(also termed chronic ulcerative jejunitis, multifocal ulcerated microlymphomas, ulcerative jejunoilitis, and chronic ulcerative jejunoilitis) is regarded as a rare complications or severe form of type ii rcd in which the jejunum or jejunum plus ileum portions of the small intestine contain multifocal ulcers. patients with this disorder have a higher risk of developing eatl than other type ii rcd patients. eatl besides the genetic gene abnormalities found in type ii rcd, the malignant iel in eatl consist of one or more subpopulations that have mutations: in other jak-stat pathway genes viz., stat5b, jak3, and socs1 (socs1 inhibits stat signaling); tumor suppressor genes bcl11b and setd2 (setd2 is also involved in regulating lymphocyte development); another gene involved in lymphocyte development, prdm1; a gene promoting activation of the tumor suppressor p53, irf1; dna repair genes brip1 and tert (tert is also involved in maintaining dna telomeres and thereby chromosome stability); the nras and kras oncogenes; a gene involved in progression of the cell cycle and thereby cellular proliferation, stk10; a gene involved in promoting cell death by apoptosis, dapk3; a gene involved in regulating interferon gamma actions, inhibiting toll-like receptor signaling, and regulating activation of innate and adaptive immune systems, irf4; a gene involved in cell signaling through various cell receptors, gnas; a gene involved in production of the immunoglobulin, iga, bbx; and two chromatin remodeling genes, tet2 and ylpm1. these cells also overexpress or under express various genes that impact cell survival, growth, and malignancy. it is likely that one or more of these genetic and gene expression abnormalities contribute to the malignant behavior of eatl. diagnosis the diagnosis of eatl is based on endoscopic findings of: 1) flattened duodenal folds and small intestinal fissures and ulcers; 2) biopsy findings of small intestinal inflammation, increased iel, villous atrophy, and crypt hyperplasia; 3) hla-dg serology typing and/or gene allele analyses showing results compatible with coeliac disease (see above section on genetics); and 4) positive serology tests for iga antitissue translutamase antibodies, iga antibodies to deamidated gliadin peptides, igg antibodies to deamidated gliadin peptides, and/or iga antibodies to antitissue translutamase. about 35% of eatl cases will be found to have spread of the disease to extra-intestinal sites with lesions in the mesenteric lymph nodes (~35% of cases), bone marrow (<10% of cases), and, uncommonly, blood that contain iel with the same genetic abnormalities and cell markers as those found in the iel of their intestinal lesions. intestinal biopsy specimens of eatl lesions also commonly show the presence of mucosal inflammatory cells (particularly eosinophils and histiocytes); a greatly expanded population of medium- to large-sized or anaplastic iel expressing icd3 as well as cytotoxic and cell activation markers (e.g. granzyme b and usually tia1 and perforin); and, frequently cd30. in most cases these iel also show genetic abnormalities, particularly activating mutations in jak1 and/or stat3 and to lesser extents those cited in the above section on eatl. the malignant iel in eatl do not express cd56. rarely, patients present with eatl who have no gastrointestinal symptoms of celiac disease but rather with extra-intestinal manifestations that are associated with the disease such as dermatitis herpetiformis, psoriasis, other chronic skin conditions, dental enamel defects, gluten-induced cerebellar ataxia, arthritis, and arthralgias. differential diagnosis other gastrointestinal t-cell lymphomas can resemble, and therefore need to be differentiated from, eatl. these include: monomorphic epitheliotropic intestinal t cell lymphoma is distinguished from eatl in that it is not associated with coeliac disease; is more common in asians than northern europeans; and their small intestine lesions show little or no inflammatory cells plus numerous small- to medium-sized, normal appearing iel that express cd56 but may not express cd30. the genetic abnormalities found in monomorphic epitheliotropic intestinal t cell lymphoma are similar to those in eatl. small intestinal adenocarcinoma, while rare, is far more frequent in coeliac disease than in the general population. unlike eatl, it often occurs in celiac disease patients who, while otherwise well-maintained on a gluten-free diet, have vague gastrointestinal symptoms such as fatigue, malaise, and weight loss. however, it can cause severe symptoms such as bowel obstruction and intestinal bleeding. also unlike eatl, the adenocarcinoma often occurs in women and younger (<50 years old) individuals; is more likely to begin as a non-maligant adenoma; and has the histology typical of an adenocarcinoma. peripheral t-cell lymphoma not otherwise specified (ptcl-nos) and anaplastic large cell lymphoma (alcl) are heterogeneous sets of aggressive t cell lymphomas that exhibit variable morphologies. unlike eatl, they are not associated with coeliac disease and rarely present as an intestinal lymphoma without involvement of extra-intestinal tissues. ptcl-nos's genetic abnormalities differ from those in eatl: its malignant cells have recurrent mutations in tet2, idh2, dnmt3a, rhoa, vav1, and/or cd28 genes, rearrangements of the itk gene with the syk, fer, and erbb4 genes, and/or rearrangements of the tp63 gene. alcl likewise exhibits different mutations than those occurring in eatl; its malignant cells, similar to those in ptcl-nos, have recurrent mutations in vav1, rearrangements of the itk gene with the syk, fer, and erbb genes, and/or rearrangements of the tp63 gene. however, alcl also has distinctive genetic abnormalities: malignant cells in the alk+ form of alcl have a translocation between the npm1 and alk genes to form a gene encoding the chimeric protein, npm-alk while the malignant cells in the alk- form of alcl have translocations of either the dusp22 or tp63 genes. epstein–barr virus–associated lymphoproliferative diseases are a large group of benign, pre-malignant and malignant lymphoproliferative diseases that are associated with the infection of lymphocytes by the epstein–barr virus. one of these diseases, extranodal nk/t cell lymphoma, nasal type may develop primarily in the small intestine but unlike eatl often involves lesions in the nasal cavity, pharynx, lung, skin, or other tissues. furthermore, the