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| | {{Short description|A rare type of T-cell lymphoma associated with celiac disease}} |
| {{short description|Complication of coeliac disease}} | | {{short description|Complication of coeliac disease}} |
| {{Infobox medical condition (new) | | {{Infobox medical condition (new) |
| | name = Enteropathy-associated T-cell lymphoma (formerly termed enteropathy-associtated T-cell lymphoma, type 1) | | | name = Enteropathy-associated T-cell lymphoma (formerly termed enteropathy-associated T-cell lymphoma, type 1) |
| | synonyms = Enteropathy-associated T-cell lymphoma, type I | | | synonyms = Enteropathy-associated T-cell lymphoma, type I |
| | image = Enteropathy-associated T cell lymphoma - low mag.jpg | | | image = Enteropathy-associated T cell lymphoma - low mag.jpg |
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| | pronounce = | | | pronounce = |
| | width = 150 | | | width = 150 |
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| | | symptoms = Weight loss, diarrhea, abdominal pain, nausea, vomiting, fatigue, fever, malabsorption, and gastrointestinal bleeding |
| | symptoms = | |
| | field = [[Oncology]], [[hematology]], [[gastroenterology]] | | | field = [[Oncology]], [[hematology]], [[gastroenterology]] |
| | complications = [[Bowel obstruction]]s, [[bowel perforation]]s | | | complications = [[Bowel obstruction]]s, [[bowel perforation]]s, [[intestinal perforation]], secondary infections due to immunosuppression |
| | onset = | | | onset = Typically occurs after long-term, untreated [[Celiac disease]] |
| | duration = | | | duration = Variable, can range from months to years depending on early detection and treatment |
| | types = | | | types = Primarily classified into two subtypes: Type I (typical) and Type II (atypical) |
| | causes = Complication of [[Celiac disease]] | | | causes = Complication of [[Celiac disease]] |
| | risks = [[Genetic predisposition]] | | | risks = Genetic predisposition, long-standing untreated celiac disease, [[immunosuppression]], chronic intestinal inflammation |
| | diagnosis = | | | diagnosis = Diagnosis is confirmed by histological examination of biopsy specimens, usually from the small intestine. [[Immunohistochemistry]] is used to identify the characteristic T-cell markers. |
| | differential = | | | differential = Chronic [[inflammatory bowel disease]], [[Crohn's disease]], [[intestinal lymphoma]], [[malabsorption syndromes]] |
| | prevention = [[Gluten-free diet]] | | | prevention = [[Gluten-free diet]], early detection and management of celiac disease, continuous monitoring of individuals with celiac disease for signs of lymphoma |
| | treatment = | | | treatment = Chemotherapy, immunotherapy, radiation therapy, bone marrow transplantation in advanced cases, and a strict gluten-free diet to prevent disease progression |
| | medication = | | | medication = [[Chemotherapy]] agents such as CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), [[targeted therapy]] (e.g., alemtuzumab), and other immunosuppressive treatments may be used. |
| | prognosis = guarded | | | prognosis = Guarded, with poor outcomes in advanced stages, but can improve with early detection and treatment. The prognosis is significantly improved with a strict gluten-free diet. |
| | frequency = | | | frequency = Rare, approximately 1-2 cases per 1 million people annually |
| | deaths = | | | deaths = High mortality rate in advanced stages due to complications such as infection, bowel perforation, or progression to other types of 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]].<ref name="pmid25925928">{{cite journal | vauthors = Nijeboer P, Malamut G, Mulder CJ, Cerf-Bensussan N, Sibon D, Bouma G, Cellier C, Hermine O, Visser O | title = Enteropathy-associated T-cell lymphoma: improving treatment strategies | journal = Digestive Diseases | volume = 33 | issue = 2 | pages = 231–5 | date = 2015 | pmid = 25925928 | doi = 10.1159/000369542 | url = }}</ref> While a relatively rare disease, it is the most common type of primary gastrointestinal T-cell lymphoma.<ref>{{cite journal |author=Isaacson PG |title=Gastrointestinal lymphoma |journal=Hum. Pathol. |volume=25 |issue=10 |pages=1020–9 |date=October 1994 |pmid=7927306 |doi=10.1016/0046-8177(94)90060-4}}</ref> | | '''Enteropathy-associated T-cell lymphoma''' (EATL) is a rare type of [[non-Hodgkin lymphoma]] that originates from [[T-cells]] and is associated with [[celiac disease]]. It primarily affects the [[small intestine]] and is characterized by the proliferation of malignant T-cells in the intestinal lining. |
