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 affected by the disease's intense inflammation.^[1] While a relatively rare disease, it is the most common type of primary gastrointestinal T-cell lymphoma.^[2]

EATL had been defined as a single type of small intestine lymphoma, but in 2008, the World Health Organization (WHO) divided the disease into two subtypes: 1) EATL type I, which occurs in individuals with coeliac disease, a chronic immune disorder causing 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 without coeliac disease. While type I and II EATL share many similar features, post-2008 studies found some significant differences between the two types. In 2016, the WHO redefined the two diseases as separate entities, keeping the term enteropathy-associated T-cell lymphoma for the coeliac disease-associated lymphoma and terming type 2 disease as monomorphic epitheliotropic intestinal T cell lymphoma (MEITL).^[3] EATL is five to ten times more common than is MEITL.^[4] The WHO also defined a third type of intestinal T-cell lymphoma that cannot not be classified as EATL or MEITL as peripheral T-cell lymphoma not otherwise specified (ITCL-NOS).^[5]

EATL arises from the malignant transformation of small-intestinal

Optimal treatment of EATL has used regimens consisting of intensive chemotherapy, hematopoietic stem cell transplantation and, in cases with bulky, obstructive and/or perforated bowel disease, surgical intervention.^[3] The disease has a five-year overall survival rate of only ~20%.^[8] However, recent studies focusing on the malignant IEL in EATL have increased 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.^[7]

Presentation

EATL typically occurs in patients with a history of coeliac disease and who may have been previously diagnosed with Type I or II refractory disease,^[9] but in any case, affected individuals present with worsening coeliac disease symptoms of abdominal pain, malabsorption, diarrhea, weight loss, fever or night sweats.^[10][3] EATL diagnosis is more likely if symptoms develop suddenly,^[4] or if the serious symptoms of bowel obstruction and/or bowel perforation caused by bulky EATL masses develop.^[10] Patients with ulcerative jejunitis usually present with more severe symptoms, including more frequent bowel perforations and obstructions.^[10] Some patients with no history of coeliac disease present with symptoms or signs of a small-intestinal lymphoma but on diagnostic workup are found to have coeliac disease.^{[citation needed]}

Pathophysiology

Genetics

The cause of EATL, while not fully understood, is by definition related to celiac disease. Individuals are

• Celiac disease affects ~1% of the population in most parts of the world.[3]
• 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.^[12]
• About 2–3% of individuals who inherit these HLA-DQ2 and/or HLA-DQ8 serotypes develop coeliac disease.^[10]
• About 90% of coeliac disease patients are
  HLA-DQA1*03 plus HLA-DQB1*0302 alleles at the respective HLA-DQA1 and DAQB1 loci.^[9]
• Less than 1% of all individuals with coeliac disease develop EATL.[9]
• Individuals homozygous for the HLADQB1*0201 allele at the HLA-DQB1 locus develop a particularly severe and tissue-damaging form of coeliac disease^[15] and have a greatly increased rate of developing EATL.^[3]
• 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.^[3]

Intraepithelial lymphocytes

IEL are a diverse population of lymphocytes, which unlike most peripheral lymphocytes, do not recirculate through the

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^[16]) 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.^[3] 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.^[9]

De novo 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 from 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.^[3]

Type I refractory coeliac disease

Type I RCD patients, who constitute 15–23% of all patients with RCD,^[17] are refractory to the gluten diet as evidenced by their worsening symptoms, increased tissue destruction,^[10] and rising numbers of TCRαβ+CD*αβ+IEL in tissue lesions.^[3] 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.^[10] 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.^[3]

Type II refractory coeliac disease

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.

Ulcerative jejunitis[16] (also termed chronic ulcerative jejunitis, multifocal ulcerated microlymphomas,^[8] ulcerative jejunoilitis,^[10] and chronic ulcerative jejunoilitis^[3]) 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.^[10][16]

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.,

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.^[8] The genetic abnormalities found in Monomorphic epitheliotropic intestinal T cell lymphoma are similar to those in EATL.^[20]
• Small intestinal adenocarcinoma, while rare, is far more frequent in coeliac disease than in the general population.^[10][21] 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.^[21] However, it can cause severe symptoms such as bowel obstruction^[22] and intestinal bleeding.^[23] Also unlike EATL, the adenocarcinoma often occurs in women and younger (<50 years old) individuals;^[22] is more likely to begin as a non-maligant adenoma;^[24] and has the histology typical of an adenocarcinoma.^[25]
• chimeric protein, NPM-ALK while the malignant cells in the ALK- form of ALCL have translocations of either the DUSP22 or TP63 genes.^[27]
• 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.^[28] Furthermore, the malignant T cells in this disease express readily detectable products encoded by the Epstein–Barr virus's genes^[29] whereas those of EATL are not infected with this virus and therefore do not express these viral products.^[8]
• JAK2 fusion gene.^[31]

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.[9] 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.^[4][16]

Management

Treatment of refractory celiac disease

Efforts have also been made to treat refractory coeliac disease in order to prevent EATL. Treatment with

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;.^[9] These examinations should also be used whenever patients with refractory disease experience worsening symptoms.^[16]

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.^[4][32] Previous chemotherapy treatment regimens that did not use autologous stem cell transplantation reported poor prognoses with overall 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.^[4]

Research

Clinical trials

A phase 2 study sponsored by the Imagine Institute

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.^[37] The study found potential therapeutic effects of the treatment in that it halted the malignant progression of IEL in these patients.^[17] 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.^[38]

See also

• Lymphoma
• Mucosa-associated lymphoid tissue

References