| Monomorphic epitheliotropic intestinal T cell lymphoma | |
|---|---|
| Other names | Enteropathy-associated T cell lymphoma, type II |
| Specialty | Hematology and Oncology |
| Symptoms | GI tract symptoms |
| Duration | Rapidly progressive |
| Causes | Malignant T cells |
| Prognosis | Poor |
Monomorphic epitheliotropic intestinal T cell lymphoma (MEITL) (formerly termed enteropathy-associated T cell lymphoma, type II) is an extremely rare peripheral T-cell lymphoma that involves the malignant proliferation of a type of lymphocyte, the T cell, in the gastrointestinal tract (i.e. GI tract). [1] Over time, these T cells commonly spread throughout the mucosal lining of a portion of the GI tract [2] (particularly the jejunum and ileum of the small intestine [3] ), lead to GI tract nodules and ulcerations, and cause symptoms such as abdominal pain, weight loss, diarrhea, obstruction, bleeding, and/or perforation. [2]
In 2008, the World Health Organization defined a specific type of lymphoma, enteropathy-associated T cell lymphoma (EATL), as having two different types: EATL type I, a lymphoma occurring in patients with the chronic, autoimmune GI tract disorder, celiac disease, and EATL type II, a similar bowel lymphoma that was not associated with celiac disease. However, subsequent studies found significant clinical, pathologic, and pathophysiological differences between these two types of lymphoma. Consequently, the World Health Organization (2016) redefined these lymphomas as separate entities, terming the celiac disease-associated lymphoma as enteropathy-associated T cell lymphoma (EATL) and the lymphoma not associated with celiac disease as monomorphic epitheliotropic intestinal T cell lymphoma (MEITL). [4] MEITL is only 1/5 to 1/10 as common as EATL. [5] The Organization (2016) also termed a third type of intestinal T cell lymphoma that could not be classified as ATL or MEITL as intestinal T cell lymphoma, not otherwise specified. [6]
MEITL is a highly aggressive GI tract lymphoma [7] which typically has had very short survival times following its diagnosis. [2] The disease often occurs in elderly patients who are afflicted with other ailments and consequently have little tolerance for the standard chemotherapy regimens that are used to treat other types of lymphomas. Moreover, these therapeutic regimens have shown little effectiveness in treating MEITL. To date, the best but still only marginally effective therapeutic interventions for the disease have been treatments that incorporate hematopoietic stem cell transplantation into chemotherapy plus surgical (when needed to treat local bowel issues such as obstruction or perforation) regimens. [3]
MEITL has been seen more often in Asians and individuals of Hispanic descent, in males (male to female ratio of ~2 to 1), and in mature or elderly individuals (median age ~60 years). [2] Patients may present with irregular bowel movements, abdominal pain, hematochezia (i.e. the anal passage of fresh blood), [2] B symptoms (i.e. fever, night sweats, weight loss), loss of appetite, [5] and/or bowel perforations and/or obstructions. [2]
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). [3] 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. [8]
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. [4] Genetic abnormalities commonly found in MEITL that do have potentially pro-malignant effects include:
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. [4]
The symptoms of MEITL are generally non-specific. The diagnosis depends on endoscopic findings in the GI tract, histological findings on biopsied specimens from involved areas of the GI tract, evidence of disease involvement outside of the GI tract, and the differentiation of MEITL from other GI tract lymphomas and benign lymphoproliferative diseases. Endoscopy typically shows multiple raised and/or ulcerated lesions involving the jejunum or ileum, and less commonly, the duodenum, stomach, or colon. [3] These lesions may occur at multiple sites or spread throughout large areas of the GI tract. Biopsied tissues show abnormally broad intestinal villi caused by the infiltration of sheets of uniformly-sized lymphocytes. These lymphocytes may also infiltrate and disrupt the architecture of nearby intestinal crypts and the epithelial lining. Unlike celiac disease-associated EATL, the lesions usually have little evidence of inflammatory cells (particularly lymphoplasmacytoid cells, i.e. cells showing a mixture of B cell and plasma cell morphological features) or of infiltration of the epithelium lining by the types of lymphocytes seen in celiac disease. [2] The lymphocytes in these lesions are T cells expressing the marker molecules and genetic abnormalities given in the above Pathophysiology section. [3] [4] [8] CT scans commonly reveal involvement of mesenteric lymph nodes. [2] Advanced cases have involvement of the bone marrow [5] and/or dissemination into other organs. [9]
MEITL must be differentiated from the following GI tract disorders with which it shares some common features.
There is no standard treatment for MEITL. Most individuals have been treated by surgical resections of involved areas with or without anthracycline-based chemotherapy. In these cases, responses have been short-lived and/or poor with 1 year overall survival rates, 1 year progression free survival rates, and median survival times of 36%, 21%, and 7 months, respectively. [5] A retrospective study of patients treated with resection, chemotherapy and autologous hematopoietic stem cell transplantation had a higher 1-year and 5-year overall survival (100%, 33%) compared to one-year survival (73%) and five-year survival (14%) without transplantation; a second retrospective study supported the usefulness of transplantation in that high-dose lymphoma chemotherapy followed by transplantation and standard-dose lymphoma chemotherapy with or without surgical resection increased 5-year overall survival from 22 to 60% and 5-year disease progression-free survival from 22 to 52%. [13] While further studies, particularly randomized controlled trials, are needed to investigate the best treatments for MEITL, the use of lymphoma chemotherapy, hematopoietic stem cell transplantation, and, where needed, surgical resections are the currently recommended treatments for MEITL. [3]