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| 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).<ref name="pmid29943210">{{cite journal | vauthors = Chander U, Leeman-Neill RJ, Bhagat G | title = Pathogenesis of Enteropathy-Associated T Cell Lymphoma | journal = Current Hematologic Malignancy Reports | volume = 13 | issue = 4 | pages = 308–317 | date = August 2018 | pmid = 29943210 | doi = 10.1007/s11899-018-0459-5 | url = }}</ref> EATL is 5- to 10-times more common than MEITL.<ref name="pmid27900603">{{cite journal | vauthors = Ondrejka S, Jagadeesh D | title = Enteropathy-Associated T-Cell Lymphoma | journal = Current Hematologic Malignancy Reports | volume = 11 | issue = 6 | pages = 504–513 | date = December 2016 | pmid = 27900603 | doi = 10.1007/s11899-016-0357-7 | url = }}</ref> 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).<ref name="pmid29741263">{{cite journal | vauthors = Matutes E | title = The 2017 WHO update on mature T- and natural killer (NK) cell neoplasms | journal = International Journal of Laboratory Hematology | volume = 40 Suppl 1 | issue = | pages = 97–103 | date = May 2018 | pmid = 29741263 | doi = 10.1111/ijlh.12817 | url = | doi-access = free }}</ref>
| | ==Pathophysiology== |
| | EATL is closely linked to [[celiac disease]], an autoimmune disorder triggered by the ingestion of [[gluten]]. In individuals with celiac disease, chronic inflammation of the small intestine can lead to the development of EATL. The persistent immune response against gluten results in damage to the intestinal mucosa, which may eventually lead to the transformation of normal T-cells into malignant ones. |
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| EATL arises from the malignant transformation of small intestinal [[intraepithelial lymphocyte]]s (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).<ref name="pmid28787597">{{cite journal | vauthors = Hoytema van Konijnenburg DP, Mucida D | title = Intraepithelial lymphocytes | journal = Current Biology | volume = 27 | issue = 15 | pages = R737–R739 | date = August 2017 | pmid = 28787597 | doi = 10.1016/j.cub.2017.05.073 | url = | doi-access = free }}</ref> At these sites, IEL are exposed and regulate immune responses to non-dietary and dietary [[antigen]]s, [[pathogen]]ic and non-pathogenic organisms, and injured self tissues.<ref name="pmid29221933">{{cite journal | vauthors = Olivares-Villagómez D, Van Kaer L | title = Intestinal Intraepithelial Lymphocytes: Sentinels of the Mucosal Barrier | journal = Trends in Immunology | volume = 39 | issue = 4 | pages = 264–275 | date = April 2018 | pmid = 29221933 | doi = 10.1016/j.it.2017.11.003 | url = }}</ref> Gastrointestinal tract IEL are in the [[epithelium]] of the small intestine, colon, stomach, and esophagus, residing between the epithelial cells which line these organs' [[Lumen (anatomy)|lumens]].<ref name="pmid29221933"/> These IEL often exhibit [[NK cell|natural killer]] and [[cytotoxic T cell]] cell activation markers,<ref name="pmid28787597"/> contain various toxic agents (e.g. [[perforin]], [[granzyme]]), and therefore are capable, if activated, of causing severe tissue injuries.<ref name="pmid27900603"/> In celiac disease, the IEL react to the [[glutelin]]s 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.<ref name="pmid25925928"/>
| | There are two types of EATL: |
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| 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.<ref name="pmid29943210"/> The lymphoma has had a 5-year overall survival rate of only ~20%.<ref name="pmid25639480">{{cite journal | vauthors = Foukas PG, de Leval L | title = Recent advances in intestinal lymphomas | journal = Histopathology | volume = 66 | issue = 1 | pages = 112–36 | date = January 2015 | pmid = 25639480 | doi = 10.1111/his.12596 | url = }}</ref> 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.<ref name="pmid29221933"/>
| | * '''Type I EATL''': This is the classic form associated with celiac disease. It is more common in individuals of Northern European descent and is characterized by the presence of large, pleomorphic T-cells. |
| | * '''Type II EATL''': Also known as monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL), this form is not associated with celiac disease and can occur in individuals without gluten sensitivity. It is characterized by monomorphic, small to medium-sized T-cells. |
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| ==Presentation== | | ==Clinical Presentation== |
| EATL typically occurs in individuals aged 60–70 who, like coeliac disease patients, are descendants of Northern Europeans.<ref name="pmid29943210"/> Patients with a history of coeliac disease who develop EATL may have been previously diagnoses with Type I or II RFD<ref name="pmid26060109"/> but in any case present with worsening of their disease symptoms of abdominal pain, [[malabsorption]], diarrhea, weight loss, fever, and/or [[night sweats]].<ref name="pmid28078381"/> The diagnosis of EATL is more likely if the latter symptoms develop suddenly.<ref name="pmid27900603"/> or if the serious symptoms of [[bowel obstruction]] and/or [[Gastrointestinal perforation|bowel perforation]] caused by bulky EATL masses develop.<ref name="pmid28078381"/> Individuals with ulcerative jejunitis usually present with more severe symptoms, including more frequent bowel perforations and obstructions.<ref name="pmid28078381"/> Some patients with no history of coeliac disease present with symptoms and/or signs of a small intestinal lymphoma but on diagnostic workup are found to have coeliac disease.
