Kutting 1997), Campylobacter jejuni-associated immunoproliferative small intestinal disease (Lecuit 2004) and Chlamydia psittaci-associated ocular adnexal MALT lymphomas (Ferreri 2005). 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 (Vallisa 2005) 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 (Vallisa 2005).
Achuthan R, Bell SM, Leek JP, Roberts P, Horgan K, Markham AF, et al. Novel translocation of the BCL10 gene in a case of mucosa associated lymphoid tissue lymphoma. Genes Chromosomes Cancer 2000; 29: 347-349 [Medline]
Al Saleem T, Al Mondhiry H. Immunoproliferative small intestinal disease (IPSID): a model for mature B-cell neoplasms. Blood 2005; 105: 2274-2280 [Medline]
Auer IA, Gascoyne RD, Connors JM, Cotter FE, Greiner TC, Sanger WG, et al. t(11;18)(q21;q21) is the most common translocation in MALT lymphomas. Ann Oncol 1997; 8: 979-985 [Medline]
Aviles A, Delgado S, Huerta-Guzman J. Marginal zone B cell lymphoma of the parotid glands: results of a randomised trial comparing radiotherapy to combined therapy. Eur J Cancer B Oral Oncol 1996; 32B: 420-422 [Medline]
Bailey EM, Ferry JA, Harris NL, Mihm MCJ, Jacobson JO, Duncan LM. Marginal zone lymphoma (low-grade B-cell lymphoma of mucosa-associated lymphoid tissue type) of skin and subcutaneous tissue: a study of 15 patients [see comments]. Am J Surg Pathol 1996; 20: 1011-1023 [Medline]
Banham AH, Connors JM, Brown PJ, Cordell JL, Ott G, Sreenivasan G, et al. Expression of the FOXP1 transcription factor is strongly associated with inferior survival in patients with diffuse large B-cell lymphoma. Clin Cancer Res 2005; 11: 1065-1072 [Medline]
Banks PM. Incorporation of immunostaining data in anatomic pathology reports. Am J Surg Pathol 1992; 16: 808 [Medline]
Barrans SL, Fenton JA, Banham A, Owen RG, Jack AS. Strong expression of FOXP1 identifies a distinct subset of diffuse large B-cell lymphoma (DLBCL) patients with poor outcome. Blood 2004; 104: 2933-2935 [Medline]
Bayerdorffer E, Neubauer A, Rudolph B, Thiede C, Lehn N, Eidt S, et al. Regression of primary gastric lymphoma of mucosa-associated lymphoid tissue type after cure of Helicobacter pylori infection. MALT Lymphoma Study Group [see comments]. Lancet 1995; 345: 1591-1594 [Medline]
Berger F, Felman P, Sonet A, Salles G, Bastion Y, Bryon PA, et al. Nonfollicular small B-cell lymphomas: a heterogeneous group of patients with distinct clinical features and outcome. Blood 1994; 83: 2829-2835 [Medline]
Bertoni F, Conconi A, Capella C, Motta T, Giardini R, Ponzoni M, et al. Molecular follow-up in gastric mucosa-associated lymphoid tissue lymphomas: early analysis of the LY03 cooperative trial. Blood 2002; 99: 2541-2544 [Medline]
Carbone A, Gloghini A, Pinto A, Attadia V, Zagonel V, Volpe R. Monocytoid B-cell lymphoma with bone marrow and peripheral blood involvement at presentation [see comments]. Am J Clin Pathol 1989; 92: 228-236 [Medline]
Carbone PP, Kaplan HS, Musshoff K, Smithers DW, Tubiana M. Report of the Committee on Hodgkin’s Disease Staging Classification. Cancer Res 1971; 31: 1860-1861 [Medline]
Coffer PJ, Burgering BM. Forkhead-box transcription factors and their role in the immune system. Nat Rev Immunol 2004; 4: 889-899 [Medline]
Cogliatti SB, Schmid U, Schumacher U, Eckert F, Hansmann ML, Hedderich J, et al. Primary B-cell gastric lymphoma: a clinicopathological study of 145 patients. Gastroenterology 1991; 101: 1159-1170 [Medline]
