Enteropathy-associated T-cell Lymphoma Patients Research Articles

Outcomes in Patients with Enteropathy-Associated T-Cell Lymphoma (EATL) and Hepatosplenic T-Cell Lymphoma (HSTCL): A Population Based Analysis Using the SEER Data

Introduction and AimHepatosplenic T-cell lymphoma (HSTCL) and Enteropathy-associated T-cell Lymphoma (EATL) are rare aggressive peripheral T-cell lymphomas with dismal outcomes. Due to their rarity there is paucity of data on disease epidemiology and survival outcomes. We analyzed these rare diseases using Surveillance, Epidemiology and End Results (SEER) data to identify patient and disease factors that impact survival.MethodsUsing the SEER data, cases of HSTCL and EATL diagnosed between 1996 and 2014 were identified based on the ICD-O3 codes 9716 and 9717, respectively. Proportions were compared using chi-squared tests. Multivariable Cox proportional hazards models and stepwise regression were used to analyze disease-specific overall survival. Computations were performed in R.ResultsWe identified 122 patients with HSTCL and 163 with EATL; both had male predominance with 69% in HSTCL and 58% in EATL (p=0.07). Median age was 38 years (range 4-83) in HSTCL and 64 years (range 23-96) in EATL patients. The HSTCL group was much younger with 79% aged <55 years compared to only 26% in the EATL group (P=<0.0001) (Table 1). Although both groups were primarily Caucasian - 61% in HSTCL and 77% in EATL, 27% of HSTCL patients were of African American race. While the majority of the HSTCL (53%) were diagnosed in 2008-2014, 55% of EATL pts were diagnosed in 1996-2008. Disease characteristics also differed between these entities with HSTCL mostly being advanced stage (81%) and EATL largely early stage (58%) at diagnosis; 79% of HSTCL patients had stage IV compared to only 31% in EATL (p<0.0001). Treatments in HSTCL pts included chemotherapy (83%) surgery (43%) radiation therapy (10%). On the contrary, surgery (70%) was the most common treatment in EATL followed by chemotherapy (55%) and radiation therapy (3%). Median OS for EATL and HSTCL were 9 (95% CI 715) and 5 months (95% CI 37), respectively (log-rank P= 0.0018 (Figure 1A). In univariate analysis, surgery (HR: 0.62, 95% CI: 0.39-0.96, p=0.032), and radiation therapy (HR: 0.3, 95% CI: 0.16-0.96, p=0.042) was associated with superior OS, while there was increased risk of mortality with advanced age (HR: 1.6, 95% CI: 1.01-2.79, p=0.043) in HSTCL patients. Sex, race, marital status, year of diagnosis, use of chemotherapy and stage failed to predict survival in HSTCL. However, in EATL advanced stage (HR: 1.48, 95% CI: 0.99-2.20, p=.052) was associated with inferior OS and use of chemotherapy (HR: 0.46, 95% CI: 0.31-0.67, p=.0001) was a positive predictor for OS. On stepwise regression analysis, surgery (HR 0.57; p=0.014) and radiation therapy (HR 0.33; p= 0.019) were associated with improved survival in patients with HSTCL, whereas in EATL patients receiving chemotherapy improved survival (HR 0.42; p<0.001) (Figure 1B) and advanced stage correlated with reduced survival (HR 1.60; p=0.01).ConclusionTo our knowledge, this is the first and largest United States population based study of patients diagnosed with HSTCL and EATL. Our analysis showed that HSTCL is commonly diagnosed in younger, males with increased incidence in African American population compared to EATL. Although surgical interventions were commonly used in both entities, it was more frequent in EATL. While surgery and radiation improved survival in HSTL, chemotherapy was the significant factor in EATL. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Enteropathy-Associated T cell Lymphoma.

