Enteropathy-associated T-cell lymphoma

Enteropathy-associated T-cell lymphoma (EATL), previously termed enteropathy-associated T-cell lymphoma, type I and at one time termed enteropathy-type T-cell lymphoma (ETTL), is a complication of coeliac disease in which a malignant T-cell lymphoma develops in areas of the small intestine afflicted by the disease's intense inflammation. While a relatively rare disease, it is the most common type of primary gastrointestinal T-cell lymphoma.aggressive: Sézary disease Enteropathy-associated T-cell lymphoma (EATL), previously termed enteropathy-associated T-cell lymphoma, type I and at one time termed enteropathy-type T-cell lymphoma (ETTL), is a complication of coeliac disease in which a malignant T-cell lymphoma develops in areas of the small intestine afflicted by the disease's intense inflammation. While a relatively rare disease, it is the most common type of primary gastrointestinal T-cell lymphoma. Prior to 2008, EATL was defined as a single type of small intestina lymphoma but in that year the World Health Organization divided the disease into two subtypes: 1) EATL type I which occurs in individuals with coeliac disease, a chronic immune disorder wherein individuals mount inflammatory responses to dietary gluten primarily in the upper reaches (i.e. jejunum and duodenum) of the small intestine and 2) EATL type II, a disorder similar to EATL type I that occurs in individuals who do not have coeliac disease. While type I and II EATL share many similar features, post-2008 studies found some significant differences between the two types of EATL. In consequence, the World Health Organization of 2016 redefined the two diseases as separate entities, keeping the term enteropathy-associted T cell lymphoma for the coeliac disease-associated lymphoma and terming the lymphoma not associated with coeliac disease monomorphic epitheliotropic intestinal T cell lymphoma (MEITL). EATL is 5- to 10-times more common than MEITL. The Organization (2016) also defined a third type of intestinal T cell lymphoma that could not be classified as EATL or MEITL as peripheral T-cell lymphoma not otherwise specified (ITCL-NOS). EATL arises from the malignant transformation of small intestinal intraepithelial lymphocytes (IEL). IEL are a heterogeneous group of principally T cell lymphocytes, that reside in epithelial tissues which interface the environment such as the mucosa of the bronchi, reproductive tract, and gastrointestinal tract (GI tract). At these sites, IEL are exposed and regulate immune responses to non-dietary and dietary antigens, pathogenic and non-pathogenic organisms, and injured self tissues. Gastrointestinal tract IEL are in the epithelium of the small intestine, colon, stomach, and esophagus, residing between the epithelial cells which line these organs' lumens. These IEL often exhibit natural killer and cytotoxic T cell cell activation markers, contain various toxic agents (e.g. perforin, granzyme), and therefore are capable, if activated, of causing severe tissue injuries. In celiac disease, the IEL react to the glutelins in dietary gluten by: increasing their numbers; becoming pathologically active; producing chronic inflammation that injures intestinal cells; interfering with nutrient absorption; and creating an environment conducive to their malignant transformation into EATL. Optimal treatment of EATL has used regimens consisting of intensive chemotherapy, hematopoietic stem cell transplantation, and, in cases where there is bulky, obstructive, and/or perforated bowel disease, surgical intervention. The lymphoma has had a 5 year overall survival rate of only ~20%. However, recent studies focusing on the malignant IEL in EATL have increased our understanding of the disease and suggested newer chemotherapy-based strategies and novel molecular targets that might be attacked therapeutically to improve the disease's prognosis. The cause of EATL, while not fully understood, is by definition related to celiac disease. Individuals are genetically predisposed to develop celiac disease because of the specific types of HLA-DQ proteins expressed by their antigen-presenting cells (APC). HLA-DQ proteins are on the surface of APC and function to present foreign or self antigens to the T cell receptors (TCR) expressed on the surface of T-cells and thereby to stimulate these cells either to initiate or suppress immune responses to the presented antigens. HLA-DQ proteins are composed of α and β polypeptide chains encoded by the HLA-DQA1 and HLA-DQB1 genes, respectively. Since there are several different alleles (i.e. gene variants) at these two genetic loci, individuals are usually heterozygous, i.e. have inherited different