malignant t cells in this disease express readily detectable products encoded by the epstein–barr virus's genes whereas those of eatl are not infected with this virus and therefore do not express these viral products. indolent t cell lymphoproliferative disorder of the gastrointestinal tract (itcld-gt)) is a rare, slowly progressive, and potentially premalignant disorder of the gi tract that may be mistaken of eatl, particularly with respect to the severity of its symptoms, the gross pathology of its intestinal lesions, and the presence in its intestinal lesions of t cells that have monoclonal rearrangements of their tcr as well as genetic abnormalities in the jak/stat signaling pathway. unlike eatl, itcld-gt is not associated with coeliac disease; often involves symptomatic lesions of the upper gi tract (i.e. stomach, esophagus, and pharynx); and has gi tract lesions populated by t cells that express cd3 (rather than icd3), do not express cd56, and, in many cases, express an abnormal stat3-jak2 fusion gene. prevention strict adherence to a gluten-free diet has been shown in some but not all studies to prevent in a significant number of cases the progression of coeliac disease to type i rcd, type ii rcd, and eatl. for example, an italian study of 1757 patients found that the morbidity of eatl over 3 years fell from 6.42 to 0.22 in coeliac disease patients kept on a strict gluten-free diet. while two other studies found that the risk of malignancy in the diseases did not fall on this diet, current opinion strongly favors using it in all stages of coeliac disease. management treatment of refractory celiac disease efforts have also been made to treat refractory coeliac disease in order to prevent eatl. treatment with corticosteroids, particularly budesonide gives temporary improvement in symptoms and histological responses in 30-40% of patients but few have attained a good overall response. the addition of azathioprine, cyclosporin, or a monoclonal antibody directed against tumor necrosis factor-α to the corticosteroid regimen, the use, as single agents, of purine analogs (i.e. pentostatin, cladribine) or monoclonal antibody directed against cd52 as well as the use of intensive chemotherapy regimens have shown little therapeutic effects. furthermore, azathioprine, anti-cd52 antibody, and cladribine have been reported to increase the disease's progression to eatl. in summary, the role these drugs, intensive chemotherapy regimens, and hematopoietic stem cell transplantation in the treatment of refractory coeliac disease is unclear and has not been shown to improve, and in some cases may worsen, the chances that type i and type ii rcd, will progress to eatl. patients with refractory coeliac disease, especially those with type ii rcd, should be examined at regular intervals for the development of eatl using magnetic resonance imaging, capsule endoscopy, ct scan, and positron emission tomography;. these examinations should also be used whenever patients with refractory disease experience worsening symptoms. treatment of eatl in eligible patients, surgery where necessary (required in >80% of patients) to repair obstructed or perforated bowel or remove bulky disease followed by a conditioning regimen of high-dose chemotherapy (usually the chop regimen) and autologous stem cell transplantion has been the mainstay of treating eatl. previous chemotherapy treatment regimens that did not use autologous stem cell transplantation reported poor prognoses with overal survival, progression free, and mortality rates over a 5-year period of 22%, 3%, and 81%. respectively whereas a regimen that included intensive chemotherapy, conditioning, and autologous stem cell transplantation had rates of 60%, 52%, and 39%, respectively. research clinical trials a phase 2 study sponsored by the imagine institute and being conducted in paris, france is recruiting patients to examine the efficacy and side effects of a new treatment regimen on eatl. the regimen consists of treatment with brentuximab vedotin plus chp (i.e. cyclophosphamide, adriamycin, prednisone) followed by consolidation chemotherapy and autologous hematopoietic stem cell transplantation. brentuximab vedotin is a chimeric monoclonal antibody that is complexed to the antimitotic agent, monomethyl auristatin e; the drug binds to the cell-membrane protein cd30 to deliver thereby the antimitotic aged into cd30-bearing target cells. this study is based on a phase 1 study finding that a regimen consisting of brentuximab vedotin plus chp achieved objective responses in all 26 patients tested, with complete remissions obtained in the only patient with eatl, all 6 patients with alcl, and 16 of 19 patients with other types of t-cell/nk-cell lymphomas. a phase 1 study sponsored by the national institutes of health clinical center is recruiting patients that have cd30-expressing lymphomas such as eatl to examine the effects of a conditioning drug regimen (i.e. cyclophosphamide and fludarabine) followed by infusions of the patients' chimeric antigen receptor t cells that have been modified to target and destroy cells bearing cd30. a phase 1 study sponsored by the nih and mayo clinic usa is recruiting patients with peripheral t-cell lymphomas, including eatl, to study the efficacy and toxicity of nivolumab. nivolumab is monoclonal antibody checkpoint inhibitor that binds to the programmed cell death protein 1 (pd-1) thereby blocking this protein from being activated by programmed death-ligand 1 (pd-l1). many types of cancer cells increase their expression of pd-li in order to inhibit immune cells that express pd-1 from killing them. nivolumab blocks this inhibition and has been found effective in suppressing the growth of certain cancers. clinical trials a recently completed phase 2, randomized, double-blinded, placebo-controlled, parallel group study evaluated the efficacy and safety of a monoclonal antibody (termed amg 714) directed against il-15 in adult patients with type ii rcd. the study found potential therapeutic effects of the treatment in that it halted the malignant progression of iel in these patients. expanded access or compassionate use requests for amg 714 may be considered for adult patients with biopsy-proven type ii rcd who have failed all available treatment options and do not have eatl. to request access, use responsible party contact information found by hitting the "more info..." linkage on the following clinical trials page.