ABSTRACT: Marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT) lymphoma is an indolent B-cell non-Hodgkin lymphoma arising from the lymphoid tissue at extranodal sites. It is genetically characterized by different, usually mutually exclusive, genetic abnormalities that lead to activation of the nuclear factor kappa B (NF-κB) pathway. These lymphomas can arise in any extranodal organ or tissue; however, the stomach—where MALT lymphoma development has been strongly linked to chronic Helicobacter pylori infection—is the most common site. Other microorganisms have been associated with non-gastric MALT lymphomas, but the evidence for such associations is weaker. Treatment aimed at eradicating H pylori infection results in remission of gastric MALT lymphoma in most patients and represents a model of anticancer treatment based on the eradication of the causative factor. Treatment of non-gastric MALT lymphomas is much less well established; either radiotherapy or systemic therapy (with chemotherapy and/or rituximab(Drug information on rituximab) [Rituxan]) can be effective, while antibiotic therapies (eg, doxycycline(Drug information on doxycycline) in ocular adnexal lymphomas) should still be considered investigational.
Definition and Classification of Marginal Zone Lymphomas
According to the fourth edition of the World Health Organization (WHO) classification of tumors of hematopoietic and lymphoid tissues, the group of B-cell marginal zone lymphomas (MZL) comprises three different entities. These are MZL of mucosa-associated lymphoid tissue (MALT), nodal MZL (previously known as monocytoid lymphoma), and splenic MZL (with or without circulating villous lymphocytes).[1-3] While primary splenic and nodal MZLs are quite rare, each comprising approximately 1% to 2% of lymphomas, the extranodal MZL of MALT (currently named MALT lymphoma) is not uncommon, representing approximately 8% of the total number of non-Hodgkin lymphoma cases.
Pathological Features of MALT Lymphomas
Macroscopically, MALT lymphomas are often indistinguishable from the inflammatory lesion from which the lymphoma arises, but they can also present with obvious tumor masses. These lymphomas are often multifocal, with small, often microscopic clonally identical foci of lymphoma scattered throughout the involved organ. MALT lymphoma is defined as an extranodal lymphoma composed of heterogeneous B cells, including small lymphocytes with round nuclei and clumped chromatin (sometimes centrocyte-like), monocytoid cells, and plasmacytoid cells. One or more cytological features can predominate, or the different types of cells can coexist to various degrees within the same case. Scattered large cells (immunoblast- and centroblast-like) are usually present, but these are in the minority and their prognostic significance is not fully understood. Nevertheless, evaluation for a potential associated large B-cell lymphoma by analysis of extra-follicular components for transformed large B cells is essential because when the blast cells form solid or sheet-like proliferations, a separate diagnosis of a diffuse large B-cell lymphoma should be made. Plasma cell differentiation is often present in MALT lymphomas, as well as a number of non-neoplastic, reactive T cells. Neoplastic B cells can infiltrate and disrupt the mucosal crypts and glands, forming lymphoepithelial lesions. These latter, although highly characteristic of MALT lymphoma, especially gastric lymphoma, are not pathognomonic, nor is their presence essential for the diagnosis, since they can also be detected in some reactive conditions[6,7] and in other lymphoma subtypes.[8,9]
There is no specific immunohistochemical marker for MALT lymphoma at present. The tumor cells typically express IgM, less often IgA or IgG; they are positive for CD20, CD79a, CD21, and CD35, and they are negative for CD5, CD23, CD10, and cyclinD1, recapitulating the immunophenotype of normal marginal zone B cells. Stains for cytokeratin can help in the identification of lymphoepithelial lesions. The immunoglobulin light chain restriction is often difficult to demonstrate in small biopsy specimens.
The demonstration of B-cell monoclonality by polymerase chain reaction (PCR) has been proposed to help differentiate between a florid reactive lymphoid reaction and MALT lymphoma. However, monoclonality can be seen in benign inflammations, such as chronic gastritis,[10-12] and conversely, PCR may fail to detect monoclonality in up to 15% of cases of overt MALT lymphoma, causing false-negative results, due to the presence of a high load of immunoglobulin heavy chain (IGHV) somatic mutations.[13,4]Thus, MALT lymphoma should not be diagnosed in the absence of clear histological evidence.
MALT Lymphoma Biology
MALT lymphoma usually arises in mucosal sites where lymphocytes are not normally present and where MALT is acquired in response to either chronic infectious conditions or autoimmune processes, such as Hashimoto thyroiditis or Sjögren syndrome. Helicobacter pylori gastritis is the best studied condition, but other infectious agents have been implicated in the pathogenesis of MALT lymphomas arising in the skin (Borrelia burgdorferi), in the ocular adnexa (Chlamydophila psittaci), and in the small intestine (Campylobacter jejuni).