| | Patients with EATL often present with non-specific symptoms, which can include: |
| == Pathophysiology ==
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| === Genetics ===
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| The cause of EATL, while not fully understood, is by definition related to celiac disease. Individuals are [[genetic predisposition|genetically predisposed]] to develop celiac disease because of the specific types of [[HLA-DQ]] proteins expressed by their [[antigen-presenting cell]]s (APC). HLA-DQ proteins are on the surface of APC and function to present foreign or self [[antigen]]s to the [[T cell receptor]]s (TCR) expressed on the surface of T-cells and thereby to stimulate these cells either to initiate or suppress [[immune response]]s to the presented antigens. HLA-DQ proteins are composed of α and β [[Peptide#length|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 [[Locus (genetics)|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.<ref name="pmid29674648">{{cite journal | vauthors = Mayassi T, Jabri B | title = Human intraepithelial lymphocytes | journal = Mucosal Immunology | volume = 11 | issue = 5 | pages = 1281–1289 | date = September 2018 | pmid = 29674648 | pmc = 6178824 | doi = 10.1038/s41385-018-0016-5 | url = }}</ref> The genetic predisposition to develop coeliac disease is clinically determined by identifying the [[serotype]]s 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:
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| *Celiac disease affects ~1% of the population in most parts of the world.<ref name="pmid29943210"/> | | * Abdominal pain |
| *Ninety to one hundred percent of patients with coeliac disease have inherited genes at the HLA-DQ locus that encode [[HLA-DQ2]] and/or [[HLA-DQ8]] [[serotype]] proteins.<ref name="pmid28084899">{{cite journal | vauthors = Paul SP, Hoghton M, Sandhu B | title = Limited role of HLA DQ2/8 genotyping in diagnosing coeliac disease | journal = Scottish Medical Journal | volume = 62 | issue = 1 | pages = 25–27 | date = February 2017 | pmid = 28084899 | doi = 10.1177/0036933016689008 | url = }}</ref>
| | * Weight loss |
| *About 2-3% of individuals who inherit these HLA-DQ2 and/or HLA-DQ8 serotypes develop coeliac disease.<ref name="pmid28078381">{{cite journal | vauthors = Al-Bawardy B, Codipilly DC, Rubio-Tapia A, Bruining DH, Hansel SL, Murray JA | title = Celiac disease: a clinical review | journal = Abdominal Radiology (New York) | volume = 42 | issue = 2 | pages = 351–360 | date = February 2017 | pmid = 28078381 | doi = 10.1007/s00261-016-1034-y | url = }}</ref>
| | * Diarrhea |
| *About 90% of coeliac disease patients are [[Zygosity#homozygous|homozygous]] for (i.e. inherited from both parents) either the [[HLA-DQ2#DQ2.5|''HLADQA1*0501'']]<ref>https://www.ebi.ac.uk/cgi-bin/ipd/imgt/hla/get_allele.cgi?DQB1*0501</ref> or [[HLA-DQ2#Other|''HLADQA1*0505'']] alleles at the [[HLA-DQA1]] locus plus either the [[HLA-DQ2#DQB1*0201|''HLADQB1*0201'']]<ref>https://www.ebi.ac.uk/cgi-bin/ipd/imgt/hla/get_allele.cgi?DQB1*0201</ref> or [[HLA-DQB1#Celiac disease|HLA-DQB1*0202]] alleles at the HLA-DQB1 locus; <5% of coeliac disease patients are [[Zygosity#Heterozygos|heterozygous]] (i.e. inherited from just one parent) for these alleles; and 5-10% of coeliac disease patients have inherited [[HLA-DQA1#other|HLA-DQA1*03]] plus [[HLA-DQB1#Celiac disease|HLA-DQB1*0302]] alleles at the respective HLA-DQA1 and DAQB1 loci.<ref name="pmid26060109">{{cite journal | vauthors = Malamut G, Cellier C | title = Complications of coeliac disease | journal = Best Practice & Research. Clinical Gastroenterology | volume = 29 | issue = 3 | pages = 451–8 | date = June 2015 | pmid = 26060109 | doi = 10.1016/j.bpg.2015.05.005 | url = }}</ref> | | * Intestinal obstruction |
| *Less than 1% of all individuals with coeliac disease develop EATL.<ref name="pmid26060109"/> | | * Perforation of the intestine |
| *Individuals homozyqous for the ''HLADQB1*0201'' allele at the [[HLA-DQB1]] locus develop a particularly severe and tissue-damaging form of coeliac disease<ref name="pmid17190762">{{cite journal |vauthors=Jores RD, Frau F, Cucca F, etal | title = HLA-DQB1*0201 homozygosis predisposes to severe intestinal damage in celiac disease | journal = Scand. J. Gastroenterol. | volume = 42 | issue = 1 | pages = 48–53 | year = 2007 | pmid = 17190762 | doi = 10.1080/00365520600789859}}</ref> and have a greatly increased rate of developing EATL.<ref name="pmid29943210"/> | |
| *The vast majority of patients with coeliac disease who develop EATL have either the ''HLADQA1*0501'' or ''HLADQB1*0201'' allele (see previous paragraphs) at the [[HLA-DQB1]] locus.<ref name="pmid29943210"/> | |
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| === Intraepithelial lymphocytes ===
| | Due to its association with celiac disease, patients may also exhibit symptoms related to gluten sensitivity, such as malabsorption and nutritional deficiencies. |
