The malignant T cells in MEITL can be identified by: their expression of cluster of differentiation (i.e. CD) cell surface molecules CD3, CD8, and CD56; by their failure to express CD4, CD5, or CD30; and, in particular, by their overexpression of megakaryocyte-associated tyrosine kinase. They are not infected with the Epstein-Barr virus and therefore do not express this virus's products (e.g. EBER1 or EBER2). In most individuals with the disease, these T cells are γδ rather than αβ T-cells based on their expression of γδ rather than αβ T-cell receptors. They also commonly express cytotoxic T cell activation markers such as TIA1, granzyme B, and perforin and therefore may have derived from or be related to cytotoxic T cell lymphocytes. However, in up to 25% of cases the malignant cells in MEITL also express markers of B cell lymphocytes. Detection of these "tumor marker" molecules on or in the lymphocytes of diseased tissues is critical for diagnosing MEITL; however, it does not clearly establish the original type of lymphocytes which became MEITL's malignant cells. This issue requires further studies. MEITL is thought to arise from intraepithelial lymphocytes that normally reside in the epithelial lining of the GI tract and over time acquire abnormalities that promote their survival, proliferation, avoidance of the immune system, and thereby malignancy. These cells are not infected with the Epstein-Barr virus and therefore have not become malignant as a consequence of this virus's malignancy-producing effects on lymphocytes as it does in other types of GI tract lymphomas. Rather, the malignant T cells in MEITL bear various genetic abnormalities that may promote their malignancy. Restriction fragment length polymorphism studies indicate that these cells have abnormal gains in minisatellites, i.e. repetitive small DNA sequences, in chromosomes 1, 5, 7, 8, 9, 13, 16, and 18. These minisatellites disrupt the production of some genes but the potential relevancies of these disruptions have not been defined. Genetic abnormalities commonly found in MEITL that do have potentially pro-malignant effects include: * Losses on the short (i.e. "p") arm around position 21.3 on one of the two inherited chromosomes 9. This results in a loss of heterozygosity for two genes, the CDKN2A gene which encodes cyclin-dependent kinase Inhibitor 2A, a protein that regulates cell proliferation and the CDKN2B gene which encodes multiple tumor suppressor 2, a protein that regulates cell death and tumor formation. * A similar loss of heterzygosity on the p arm of chromosome 17 at positions 12 through 13.2. This results in the loss of one of the inherited TP53 genes. TP53 encodes tumor suppressor p53, a protein that regulates cell proliferation, death, and tumor formation. * Mutations in JAK-STAT signaling pathway genes (i.e. JAK3 and STAT5B). This pathway regulates cell proliferation, death, and tumor formation. * Mutations in MAPK/ERK pathway genes (i.e. BRAF and KRAS). This pathway regulates cellular proliferation. * Mutations in the GNA12 gene. This gene encodes Gα12, a G alpha subunit that is required for stimuli to regulate cell function through Gα12-coupled receptors. * Mutations in the chromatin remodeling gene, SETD2. This gene encodes SET domain containing 2, a protein that acts to reduce the occurrence of gene deletions and tumor formation. * Mutations in the CREBBP gene. This gene encodes CREB-binding protein, a protein that activates various transcription factors some of which are implicated in tumor development. * Increased expression of the Myc proto-oncogene. When over-expressed, this genes product, the transcription factor, MYC, stimulates other genes to make their products, some of which stimulate cell proliferation. Further studies are required to determine which, if any, of these genetic abnormalities play a role in the development and/or progression of MEITL and therefore are therapeutic targets for treating the disease.
Monomorphic epitheliotropic intestinal T cell lymphoma
Enteropathy-associated T-cell lymphoma
Duodenal-type follicular lymphoma
Hepatosplenic T-cell lymphoma
Splenic lymphoma with villous lymphocytes
Diffuse large B-cell lymphoma associated with chronic inflammation
Hereditary progressive mucinous histiocytosis
MALT lymphoma