Coiffier B, Thieblemont C, Felman P, Salles G, Berger F. Indolent nonfollicular lymphomas: characteristics, treatment, and outcome. Semin Hematol 1999; 36: 198-208 [Medline]
Conconi A, Martinelli G, Thieblemont C, Ferreri AJ, Devizzi L, Peccatori F, et al. Clinical activity of rituximab in extranodal marginal zone B-cell lymphoma of MALT type. Blood 2003; 102: 2741-2745 [Medline]
Cordier JF, Chailleux E, Lauque D, Reynaud-Gaubert M, Dietemann-Molard A, Dalphin JC, et al. Primary pulmonary lymphomas. A clinical study of 70 cases in nonimmunocompromised patients. Chest 1993; 103: 201-208 [Medline]
de Jong D, Aleman BM, Taal BG, Boot H. Controversies and consensus in the diagnosis, work-up and treatment of gastric lymphoma: an international survey. Ann Oncol 1999; 10: 275-280 [Medline]
de Jong D, Boot H, van Heerde P, Hart GA, Taal BG. Histological grading in gastric lymphoma: pretreatment criteria and clinical relevance. Gastroenterology 1997; 112: 1466-1474 [Medline]
Dierlamm J, Pittaluga S, Wlodarska I, Stul M, Thomas J, Boogaerts M, et al. Marginal zone B-cell lymphomas of different sites share similar cytogenetic and morphologic features [see comments]. Blood 1996; 87: 299-307 [Medline]
Du M, Diss TC, Xu C, Peng H, Isaacson PG, Pan L. Ongoing mutation in MALT lymphoma immunoglobulin gene suggests that antigen stimulation plays a role in the clonal expansion. Leukemia 1996b; 10: 1190-1197 [Medline]
Du MQ, Peng HZ, Dogan A, Diss TC, Liu H, Pan LX, et al. Preferential dissemination of B-cell gastric mucosa-associated lymphoid tissue (MALT) lymphoma to the splenic marginal zone. Blood 1997; 90: 4071-4077 [Medline]
Du MQ, Xu CF, Diss TC, Peng HZ, Wotherspoon AC, Isaacson PG, et al. Intestinal dissemination of gastric mucosa-associated lymphoid tissue lymphoma. Blood 1996a; 88: 4445-4451 [Medline]
Eidt S, Stolte M, Fischer R. Factors influencing lymph node infiltration in primary gastric malignant lymphoma of the mucosa-associated lymphoid tissue. Pathol Res Pract 1994; 190: 1077-1081 [Medline]
Farinha P, Gascoyne RD. Molecular pathogenesis of mucosa-associated lymphoid tissue lymphoma. J Clin Oncol 2005; 23: 6370-6378 [Medline]
Ferreri AJ, Guidoboni M, Ponzoni M, De Conciliis C, Dell’Oro S, Fleischhauer K, et al. Evidence for an association between Chlamydia psittaci and ocular adnexal lymphomas. J Natl Cancer Inst 2004; 96: 586-594 [Medline]
Ferreri AJ, Ponzoni M, Guidoboni M, De Conciliis C, Resti AG, Mazzi B, et al. Regression of ocular adnexal lymphoma after Chlamydia psittaci-eradicating antibiotic therapy. J Clin Oncol 2005; 23: 5067-5073 [Medline]
Fischbach W, Goebeler-Kolve M, Starostik P, Greiner A, Muller-Hermelink HK. Minimal residual low-grade gastric MALT-type lymphoma after eradication of Helicobacter pylori. Lancet 2002; 360: 547-548 [Medline]
Fisher RI, Dahlberg S, Nathwani BN, Banks PM, Miller TP, Grogan TM. A clinical analysis of two indolent lymphoma entities: mantle cell lymphoma and marginal zone lymphoma (including the mucosa-associated lymphoid tissue and monocytoid B-cell subcategories): a Southwest Oncology Group study. Blood 1995; 85: 1075-1082 [Medline]
Garbe C, Stein H, Dienemann D, Orfanos CE. Borrelia burgdorferi-associated cutaneous B cell lymphoma: clinical and immunohistologic characterization of four cases. J Am Acad Dermatol 1991; 24: 584-590 [Medline]
Hammel P, Haioun C, Chaumette MT, Divine M, Gaulard P, Reyes F, et al. Monochemotherapy as treatment of low grade B-cell gastric mucosa associated lymphoid tissue (MALT) lymphoma (Meeting abstract). Proc Annu Meet Am Soc Clin Oncol 1994; 13: A1290 [Medline]