| IEL are a diverse population of lymphocytes, which unlike most peripheral lymphocytes, do not recirculate through the [[circulatory system|blood]] and/or [[lymphatic system]] but rather reside permanently in the [[epithelium]] of various organs.<ref name="pmid29674648"/> 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, [[pathogen]]s, and damaged tissues.<ref name="pmid28787597"/> 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]]; [[CD8]]αβ; and/or [[CD8]]αα by individual IEL.. A fifth TCL+IEL subtype, TCRαβ+CD8αα+, occurs in mice but its presence in the human intestine is disputed.<ref name="pmid29674648"/> Human TCR-IEL are also divided into 4 sub-types: their: ILC1-like IEL have [[Morphology (biology)|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 [[T helper cell#Proliferation|Th1 cells]], make [[Interleukin 17]] (IL-17) and [[Interleukin 22]] (IL-22) [[cytokines]] and express the [[RAR-related orphan receptor gamma#RORγt|RORγt]] transcription factor and [[NKp44]]; iCD3-IEL express [[CD3 (immunology)|iCD3]]; and iCD8α-IEL express iCD3 and CD8α.<ref name="pmid29221933"/> [[CD3 (immunology)|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]]<ref name="pmid29674648"/> 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).<ref name="pmid29221933"/> These cells also express [[CD103]] and, frequently, [[CD30]].<ref name="pmid27900603"/>
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| === Acquisition of malignancy === | | ==Diagnosis== |
| 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<ref name="pmid27803799">{{cite journal | vauthors = Nasr I, Nasr I, Campling H, Ciclitira PJ | title = Approach to patients with refractory coeliac disease | journal = F1000Research | volume = 5 | issue = | pages = 2544| date = 2016 | pmid = 27803799 | pmc = 5074352 | doi = 10.12688/f1000research.9051.1 | url = }}</ref>) 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.<ref name="pmid29943210"/> 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.<ref name="pmid26060109"/>
| | The diagnosis of EATL involves a combination of clinical evaluation, imaging studies, and histopathological examination. Key diagnostic steps include: |
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| ==== ''De novo'' EATL ====
| | * '''Endoscopy and Biopsy''': Endoscopic examination of the small intestine with biopsy is crucial for identifying the characteristic histological features of EATL. |
| ''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.<ref name="pmid29943210"/> | | * '''Imaging''': [[CT scan]]s and [[MRI]] may be used to assess the extent of the disease and identify complications such as intestinal obstruction or perforation. |
| | * '''Histopathology''': Examination of biopsy samples reveals atypical T-cells infiltrating the intestinal mucosa. Immunohistochemical staining is used to confirm the T-cell origin of the lymphoma. |
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| ==== Type I refractory coeliac disease ==== | | ==Treatment== |
| Type I RCD patients, who constitute 15-23% of all patients with RCD,<ref name="pmid30820708">{{cite journal | vauthors = Cichewicz AB, Mearns ES, Taylor A, Boulanger T, Gerber M, Leffler DA, Drahos J, Sanders DS, Thomas Craig KJ, Lebwohl B | title = Diagnosis and Treatment Patterns in Celiac Disease | journal = Digestive Diseases and Sciences | volume = 64| issue = 8| pages = 2095–2106| date = March 2019 | pmid = 30820708 | doi = 10.1007/s10620-019-05528-3 | url = }}</ref> are refractory to the gluten diet as evidenced by their worsening symptoms, increased tissue destruction,<ref name="pmid28078381"/> and rising numbers of TCRαβ+CD*αβ+IEL in tissue lesions.<ref name="pmid29943210"/> 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.<ref name="pmid28078381"/> 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.<ref name="pmid29943210"/>
| | The treatment of EATL is challenging due to its aggressive nature and the poor overall prognosis. Treatment options may include: |
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| ==== Type II refractory coeliac disease ====
| | * '''Chemotherapy''': Combination chemotherapy regimens are commonly used, although the response rates are variable. |
| Type I RCD patients may progress to Type II RCD as evidenced by their more severe symptoms, increased intestinal tissue destruction, and expanding numbers of intestinal IEL, particularly iCD3+IEL.<ref name="pmid29943210"/> Their IEL typically consist of genetically different subpopulations of cells that have a [[monoclonal]] rearrangement of their TCR and therefore are descendent from a single ancestral cell.<ref name="pmid28078381"/> Subpopulations of these IEL also have one or more of the following genetic abnormalities: [[trisomy]] of chromosome 1's long (or "q") arm at position 22-44 (abbreviated 1-q22-24); genomic alterations around the ''[[TP53]]'' [[tumor suppressor]] gene at position 13.1 on the short or "p" arm of chromosome 17; genomic alterations around the ''[[CDKN2A]]'' tumor suppressor and ''[[CDKN2B]]'' cell proliferation regulator at position p21.3 on chromosome 9 that result in [[loss of heterozygosity]] for both genes; and/or [[Mutations#By effect on function|activating mutations]] in ''[[JAK1]]'' (75% of cases) and ''[[STAT3]]'' (25% of cases). In Type II RCD, the same types of abnormal ILE found in the small intestine may be detected in the colon, stomach,<ref name="pmid26060109"/> [[mesenteric lymph nodes]], blood, bone marrow, and epithelium of the airways and skin.