alleles from each parent at each locus; uncommonly, however, individuals are homozygous at one or both loci because their parents have the same alleles at one or both loci. The HLA-DQ proteins that predispose individuals to coeliac disease bind and respond specifically to gluten-related antigens presented to them by APC. The genetic predisposition to develop coeliac disease is clinically determined by identifying the serotypes of an individual's APC's HLA-DQ proteins using serotype-specific antibody preparations and/or by identifying the alleles at an individual's HLA-DQA1 and HLA-DQB1 genetic loci. Studies show that: IEL are a diverse population of lymphocytes, which unlike most peripheral lymphocytes, do not recirculate through the blood and/or lymphatic system but rather reside permanently in the epithelium of various organs. In the GI tract, IEL localize between the epithelial cells lining the colon, small intestine, stomach, and esophagus where they serve to maintain the mucosal barrier, combat infection by pathogens, and regulate immune responses to antigens originating from the diet, pathogens, and damaged tissues. Human IEL are classified into those which express the TCR (i.e TCL+IEL) and those which do not (i.e. TCR-IEL). TCL+IEL are further divided into 4 subtypes, TCRαβ+CD4+ IEL, TCRαβ+CD4+CD8αα+ IEL, TCRαβ+CD8αβ+ IEL, and TCRλδ+CD8αα+. These subtypes are based on the expression of alpha (α) and beta (β) chain-containing TCR (i.e. αβTCR); gamma (γ) and delta (δ) chain-containing TCR (i.e. γδTCR); CD4; CD8αβ; and/or CD8αα by individual IEL.. A fifth TCL+IEL subtype, TCRαβ+CD8αα+, occurs in mice but its presence in the human intestine is disputed. Human TCR-IEL are also divided into 4 sub-types: their: ILC1-like IEL have morphological and functional similarities to normal intestinal epithelial cells and express NKp46; ICL3-like IEL have morphological similarities to normal epithelial cells and, similar to Th1 cells, make Interleukin 17 (IL-17) and Interleukin 22 (IL-22) cytokines and express the RORγt transcription factor and NKp44; iCD3-IEL express iCD3; and iCD8α-IEL express iCD3 and CD8α. CD3 designates a protein complex that is attached to the cell surface membrane whereas iCD3 refers to a CD3 protein complex in which one or more of its proteins resides abnormally in the cell's cytosol Studies suggest that iCD3+IEL are the principal cell type that becomes malignant in EATL cases that are not classified as de novo (see next section). These cells also express CD103 and, frequently, CD30. Coeliac disease patients may be asymptomatic, minimally symptomatic, and/or well-controlled on a gluten-free diet (i.e. a diet free of cereal, rye, wheat, and barley) but nonetheless develop EATL. About ~46% of all AETL cases occur in this setting and have had their malignancy described as de novo EATL. The remaining ~54% of EATL cases develop in coeliac disease patients whose disease becomes refractory to dietary control, exhibits increasing symptoms, and progress over ~4–10 years through Type I refractor coeliac disease (Type 1 RCD) and Type II refractory coeliac disease (Type II RCD) to become EATL. The rates at which non-refractory celiac disease, Type I RCD, and Type II RCD progress to de novo or EATL are <1%, 3-14%, and 33-52%, respectively. De novo EATL can occur in individuals whose coeliac disease was undiagnosed until EATL was found or who have mild/well-controlled coeliac disease. The findings in these patients usually differ little form those found in mild/well-controlled cases that do not progress to EATL; their small intestinal mucosa is populated by increased number of IEL and exhibits tissue destruction (e.g. small intestinal villus atrophy), Nonetheless, their IEL are normal-appearing, small cells that on examination are polyclonal (i.e. genetically diverse), express CD3 and CD8, and do not have genetic abnormalities. The mechanism behind the development of EATL in these individuals is not understood. Type I RCD patients, who constitute 15-23% of all patients with RCD, are refractory to the gluten diet as evidenced by their worsening symptoms, increased tissue destruction, and rising numbers of TCRαβ+CD*αβ+IEL in tissue lesions. Some Type I RCD patients may have failed to respond to the diet from the onset of their disease. If either cases, these patients show no change in the normal appearance and polyclonal nature of their small intestinal IEL and these IEL show no genetic abnormalities. The cause for these coeliac disease patients progressing to Type I RCD, after excluding the very common problem of failure to fully exclude gluten from their diets, is either due to their genetic makeup (see above section on genetics) or is unknown.