Harris NL, Jaffe ES, Diebold J, Flandrin G, Muller-Hermelink HK, Vardiman J, et al. World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues: report of the Clinical Advisory Committee meeting-Airlie House, Virginia, November 1997. J Clin Oncol 1999; 17: 3835-3849 [Medline]
Harris NL, Jaffe ES, Stein H, Banks PM, Chan JK, Cleary ML, et al. A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group [see comments]. Blood 1994; 84: 1361-1392 [Medline]
Hoshida Y, Kusakabe H, Furukawa H, Kasugai T, Miwa H, Ishiguro S, et al. Reassessment of gastric lymphoma in light of the concept of mucosa- associated lymphoid tissue lymphoma: analysis of 53 patients. Cancer 1997; 80: 1151-1159 [Medline]
Hussell T, Isaacson PG, Crabtree JE, Spencer J. The response of cells from low-grade B-cell gastric lymphomas of mucosa- associated lymphoid tissue to Helicobacter pylori. Lancet 1993; 342: 571-574 [Medline]
Hyjek E, Isaacson PG. Primary B cell lymphoma of the thyroid and its relationship to Hashimoto’s thyroiditis. Hum Pathol 1988b; 19: 1315-1326 [Medline]
Hyjek E, Smith WJ, Isaacson PG. Primary B-cell lymphoma of salivary glands and its relationship to myoepithelial sialadenitis. Hum Pathol 1988a; 19: 766-776 [Medline]
Isaacson PG, Muller-Hermelink HK, Piris MA, et al. Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma). In: Jaffe ES, Harris NL, Stein H, et al, Editors. World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon: IARC Press. 2001a; 157-160 [Medline]
Isaacson PG, Nathwani BN, Piris MA, et al. Nodal marginal zone B-cell lymphoma. In: Jaffe ES, Harris NL, Stein H, et al, editors. World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon: IARC Press. 2001b; 161 [Medline]
Isaacson PG, Piris MA, Catovsky D, et al. Splenic marginal zone lymphoma. In: Jaffe ES, Harris NL, Stein H, et al, editors. World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon: IARC Press. 2001c; 135-137 [Medline]
Isaacson PG. Extranodal lymphomas: the MALT concept. Verh Dtsch Ges Pathol 1992; 76:14-23: 14-23 [Medline]
Isaacson PG. Gastric MALT lymphoma: from concept to cure. [Review] [96 refs]. Ann Oncol 1999; 10: 637-645 [Medline]
Jager G, Hofler G, Linkesch W, Neumeister P. Occurrence of a myelodysplastic syndrome (MDS) during first-line 2-chloro-deoxyadenosine (2-CDA) treatment of a low-grade gastrointestinal MALT lymphoma. Case report and review of the literature. Haematologica 2004; 89: ECR01 [Medline]
Jager G, Neumeister P, Brezinschek R, Hinterleitner T, Fiebiger W, Penz M, et al. Treatment of extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue type with cladribine: a phase II study. J Clin Oncol 2002; 20: 3872-3877 [Medline]
Kaneko Y, Sakurai S, Hironaka M, Sato S, Oguni S, Sakuma Y, et al. Distinct methylated profiles in Helicobacter pylori dependent and independent gastric MALT lymphomas. Gut 2003; 52: 641-646 [Medline]
Kodera Y, Nakamura T, Suzuki T, Yamamura Y, Nakamura S. Clinical relevance of telomerase activity in primary gastric lymphoma. Gastric Cancer 2000; 3: 57-62 [Medline]
Kutting B, Bonsmann G, Metze D, Luger TA, Cerroni L. Borrelia burgdorferi-associated primary cutaneous B cell lymphoma: complete clearing of skin lesions after antibiotic pulse therapy or intralesional injection of interferon alfa-2a. J Am Acad Dermatol 1997; 36: 311-314 [Medline]
Lecuit M, Abachin E, Martin A, Poyart C, Pochart P, Suarez F, et al. Immunoproliferative small intestinal disease associated with Campylobacter jejuni. N Engl J Med 2004; 350: 239-248 [Medline]