<ref name="pmid26060109"/> Finally, the small intestinal lesions in Type II RCD contain [[Interleukin 2|IL-2]] and [[Interleukin 21|IL-21]]<ref name="pmid28049849">{{cite journal | vauthors = Kooy-Winkelaar YM, Bouwer D, Janssen GM, Thompson A, Brugman MH, Schmitz F, de Ru AH, van Gils T, Bouma G, van Rood JJ, van Veelen PA, Mearin ML, Mulder CJ, Koning F, van Bergen J | title = CD4 T-cell cytokines synergize to induce proliferation of malignant and nonmalignant innate intraepithelial lymphocytes | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 114 | issue = 6 | pages = E980–E989 | date = February 2017 | pmid = 28049849 | pmc = 5307453 | doi = 10.1073/pnas.1620036114 | url = }}</ref> as well as increased levels of [[Interleukin 15|IL-15]].<ref name="pmid29943210"/> Laboratory studies indicate that these 3 [[cytokines]] acting individually or in [[synergy]] are potent stimulators of the [[JAK-STAT signaling pathway|JAK1/STAT3]] signaling pathway in iCD3+IEL and thereby promote these cells survival (by blocking [[apoptosis]]) and proliferation.<ref name="pmid28049849"/><ref name="pmid29380182">{{cite journal | vauthors = Chan JY, Lim ST | title = Novel findings from the Asian Lymphoma Study Group: focus on T and NK-cell lymphomas | journal = International Journal of Hematology | volume = 107 | issue = 4 | pages = 413–419 | date = April 2018 | pmid = 29380182 | doi = 10.1007/s12185-018-2406-6 | url = | doi-access = free }}</ref> The small intestinal lesions also contain [[Tumor necrosis factor superfamily|a tumor necrosis factor]] which stimulates iCD3+IEL survival and proliferation but does so by activating [[NF-κB]], [[MAPK/ERK pathway|MAPK]], and/or [[c-Jun N-terminal kinases]] rather than JAK1/STAT3 signaling pathway.<ref name="pmid28049849"/> These data suggest that: '''a)''' Type II RCD is a low grade lymphoma;<ref name="pmid26060109"/> '''2)''' the intense inflammation in Type II RCD, perhaps amplified by the cited cytokines, promotes the proliferation, survival, [[genome instability]], and consequential genetic abnormalities in IEL; and '''3)''' one or more of these factors cause the transformation of Type II RD to EATL.<ref name="pmid29943210"/><ref name="pmid26060109"/><ref name="pmid29380182"/> As currently understood, the release of IL-15 by mucosal epithelial cells, the binding of IL-15 to the [[Interleukin-15 receptor|IL-15Rβ]] [[cell surface receptor]] on iCD3+IEL, and the stimulation thereby of these cells appears particularly important in driving Type II RCD to EATL in a significant number of cases.<ref name="pmid29943210"/>
| | * '''Surgery''': Surgical intervention may be necessary to manage complications such as intestinal obstruction or perforation. |
| | * '''Stem Cell Transplantation''': In some cases, high-dose chemotherapy followed by autologous stem cell transplantation may be considered. |
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| ===== Ulcerative jejunitis ===== | | ==Prognosis== |
| Ulcerative jejunitis<ref name="pmid27803799"/> (also termed chronic ulcerative jenunitis, multifocal ulcerated microlymphomas,<ref name="pmid25639480"/> ulcerative jejunoilitis,<ref name="pmid28078381"/> and chronic ulcerative jejunoilitis<ref name="pmid29943210"/>) 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.<ref name="pmid28078381"/><ref name="pmid27803799"/>
| | The prognosis for patients with EATL is generally poor, with a median survival of less than two years. Factors influencing prognosis include the stage of the disease at diagnosis, the patient's overall health, and the response to treatment. |
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| ==== EATL ==== | | ==Related Pages== |
| 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 [[telomere]]s and thereby [[chromosome]] [[Telomere#Structure, function and evolutionary biology|stability]]); the ''[[Neuroblastoma RAS viral oncogene homolog|NRAS]]'' and ''[[KRAS]]'' [[oncogenes]]; a gene involved in [[cell cycle#DNA replication and DNA replication origin activity|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 immune system|innate]] and [[Adaptive immune system|adaptive]] immune systems, ''[[IRF4]]''; a gene involved in cell signaling through various cell receptors, ''[[GNAS complex locus|GNAS]]''; a gene involved in production of the immunoglobulin, [[IgA]], ''[[BBX (gene)|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.<ref name="pmid29943210"/><ref name="pmid28424246">{{cite journal | vauthors = Moffitt AB, Ondrejka SL, McKinney M, Rempel RE, Goodlad JR, Teh CH, Leppa S, Mannisto S, Kovanen PE, Tse E, Au-Yeung RK, Kwong YL, Srivastava G, Iqbal J, Yu J, Naresh K, Villa D, Gascoyne RD, Said J, Czader MB, Chadburn A, Richards KL, Rajagopalan D, Davis NS, Smith EC, Palus BC, Tzeng TJ, Healy JA, Lugar PL, Datta J, Love C, Levy S, Dunson DB, Zhuang Y, Hsi ED, Dave SS | title = Enteropathy-associated T cell lymphoma subtypes are characterized by loss of function of SETD2 | journal = The Journal of Experimental Medicine | volume = 214 | issue = 5 | pages = 1371–1386 | date = May 2017 | pmid = 28424246 | pmc = 5413324 | doi = 10.1084/jem.20160894 | url = }}</ref>
