MALT lymphoma pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sujit Routray, M.D. [2], Ahmed Younes M.B.B.CH [3], Ahmed Elsaiey, MBBCH [4]

Overview[edit | edit source]

MALT lymphoma is a form of lymphoma involving the mucosa-associated lymphoid tissue (MALT), frequently of the stomach, but virtually any mucosal site can be afflicted. It is a cancer originating from B cells in the marginal zone of the MALT. The evolution of gastric MALT lymphoma is a multistage process starting with the infection of H. pylori resulting in the recruitment of B- and T-cells and other inflammatory cells to the gastric mucosa. Genes involved in the pathogenesis of MALT lymphoma include FOXP1 and BCL6. Chromosomal translocations are also involved in the pathogenesis of MALT lymphoma, which include t(1;14)(p22;q32), t(11;18)(q21;q21), t(14;18)(q32;q21), and t(3;14)(p14.1;q32). Gastric MALT lymphoma is frequently associated with chronic inflammation as a result of the presence of Helicobacter pylori (72-98%). Chronic immune stimulation is also suspected in the pathogenesis of non-gastric MALT lymphoma, and hence often have a history of autoimmune disorders, such as Hashimoto's thyroiditis, Sjögren's syndrome, Celiac disease, and relapsing polychondritis. On microscopic histopathological analysis, MALT lymphoma is characterized by the presence of dense diffuse lymphoid infiltrate of marginal‐zone cells in the lamina propria with prominent lymphoepithelial lesions consisting of small atypical cells with monocytoid features. A characteristic feature of MALT lymphoma is the presence of neoplastic cells within epithelial structures with associated destruction of the glandular architecture to form lymphoepithelial lesions. The neoplastic cells of MALT lymphoma may be positive for B-cell associated antigens (CD19, CD20, CD22, CD79a) that co-express BCL-2, and are negative for CD5, CD10, CD43, and cyclin D1.

Pathophysiology[edit | edit source]

Pathogenesis[edit | edit source]

• Mucosa Associated Lymphoid Tissue lymphoma (MALT lymphoma) resembles an extranodal subtype of Non-Hodgkin lymphoma. MALT lymphoma can occur in many sites extranodal but the most common site is the stomach.^{[1][2][3][4][5][6]}

• MALT lymphoma can take place in other tissues as lung, thyroid, small intestine, and ocular adnexa.

• The beginning of MALT lymphoma can be from H. pylori infection which results in recruiting a large amount of lymphocytes to the site of infection in the stomach.
• T-cell lymphocytes recruited to the site of infection they stimulate B-cells and with underlying genetic abnormalities, B-cells undergo malignant transformation.
• Lymphocytes activation take place as the following:^[5]
  • Epithelial cells are activated with the chronic infection. They express class HLA-DR and CD80 costimulatory molecules. They present the antigens to T-cells.
  • CD80 can react with CD28 on CD4 T-cells activating T-cells.
  • CD40 ligand expressed on activated T-cells interact with CD40 on B-cells. Along side the cytokines and chemokines released from T-cells, this interaction leads to B-cell activation.
  • Activating B and T cells will result in lymphoepithelial proliferation.

Genetics[edit | edit source]