Lennert K. Malignant lymphomas: other than Hodgkin’s disease: histology, cytology, ultrastructure, immunology. Berlin: Springer-Verlag. 1978 [Medline]
Levy M, Copie-Bergman C, Traulle C, Lavergne-Slove A, Brousse N, Flejou JF, et al. Conservative treatment of primary gastric low-grade B-cell lymphoma of mucosa-associated lymphoid tissue: predictive factors of response and outcome. Am J Gastroenterol 2002; 97: 292-297 [Medline]
Li G, Hansmann ML, Zwingers T, Lennert K. Primary lymphomas of the lung: morphological, immunohistochemical and clinical features. Histopathology 1990; 16: 519-531 [Medline]
Liliemark J, Martinsson U, Cavallin-Stahl E, Svedmyr E, Porwit A, Stromberg M, et al. Cladribine for untreated or early low-grade non-Hodgkin’s lymphoma. Leuk Lymphoma 1998; 30: 573-581 [Medline]
Liu H, Ruskon-Fourmestraux A, Lavergne-Slove A, Ye H, Molina T, Bouhnik Y, et al. Resistance of t(11;18) positive gastric mucosa-associated lymphoid tissue lymphoma to Helicobacter pylori eradication therapy. Lancet 2001b; 357: 39-40 [Medline]
Liu H, Ye H, Dogan A, Ranaldi R, Hamoudi RA, Bearzi I, et al. T(11;18)(q21;q21) is associated with advanced mucosa-associated lymphoid tissue lymphoma that expresses nuclear BCL10. Blood 2001a; 98: 1182-1187 [Medline]
Liu H, Ye H, Ruskone-Fourmestraux A, de Jong D, Pileri S, Thiede C, et al. T(11;18) is a marker for all stage gastric MALT lymphomas that will not respond to H. pylori eradication. Gastroenterology 2002; 122: 1286-1294 [Medline]
Luppi M, Longo G, Ferrari MG, Ferrara L, Marasca R, Barozzi P, et al. Prevalence of HCV infection and second neoplasms in marginal zone lymphomas [letter; comment]. Br J Haematol 1997; 96: 873-8 [Medline]
Martinelli G, Laszlo D, Ferreri AJ, Pruneri G, Ponzoni M, Conconi A, et al. Clinical activity of rituximab in gastric marginal zone non-Hodgkin’s lymphoma resistant to or not eligible for anti-Helicobacter pylori therapy. J Clin Oncol 2005;23: 1979-1983 [Medline]
Mattia AR, Ferry JA, Harris NL. Breast lymphoma. A B-cell spectrum including the low grade B-cell lymphoma of mucosa associated lymphoid tissue. Am J Surg Pathol 1993; 17: 574-587 [Medline]
Medeiros LJ, Harmon DC, Linggood RM, Harris NL. Immunohistologic features predict clinical behavior of orbital and conjunctival lymphoid infiltrates. Blood 1989; 74: 2121-2129 [Medline]
Montalban C, Castrillo JM, Abraira V, Serrano M, Bellas C, Piris MA, et al. Gastric B-cell mucosa-associated lymphoid tissue (MALT) lymphoma. Clinicopathological study and evaluation of the prognostic factors in 143 patients. Ann Oncol 1995; 6: 355-362 [Medline]
Musshoff K. [Clinical staging classification of non-Hodgkin’s lymphomas (author’s transl)]. Strahlentherapie 1977; 153: 218-221 [Medline]
Neubauer A, Thiede C, Morgner A, Alpen B, Ritter M, Neubauer B, et al. Cure of Helicobacter pylori infection and duration of remission of low- grade gastric mucosa-associated lymphoid tissue lymphoma [see comments]. J Natl Cancer Inst 1997; 89: 1350-1355 [Medline]
Neumeister P, Hoefler G, Beham-Schmid C, Schmidt H, Apfelbeck U, Schaider H, et al. Deletion analysis of the p16 tumor suppressor gene in gastrointestinal mucosa-associated lymphoid tissue lymphomas. Gastroenterology 1997; 112: 1871-1875 [Medline]
Ngan BY, Warnke RA, Wilson M, Takagi K, Cleary ML, Dorfman RF. Monocytoid B-cell lymphoma: a study of 36 cases [see comments]. Hum Pathol 1991; 22: 409-421 [Medline]