| | * [[Celiac disease]] |
| | | * [[Non-Hodgkin lymphoma]] |
| == Diagnosis ==
| | * [[T-cell]] |
| | | * [[Small intestine]] |
| The diagnosis of AETL is based on [[Endoscopy|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 [[Intestinal gland|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 [[Anti-transglutaminase antibodies#Anti-tissue transglutaminase|IgA antitissue translutamase antibodies]], [[Anti-gliadin antibodies#Anti-gliadin IgA|IgA antiboides to deamidated gliadin peptides]], [[Anti-gliadin antibodies#Anti-gliadin IgG|IgG antiboides to deamidated gliadin peptides]], and/or [[Anti-transglutaminase antibodies#Anti-endomysial reactivity|IgA antibodies to antitissue translutamase]].<ref name="pmid28078381"/> About 35% of EATL cases will be found to have spread of the disease to extra-intestinal sites<ref name="pmid29943210"/> 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.<ref name="pmid27900603"/> Intestinal biopsy specimens of EATL lesions also commonly show the presence of mucosal inflammatory cells (particularly [[eosinophil]]s and [[histiocytes]]); a greatly expanded population of medium- to large-sized or [[Anaplasia|anaplastic]] IEL expressing iCD3 as well as cytotoxic and cell activation markers (e.g. [[granzyme B]] and usually [[TIA1]] and [[perforin]]); and, frequently [[CD30]].<ref name="pmid25639480"/> 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]].<ref name="pmid29943210"/><ref name="pmid28424246"/> 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]],<ref name="pmid29943210"/> [[psoriasis]], other chronic skin conditions, [[dental enamel]] defects, [[Ataxia#Gluten ataxia|gluten-induced cerebellar ataxia]], [[arthritis]], and [[arthralgia]]s.<ref name="pmid28078381"/>
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| === Differential diagnosis ===
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| Other gastrointestinal T-cell lymphomas can resemble, and therefore need to be [[Differential diagnosis|differentiated]] from, EATL. These include:
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| *[[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.<ref name="pmid25639480"/> The genetic abnormalities found in Monomorphic epitheliotropic intestinal T cell lymphoma are similar to those in EATL.<ref name="pmid28424246"/> | |
| *[[Adenocarcinoma|Small intestinal adenocarcinoma]], while rare, is far more frequent in coeliac disease than in the general population.<ref name="pmid28078381"/><ref name="pmid21060711">{{cite journal | vauthors = Richir M, Songun I, Wientjes C, Snel P, Dwars B | title = Small Bowel Adenocarcinoma in a Patient with Coeliac Disease: Case Report and Review of the Literature | journal = Case Reports in Gastroenterology | volume = 4 | issue = 3 | pages = 416–420 | date = October 2010 | pmid = 21060711 | pmc = 2975010 | doi = 10.1159/000313547 | url = }}</ref> 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.<ref name="pmid21060711"/> However, it can cause severe symptoms such as bowel obstruction<ref name="pmid30917787">{{cite journal | vauthors = Caio G, Volta U, Ursini F, Manfredini R, De Giorgio R | title = Small bowel adenocarcinoma as a complication of celiac disease: clinical and diagnostic features | journal = BMC Gastroenterology | volume = 19 | issue = 1 | pages = 45 | date = March 2019 | pmid = 30917787 | doi = 10.1186/s12876-019-0964-6 | url = | pmc = 6437995 }}</ref> and intestinal bleeding.<ref name="pmid29253057">{{cite journal | vauthors = Zullo A, De Francesco V, Manta R, Ridola L, Lorenzetti R | title = A Challenging Diagnosis of Jejunal Adenocarcinoma in a Celiac Patient: Case Report and Systematic Review of the Literature | journal = Journal of Gastrointestinal and Liver Diseases | volume = 26 | issue = 4 | pages = 411–415 | date = December 2017 | pmid = 29253057 | doi = 10.15403/jgld.2014.1121.264.zet | url = }}</ref> Also unlike EATL, the adenocarcinoma often occurs in women and younger (<50 years old) individuals;<ref name="pmid30917787"/> is more likely to begin as a non-maligant [[adenoma]];<ref name="pmid17960014">{{cite journal | vauthors = Green PH, Cellier C | title = Celiac disease | journal = The New England Journal of Medicine | volume = 357 | issue = 17 | pages = 1731–43 | date = October 2007 | pmid = 17960014 | doi = 10.1056/NEJMra071600 | url = }}</ref> and has the [[histology]] typical of an adenocarcinoma.<ref name="pmid23243535">{{cite journal | vauthors = Benhammane H, El M'rabet FZ, Idrissi Serhouchni K, El Yousfi M, Charif I, Toughray I, Mellas N, Riffi Amarti A, Maazaz K, Ibrahimi SA, El Mesbahi O | title = Small bowel adenocarcinoma complicating coeliac disease: a report of three cases and the literature review | journal = Case Reports in Oncological Medicine | volume = 2012 | issue = | pages = 935183 | date = 2012 | pmid = 23243535 | pmc = 3517832 | doi = 10.1155/2012/935183 | url = }}</ref>