• MALT lymphoma is strongly associated with chromosomal translocations as well as genetic mutations.
• Chromosomal translocations:
  • MALT lymphoma can arise as a result of many chromosomal translocation. The primary translocations associated with MALToma are the following:^[7][8]
    • t(1;14) (p22;q32)
    • t(11;18) (q21;q21)
    • t(14;18) (q32;q21)
    • t(3;14) (p14.1;q32)
  • Translocation t(1;14):^[9]
    • It is associated more with MALToma of stomach, lung, and skin. Translocation between BCL10 gene on chromosome 1 and immunoglobulin heavy chain on chromosome 14.
    • BCL10 gene is responsible for preventing apoptosis. This translocation leads to unhindered BCL10 expression and no apoptosis takes place ending up with uncontrolled proliferation of B cells.
    • Patients with t(1;14) are refractory to Helicobacter pylori (H. pylori) eradication therapy.
  • Translocation t(11;18):^[10][11]
    • This translocation was mainly reported in MALToma of lung and stomach. It is considered the most common translocation occurs in MALT lymphoma as overall.
    • It has been found associated with lymphoma at other sites as intestine, orbit and salivary glands.
    • This translocation shows fusion of BIRC2 gene on chromosome 11 and MALT1 gene on chromosome 18.
    • BIRC2 is antiapoptotic factor and overexpression can lead to unlimited cell proliferation.
    • Moreover, deletions of both genes have been reported. Deletions lead to DNA breaks which are repaired through a mechanism called non-homologous end joining (NHEJ) repair. The NHEJ repair mechanism has a high rate of error that may result in the genetic mutation responsible for the lymphoma.
  • Translocation t(14;18):
    • The translocation occurs between the heavy chain gene of immunoglobulin on chromosome 14 and MALT1 gene on chromosome 18.
    • This occurs mainly in MALT lymphomas outside the gastrointestinal tract.
  • Translocation t(3:14):
    • This translocation has shown a closer position of FOXP1 to the heavy chain gene of immunoglobulins.
    • FOXP1 is a transcription factor which plays a role in suppression of the apoptosis especially the genes suppressing the caspases.
• General role of the translocation in pathogenesis of MALT lymphoma:^[5][12]
  • The previous translocations are responsible for activating Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-kB) pathway as well as the uncontrolled expression of BCL10 and MALT1 which are antiapoptic mechanisms.
  • The BCL10 and MALT1 can bind together forming BCL2-MALT1 complex which has an important role in activating NF-kB via activation IkB kinase.
  • When the NF-kB be activate, it translocates into the nucleus to stimulate genes transcriptions especially those which encode growth factors important for cell growth and proliferation.
• TNFAIP3 gene deletion is another gene mutation associated with adnexal MALToma. It is believed that TNFAIP3 also has an important role in NF-kB pathway activation. TNFAIP3 is normaly a tumor suppressor gene.

• Other somatic mutations:
  • Missense mutations of PIM1 and cMyc are reported with some of the MALT lymphomas.^[13]
  • Framshift mutations of p53 has also been linked with pathogenesis of MALT lymphomas both gastric and extra-gastric.^[14]
  • Card11, CD79B, and Myd88 somatic mutations are also important in NF-kB activation. However, they may be associated with other subtypes of Non-Hodgkin lymphomas as splenic marginal zone lymphoma and noda marginal zone lymphoma.^[15]

Associated Conditions[edit | edit source]

• Gastric MALT lymphoma is frequently associated with chronic inflammation as a result of the presence of Helicobacter pylori (72-98%).^[1]
• Chronic immune stimulation is also suspected in the pathogenesis of non-gastric MALT lymphoma, and hence often have a history of autoimmune disorders, such as:^[6]

• Hashimoto's thyroiditis
• Sjögren's syndrome
• Celiac disease
• Relapsing polychondritis

• MALT lymphoma may be associated with infectious agents, which include:^[3]
  • Ocular adnexal MALT lymphoma and Chlamydia psittaci
  • Salivary gland MALT lymphoma and hepatitis C virus
  • Small intestinal MALT lymphoma and Campylobacter jejuni
  • Cutaneous MALT lymphoma and Borrelia afzelii infection
• MALT lymphoma can be associated with the following genetic conidtions:^[16]
  • Trisomies 3, 12, and 18: it is believed that increased the gene copies is related to lymphoma pathogenesis.

Gross Pathology[edit | edit source]

MALT lymphoma starts in the tissues or organs outside of the lymph nodes (extranodal). MALT lymphoma develops in mucosa-associated lymphoid tissue, in the mucosa, or tissue that lines body organs or body cavities including:^[6]

• Gastrointestinal tract (30-40%)
  • The stomach is the most common location for MALT lymphoma, but they can also occur in the small bowel and colon.
• Lungs
• Eyes, including the orbit
• Skin
• Salivary glands
• Thyroid gland
• Breasts

Microscopic pathology[edit | edit source]

• On microscopic histopathological analysis, MALT lymphoma is characterized by the presence of dense diffuse lymphoid infiltrate of marginal‐zone cells in lamina propria with prominent lymphoepithelial lesions and consisting of small atypical cells with monocytoid features.^[17][3]
• A characteristic feature of MALT lymphoma is the presence of neoplastic cells within epithelial structures with associated destruction of the glandular architecture to form lymphoepithelial lesions.^[18]
• The morphology of the neoplastic cells is variable with small mature lymphocytes, cells resembling centrocytes (centrocyte-like cells), or marginal zone/monocytoid B cells.
• Plasmacytoid or plasmacytic differentiation is frequent.
• Lymphoid follicles are ubiquitous to MALT lymphoma but may be indistinct as they are often overrun or colonized by the neoplastic cells. Large transformed B cells are present scattered among the small cell population. If these large cells are present in clusters or sheets, a diagnosis of associated large B-cell lymphoma should be considered.

References[edit | edit source]

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