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 Sjgren 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.
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