Nizze H, Cogliatti SB, von Schilling C, Feller AC, Lennert K. Monocytoid B-cell lymphoma: morphological variants and relationship to low-grade B-cell lymphoma of the mucosa-associated lymphoid tissue. Histopathology 1991; 18: 403-414 [Medline]
Pan L, Diss TC, Cunningham D, Isaacson PG. The bcl-2 gene in primary B cell lymphoma of mucosa-associated lymphoid tissue (MALT). Am J Pathol 1989; 135: 7-11 [Medline]
Parsonnet J, Hansen S, Rodriguez L, Gelb AB, Warnke RA, Jellum E, et al. Helicobacter pylori infection and gastric lymphoma [see comments]. N Engl J Med 1994; 330: 1267-1271 [Medline]
Peng H, Chen G, Du M, Singh N, Isaacson PG, Pan L. Replication error phenotype and p53 gene mutation in lymphomas of mucosa-associated lymphoid tissue. Am J Pathol 1996; 148: 643-648 [Medline]
Pinotti G, Zucca E, Roggero E, Pascarella A, Bertoni F, Savio A, et al. Clinical features, treatment and outcome in a series of 93 patients with low-grade gastric MALT lymphoma. Leuk Lymphoma 1997; 26: 527-537 [Medline]
Radaszkiewicz T, Dragosics B, Bauer P. Gastrointestinal malignant lymphomas of the mucosa-associated lymphoid tissue: factors relevant to prognosis. Gastroenterology 1992; 102: 1628-1638 [Medline]
Remstein ED, Kurtin PJ, Einerson RR, Paternoster SF, Dewald GW. Primary pulmonary MALT lymphomas show frequent and heterogeneous cytogenetic abnormalities, including aneuploidy and translocations involving API2 and MALT1 and IGH and MALT1. Leukemia 2004; 18: 156-160 [Medline]
Roggero E, Zucca E, Mainetti C, Bertoni F, Valsangiacomo C, Pedrinis E, et al. Eradication of Borrelia burgdorferi infection in primary marginal zone B-cell lymphoma of the skin. Hum Pathol 2000; 31: 263-268 [Medline]
Roggero E, Zucca E, Pinotti G, Pascarella A, Capella C, Savio A, et al. Eradication of Helicobacter pylori infection in primary low-grade gastric lymphoma of mucosa-associated lymphoid tissue [see comments]. Ann Intern Med 1995; 122: 767-769 [Medline]
Rohatiner A, D’Amore F, Coiffier B, Crowther D, Gospodarowicz M, Isaacson P, et al. Report on a workshop convened to discuss the pathological and staging classifications of gastrointestinal tract lymphoma. Ann Oncol 1994; 5: 397-400 [Medline]
Ruskone-Fourmestraux A, Dragosics B, Morgner A, Wotherspoon A, Dd JD. Paris staging system for primary gastrointestinal lymphomas. Gut 2003; 52: 912-913 [Medline]
Ruskone-Fourmestraux A, Lavergne A, Aegerter PH, Megraud F, Palazzo L, de Mascarel A, et al. Predictive factors for regression of gastric MALT lymphoma after anti-Helicobacter pylori treatment. Gut 2001; 48: 297-303 [Medline]
Sackmann M, Morgner A, Rudolph B, Neubauer A, Thiede C, Schulz H, et al. Regression of gastric MALT lymphoma after eradication of Helicobacter pylori is predicted by endosonographic staging. MALT Lymphoma Study Group. Gastroenterology 1997; 113: 1087-1090 [Medline]
Sanchez-Izquierdo D, Buchonnet G, Siebert R, Gascoyne RD, Climent J, Karran L, et al. MALT1 is deregulated by both chromosomal translocation and amplification in B-cell non-Hodgkin lymphoma. Blood 2003; 101: 4539-4546 [Medline]
Schechter NR, Portlock CS, Yahalom J. Treatment of mucosa-associated lymphoid tissue lymphoma of the stomach with radiation alone. J Clin Oncol 1998; 16: 1916-1921 [Medline]
Sheibani K, Burke JS, Swartz WG, Nademanee A, Winberg CD. Monocytoid B-cell lymphoma. Clinicopathologic study of 21 cases of a unique type of low-grade lymphoma. Cancer 1988; 62: 1531-1538 [Medline]