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| *[[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.<ref name="pmid25639480"/> 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)|ITK]]'' gene with the ''[[SYK (gene)|SYK]], [[FER (gene)|FER]],'' and ''[[ERBB4]]'' genes, and/or rearrangements of the ''[[TP63]]'' gene.<ref name="pmid28115372">{{cite journal | vauthors = Broccoli A, Zinzani PL | title = Peripheral T-cell lymphoma, not otherwise specified | journal = Blood | volume = 129 | issue = 9 | pages = 1103–1112 | date = March 2017 | pmid = 28115372 | doi = 10.1182/blood-2016-08-692566 | url = | doi-access = free }}</ref> 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.<ref name="pmid28115372"/> However, ALCL also has distinctive genetic abnormalities: malignant cells in the ALK+ form of ALCL have a translocation between the ''[[NPM1]]'' and ''[[Anaplastic lymphoma kinase|ALK]]'' genes to form a gene encoding the [[chimeric protein]], [[Anaplastic lymphoma kinase#Function|NPM-ALK]] whle the malignant cells in the ALK- form of ALCL have translocations of either the ''[[DUSP22]]'' or ''TP63'' genes.<ref name="pmid25869285">{{cite journal | vauthors = Hapgood G, Savage KJ | title = The biology and management of systemic anaplastic large cell lymphoma | journal = Blood | volume = 126 | issue = 1 | pages = 17–25 | date = July 2015 | pmid = 25869285 | doi = 10.1182/blood-2014-10-567461 | url = | doi-access = free }}</ref> | |
| *[[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.<ref name="pmid30213402">{{cite journal | vauthors = Yamaguchi M, Oguchi M, Suzuki R | title = Extranodal NK/T-cell lymphoma: Updates in biology and management strategies | journal = Best Practice & Research. Clinical Haematology | volume = 31 | issue = 3 | pages = 315–321 | date = September 2018 | pmid = 30213402 | doi = 10.1016/j.beha.2018.07.002 | url = }}</ref> Furthermore, the malignant T cells in this disease express readily detectable products encoded by the Epstein-Barr virus's genes<ref name="pmid30125149">{{cite journal | vauthors = Farrell PJ | title = Epstein-Barr Virus and Cancer | journal = Annual Review of Pathology | volume = 14| issue = | pages = 29–53| pmid = 30125149 | doi = 10.1146/annurev-pathmechdis-012418-013023 | url = | year = 2019 }}</ref> whereas those of EATL are not infected with this virus and therefore do not express these viral products.<ref name="pmid25639480"/>
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| *[[Indolent T cell lymphoproliferative disorder of the gastrointestinal tract]] (ITCLD-GT)) is a rare, slowly progressive, and potentially [[Precancerous condition|premalignant]] disorder of the GI tract that may be mistaken of EATL,<ref name="pmid27900603"/> particularly with respect to the severity of its symptoms, the [[gross pathology]] of its intestinal lesions,<ref name="pmid25639480"/> 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.<ref name="pmid27353398">{{cite journal | vauthors = Matnani R, Ganapathi KA, Lewis SK, Green PH, Alobeid B, Bhagat G | title = Indolent T- and NK-cell lymphoproliferative disorders of the gastrointestinal tract: a review and update | journal = Hematological Oncology | volume = 35 | issue = 1 | pages = 3–16 | date = March 2017 | pmid = 27353398 | doi = 10.1002/hon.2317 | url = }}</ref> 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]]);<ref name="pmid27353398"/> 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]].<ref name="pmid30028743">{{cite journal | vauthors = Lemonnier F, Gaulard P, de Leval L | title = New insights in the pathogenesis of T-cell lymphomas | journal = Current Opinion in Oncology | volume = 30 | issue = 5 | pages = 277–284 | date = September 2018 | pmid = 30028743 | doi = 10.1097/CCO.0000000000000474 | url = https://serval.unil.ch/resource/serval:BIB_3FF9FC10B4B3.P001/REF.pdf}}</ref> | |
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| == Prevention ==
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| 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.<ref name="pmid26060109"/> 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.<ref name="pmid27900603"/><ref name="pmid27803799"/>
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| ==Management==
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| === Treatment of refractory celiac disease ===
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| Efforts have also been made to treat refractory coeliac disease in order to prevent EATL. Treatment with [[corticosteroid]]s, particularly [[budesonide]] gives temporary improvement in symptoms and histological responses in 30-40% of patients<ref name="pmid26060109"/> but few have attained a good overall response.<ref name="pmid27803799"/> The addition of [[azathioprine]], [[cyclosporin]], or a [[monoclonal antibody]] directed against [[TNF inhibitor#Examples|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.<ref name="pmid26060109"/> 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.<ref name="pmid29943210"/><ref name="pmid28078381"/><ref name="pmid27803799"/>