MALT lymphoma presents with somatically mutated IGHV genes in all cases. IGHV sequence analysis shows a pattern of somatic hypermutation and rearrangement suggesting that the tumor cell has undergone antigen selection in germinal centers.[15,16] The presence of so-called ongoing mutations (intraclonal variation) and the biased usage of some IGHV segments (eg, 1-69 in salivary glands) indicate that the expansion of lymphoma cells could still be antigen-driven. Also, the antibodies expressed by MALT lymphoma cells often have specificity for self-antigens.[18-20] In the context of this continual antigenic stimulation, abnormal B-cell clones that acquire successive genetic abnormalities can progressively replace the normal B-cell population of the inflammatory tissue, thereby giving rise to the lymphoma.
MALT lymphomas present with a series of recurrent genomic lesions, including chromosomal translocations and unbalanced genomic aberrations (Table 1).[21-31]
The t(11;18)(q21;q21) translocation is the most common translocation, and it results in the reciprocal fusion of BIRC3—previously named cellular inhibitor of apoptosis protein 2 (cIAP2)—on 11q21 with MALT1 on 18q21.[20,31] The presence of t(11;18) is associated with a low probability of response to antibiotics and with H pylori negativity in primary gastric MALT lymphoma; it is also associated with more advanced disease.[33-35] However, MALT lymphomas with this translocation present a lower risk of transformation to diffuse large B-cell lymphoma (DLBCL).
The t(14;18)(q32;q21) translocation is cytogenetically identical to the t(14;18)(q32;q21) translocation involving BCL2 in follicular lymphoma or DLBCL; here, however, it juxtaposes the MALT1 gene to the promoter region of the IGHV genes, with subsequent MALT1 deregulation.
The t(1;14)(p22;q32) translocation causes overexpression of the BCL10 gene due to the juxtaposition of the IGHV genes and the promoter region. BCL10 is highly expressed in the nuclei of the neoplastic cells of MALT lymphomas carrying this translocation, and a high nuclear expression is also detected in t(11;18)-positive cases and in other patients as well.[34,35,37,38]
The t(3;14)(p13;q32) translocation induces the juxtaposition of the gene coding for the transcription factor FOXP1 and the enhancer region of the IGHV genes.[24,31] Unlike t(11;18) and t(14;18), t(3;14) is not strictly specific for MALT lymphomas; it can also be detected in DLBCL. Indeed, a high expression of FOXP1 seems to correlate with a poor outcome in both MALT lymphomas and DLBCL, and high expression of this transcription factor may be associated with a risk of transformation to high-grade tumors.[39,40]
Other recurrent translocations, such as the t(9;14)(9p24;q32) translocation juxtaposing the JMJD2C gene and the IGHV promoter regions, have been reported; however, their role in MALT lymphomas is uncharacterized. JMJD2C is a histone demethylase, recently shown to be deregulated by DNA amplification in primary mediastinal B-cell lymphoma and in Hodgkin lymphoma.
MALT lymphomas, together with the splenic and nodal MZLs, present gains of chromosomes 3/3q and 18/18q at a frequency higher than that seen in other B-cell tumors.[26,43-45] A new recurrent 6q23.3 deletion has been described, which, together with somatic mutations, inactivates the TNFAIP3/A20 gene.[44,46-48] The presence of gains affecting chromosomes 3 and 18 and the lack of other lesions—such as deletions at 7q31 (common in splenic MZL), at 13q14.3 (common in chronic lymphocytic leukemia), or at 11q22 (common in chronic lymphocytic leukemia or mantle cell lymphoma)—can help distinguish MALT lymphomas from other indolent lymphoid neoplasms.
Importantly, the result of at least four of the recurrent lesions (TNFAIP3 loss, BIRC3-MALT1, IGHV-BCL10, IGHV-MALT1) is the activation of the nuclear factor kappa B (NF-κB) pathway, which is central in regulating immunity, inflammation, and apoptosis, and which represents a possible therapeutic target for MALT lymphomas. Interestingly, while direct TNFAIP3 inactivation is caused by similar lesions in different lymphoma subtypes (ie, deletions and/or somatic mutations),[44,47,48,50,51] different mechanisms seem to activate BIRC3 in different MZL subtypes, as shown by a recent study reporting recurrent somatic mutations in splenic MZL that disrupt the same RING domain that is removed by t(11;18) in MALT lymphomas.
Lastly, it is worth mentioning that the chromosomal translocations are mutually exclusive, and that, unlike 3/3q and 18/18q gains and 6q23 deletions, they show a different anatomical distribution.[25,29,30]