Steinbach G, Ford R, Glober G, Sample D, Hagemeister FB, Lynch PM, et al. Antibiotic treatment of gastric lymphoma of mucosa-associated lymphoid tissue. An uncontrolled trial. Ann Intern Med 1999; 131: 88-95 [Medline]
Streubel B, Simonitsch-Klupp I, Mullauer L, Lamprecht A, Huber D, Siebert R, et al. Variable frequencies of MALT lymphoma-associated genetic aberrations in MALT lymphomas of different sites. Leukemia 2004a; 18: 1722-1726 [Medline]
Streubel B, Vinatzer U, Lamprecht A, Raderer M, Chott A. T(3;14)(p14.1;q32) involving IGH and FOXP1 is a novel recurrent chromosomal aberration in MALT lymphoma. Leukemia 2005; 19: 652-658 [Medline]
Streubel B, Ye H, Du MQ, Isaacson PG, Chott A, Raderer M. Translocation t(11;18)(q21;q21) is not predictive of response to chemotherapy with 2CdA in patients with gastric MALT lymphoma. Oncology 2004b; 66: 476-480 [Medline]
Sundeen JT, Longo DL, Jaffe ES. CD5 expression in B-cell small lymphocytic malignancies. Correlations with clinical presentation and sites of disease. Am J Surg Pathol 1992; 16: 130-137 [Medline]
Thieblemont C, Bastion Y, Berger F, Rieux C, Salles G, Dumontet C, et al. Mucosa-associated lymphoid tissue gastrointestinal and nongastrointestinal lymphoma behavior: analysis of 108 patients. J Clin Oncol 1997; 15: 1624-1630 [Medline]
Thieblemont C, Berger F, Coiffier B. Mucosa-associated lymphoid tissue lymphomas. Curr Opin Oncol 1995; 7: 415-420 [Medline]
Thieblemont C, Dumontet C, Bouafia F, Hequet O, Arnaud P, Espinouse D, et al. Outcome in relation to treatment modalities in 48 patients with localized gastric MALT lymphoma: a retrospective study of patients treated during 1976-2001. Leuk Lymphoma 2003; 44: 257-262 [Medline]
Thiede C, Wundisch T, Alpen B, Neubauer B, Morgner A, Schmitz M, et al. Long-term persistence of monoclonal B cells after cure of Helicobacter pylori infection and complete histologic remission in gastric mucosa-associated lymphoid tissue B-cell lymphoma. J Clin Oncol 2001; 19: 1600-1609 [Medline]
Tierens A, Delabie J, Pittaluga S, Driessen A, DeWolf-Peeters C. Mutation analysis of the rearranged immunoglobulin heavy chain genes of marginal zone cell lymphomas indicates an origin from different marginal zone B lymphocyte subsets. Blood 1998; 91: 2381-2386 [Medline]
Tondini C, Giardini R, Bozzetti F, Valagussa P, Santoro A, Bertulli R, et al. Combined modality treatment for primary gastrointestinal non-Hodgkin’s lymphoma: the Milan Cancer Institute experience [see comments]. Ann Oncol 1993; 4: 831-837 [Medline]
Tursi A, Cammarota G, Papa A, Cuoco L, Fedeli G, Gasbarrini G. Long-term follow-up of disappearance of gastric mucosa-associated lymphoid tissue after anti-Helicobacter pylori therapy. Am J Gastroenterol 1997; 92: 1849-1852 [Medline]
Vallisa D, Bernuzzi P, Arcaini L, Sacchi S, Callea V, Marasca R, et al. Role of anti-hepatitis C virus (HCV) treatment in HCV-related, low-grade, B-cell, non-Hodgkin’s lymphoma: a multicenter Italian experience. J Clin Oncol 2005; 23: 468-473 [Medline]
Wohrer S, Drach J, Hejna M, Scheithauer W, Dirisamer A, Puspok A, et al. Treatment of extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) with mitoxantrone, chlorambucil and prednisone (MCP). Ann Oncol 2003; 14: 1758-1761 [Medline]
Wollina U, Hahnfeld S, Kosmehl H. Primary cutaneous marginal center lymphoma – complete remission induced by interferon alpha2a. J Cancer Res Clin Oncol 1999; 125: 305-308 [Medline]
Wotherspoon AC, Doglioni C, de Boni M, Spencer J, Isaacson PG. Antibiotic treatment for low-grade gastric MALT lymphoma [letter; comment]. Lancet 1994; 343: 1503 [Medline]