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| 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]];.<ref name="pmid26060109"/> These examinations should also be used whenever patients with refractory disease experience worsening symptoms.<ref name="pmid27803799"/>
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| === Treatment of EATL ===
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| 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 [[Hematopoietic stem cell transplantation#Autologous|autologous stem cell transplantion]] has been the mainstay of treating EATL.<ref name="pmid27900603"/><ref name="pmid23361910">{{Cite journal | pmid = 23361910| year = 2013| last1 = Jantunen| first1 = E| title = Autologous stem cell transplantation for enteropathy-associated T-cell lymphoma: A retrospective study by the EBMT| journal = Blood| volume = 121| issue = 13| pages = 2529–32| last2 = Boumendil| first2 = A| last3 = Finel| first3 = H| last4 = Luan| first4 = J. J.| last5 = Johnson |first5 = P| last6 = Rambaldi| first6 = A| last7 = Haynes| first7 = A| last8 = Duchosal| first8 = M. A.| last9 = Bethge| first9 = W| last10 = Biron| first10 = P| last11 = Carlson| first11 = K| last12 = Craddock| first12 = C| last13 = Rudin| first13 = C| last14 = Finke| first14 = J| last15 = Salles| first15 = G| last16 = Kroschinsky| first16 = F| last17 = Sureda| first17 = A| last18 = Dreger| first18 = P| author19 = Lymphoma Working Party of the EBMT| doi = 10.1182/blood-2012-11-466839| doi-access = free}}</ref> Previous chemotherapy treatment regimens that did not use autologous stem cell transplantation reported poor prognoses with [[Survival rate#overall survival|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.<ref name="pmid27900603"/>
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| ==Research==
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| ==== Clinical trials ====
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| A phase 2 study sponsored by the Imagine Institute<ref>http://www.institutimagine.org/en/imagine-institute.html</ref> 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 [[Chimera (protein)|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.<ref>https://clinicaltrials.gov/ct2/show/NCT03217643?cond=Enteropathy-associated+T-cell+lymphoma&rank=1</ref>
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| 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 cell]]s that have been modified to target and destroy cells bearing CD30.<ref>https://clinicaltrials.gov/ct2/show/record/NCT03049449?cond=Enteropathy-associated+T-cell+lymphoma&rank=3</ref>
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| 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 [[PD-L1|programmed cell death protein 1]] (PD-1) thereby blocking this protein from being activated by [[PD-L1|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.<ref>https://clinicaltrials.gov/ct2/show/record/NCT03075553?cond=Enteropathy-associated+T-cell+lymphoma&rank=6</ref>
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| ==== Clinical trials ====
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| A recently completed [[Clinical trial#Phases|Phase 2]], [[Randomized experiment|randomized]], [[Blinded experiment#Double-blind trials|double-blinded]], [[Placebo-controlled study|placebo-controlled]], [[Parallel study|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.<ref>https://clinicaltrials.gov/ct2/show/NCT02633020?cond=refractory+celiac+disease&rank=1</ref> The study found potential therapeutic effects of the treatment in that it halted the malignant progression of IEL in these patients.<ref name="pmid30820708"/> [[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.<ref>https://clinicaltrials.gov/ct2/show/NCT02633020?term=NCT03439475+%5BExpandedAccessNCTId%5D&rank=1</ref>
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| ==See also==
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| * [[Lymphoma]] | |
| * [[Mucosa-associated lymphoid tissue]]
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| ==References==
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| {{Reflist}}
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| == External links == | | == External links == |
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| {{Lymphoid malignancy}} | | {{Lymphoid malignancy}} |
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| {{DEFAULTSORT:Enteropathy-Associated T-Cell Lymphoma}} | | {{DEFAULTSORT:Enteropathy-Associated T-Cell Lymphoma}} |
| [[Category:Lymphocytes]] | | [[Category:Lymphocytes]] |
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| [[Category:Lymphoma]] | | [[Category:Lymphoma]] |
| [[Category:Non-Hodgkin lymphoma]] | | [[Category:Non-Hodgkin lymphoma]] |
| {{dictionary-stub1}}
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| == Enteropathy-associated T-cell lymphoma ==
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| <gallery>
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| File:Enteropathy-associated_T_cell_lymphoma_-_low_mag.jpg|Low magnification of enteropathy-associated T-cell lymphoma
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| </gallery>
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