Wotherspoon AC, Doglioni C, Diss TC, Pan LX, Moschini A, de Boni M, et al. Regression of low grade B-cell gastric lymphoma of MALT type following eradication of Helicobacter pylori (Meeting abstract). J Pathol 1993; 170: 335A [Medline]
Wotherspoon AC, Doglioni C, Isaacson PG. Low-grade gastric B-cell lymphoma of mucosa-associated lymphoid tissue (MALT): a multifocal disease. Histopathology 1992; 20: 29-34 [Medline]
Wotherspoon AC, Finn TM, Isaacson PG. Trisomy 3 in low-grade B-cell lymphomas of mucosa-associated lymphoid tissue. Blood 1995; 85: 2000-2004 [Medline]
Wotherspoon AC, Savio A. Molecular follow-up in gastric MALT lymhomas. In: Zucca E, Editor. MALT lymphomas. Georgetown TX: Eurekah.com. 2004 [Medline]
Wotherspoon AC, Soosay GN, Diss TC, Isaacson PG. Low-grade primary B-cell lymphoma of the lung. An immunohistochemical, molecular, and cytogenetic study of a single case [see comments]. Am J Clin Pathol 1990; 94: 655-660 [Medline]
Wotherspoon AC. Gastric MALT lymphoma and Helicobacter pylori. Yale J Biol Med 1996; 69: 61-68 [Medline]
Ye H, Chuang SS, Dogan A, Isaacson PG, Du MQ. t(1;14) and t(11;18) in the differential diagnosis of Waldenstrom’s macroglobulinemia. Mod Pathol 2004; 17: 1150-1154 [Medline]
Ye H, Dogan A, Karran L, Willis TG, Chen L, Wlodarska I, et al. BCL10 expression in normal and neoplastic lymphoid tissue. Nuclear localization in MALT lymphoma. Am J Pathol 2000; 157: 1147-1154 [Medline]
Ye H, Gong L, Liu H, Hamoudi RA, Shirali S, Ho L, et al. MALT lymphoma with t(14;18)(q32;q21)/IGH-MALT1 is characterized by strong cytoplasmic MALT1 and BCL10 expression. J Pathol 2005b; 205: 293-301 [Medline]
Ye H, Liu H, Raderer M, Chott A, Ruskone-Fourmestraux A, Wotherspoon A, et al. High incidence of t(11;18)(q21;q21) in Helicobacter pylori-negative gastric MALT lymphoma. Blood 2003; 101: 2547-2550 [Medline]
Ye H, Nicholson AG, Dogan A, et al. BCL6 involved chromosomal translocation in MALT lymphoma of various sites Mod Pathol 18:258A, 2005 (abstr 1194). Mod Pathol 2005a; 18: 258A [Medline]
Zinzani PL, Magagnoli M, Ascani S, Ricci P, Poletti V, Gherlinzoni F, et al. Nongastrointestinal mucosa-associated lymphoid tissue (MALT) lymphomas: clinical and therapeutic features of 24 localized patients. Ann Oncol 1997; 8: 883-886 [Medline]
Zinzani PL, Stefoni V, Musuraca G, Tani M, Alinari L, Gabriele A, et al. Fludarabine-containing chemotherapy as frontline treatment of nongastrointestinal mucosa-associated lymphoid tissue lymphoma. Cancer 2004; 100: 2190-2194 [Medline]
Zucca E, Bertoni F, Roggero E, Cavalli F. The gastric marginal zone B-cell lymphoma of MALT type. Blood 2000; 96: 410-419 [Medline]
Zucca E, Cavalli F. Are antibiotics the treatment of choice for gastric lymphoma? Curr Hematol Rep 2004; 3: 11-16 [Medline]
Zucca E, Conconi A, Pedrinis E, Cortelazzo S, Motta T, Gospodarowicz MK, et al. Nongastric marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue. Blood 2003; 101: 2489-2495 [Medline]
Zukerberg LR, Ferry JA, Southern JF, Harris NL. Lymphoid infiltrates of the stomach. Evaluation of histologic criteria for the diagnosis of low-grade gastric lymphoma on endoscopic biopsy specimens [see comments]. Am J Surg Pathol 1990; 14: 1087-1099 [Medline]
Dr. Andrés Ferreri (Associate Editor)
San Raffaele Scientific Institute – Milan, Italy
Dr. Carlo Tondini (Editor)
START Clinical Editor – Ospedali Riuniti – Bergamo, Italy
Prof. Emanuele Zucca (Reviewer)
Oncology Institute of Southern Switzerland – Bellinzona, Switzerland