Enteropathy-associated T cell lymphoma (EATL) is a rare subtype of mature T cell lymphoma. The available literature about this rare type T cell lymphoma is relatively limited. This article provides a summary and review of the available literature addressing this entity in terms of risk factors, pathogenesis, diagnostic, and therapeutic options. EATL has two distinct subtypes. Type I EATL, now known as EATL, is closely, but not exclusively linked to celiac disease (CD), and it is primarily a disease of Northern European origin. It accounts for < 5% of peripheral T cell lymphoma (PTCL). Risk factors for EATL include advanced age, male sex, and most importantly, genetic susceptibility in the form of HLA-DQ2 homozygosity. The pathogenesis of EATL is closely related to celiac disease as it shares common pathogenic features with refractory celiac disease. The gold standard of diagnosis is histological diagnosis. EATL carries an aggressive course and a poor prognosis. Treatment of EATL includes surgery, induction chemotherapy, and consolidation in first complete remission and autologous stem cell transplant. The role of targeted and biologic therapies in newly diagnosed EATL patients along with relapsed, refractory cases is evolving and discussed in this review. EATL is an aggressive peripheral T cell lymphoma with poor overall treatment outcome using currently available therapy options. Clinical trials are considered the best approach for treatment of EATL. Early diagnosis and early referral to specialized centers would be the best way to deal with such patients. Development of new prognostic models and early surgical intervention are warranted. Prevention is where all the efforts should be spent, by counseling patients with CD regarding the importance of adherence to gluten-free diet and development of periodic surveillance programs in celiac disease patients for early detection of pre-lymphoma lesions.

Splenic volume differentiates complicated and non-complicated celiac disease.

Studies in small groups of patients indicated that splenic volume (SV) may be decreased in patients with celiac disease (CD), refractory CD (RCD) type II and enteropathy-associated T-cell lymphoma (EATL). The objective of this article is to evaluate SV in a large cohort of uncomplicated CD, RCD II and EATL patients and healthy controls. The retrospective cohort consisted of 77 uncomplicated CD (of whom 39 in remission), 29 RCD II, 24 EATL and 12 patients with both RCD II and EATL. The control group included 149 healthy living kidney donors. SV was determined on computed tomography. The median SV in the uncomplicated CD group was significantly larger than in controls (202 cm3 (interquartile range (IQR): 154-275) versus 183 cm3 (IQR: 140-232), p = 0.02). After correction for body surface area, age and gender, the ratio of SV in uncomplicated CD versus controls was 1.28 (95% confidence interval: 1.20-1.36; p < 0.001). The median SV in RCD II patients (118 cm3 (IQR 83-181)) was smaller than the median SV in the control group (p < 0.001). This study demonstrates large inter-individual variation in SV. SV is enlarged in uncomplicated CD. The small SV in RCD II may be of clinical relevance considering the immune-compromised status of these patients.

Analysis of clinicopathological features of 21 patients with enteropathy-associated T-cell lymphoma

Objective To investigate the clinicopathological and prognosis features of enteropathy-associated T-cell lymphoma (EATL). Methods 21 cases of EATL, 6 cases of peripheral T-cell lymphoma (PTCL) and 11 cases of natural-killer/T-cell lymphoma (NKTCL) were collected from January 2008 to May 2015. The immunophenotype of the tumor cell was tested by EnVision and as well as EBV-EBER for EB virus. Some patients were performed with follow-up data. Results 21 EATL patients included 14 males, 7 females and the middle age was 55 years old (40-79 years old). 15 patients affected the small bowel, 4 cases affected colon, 2 cases affected more than one site. 18 cases were mono-morpholohic EATL while 3 cases were classical EATL. The expression rates of neoplastic cells for CD3e, CD4, CD8, CD56, Granzyme B, TIA-1 were 95.24 % (20/21), 20.00 % (3/15), 73.68 % (14/19), 85.71 % (18/21), 64.71 % (11/17), 88.89 % (16/18) respectively. The expression of EBER in EATL patients (0, 0/21) was obviously lower than that in NKTCL patients (100 %, 11/11). 17 EATL patients had follow-up data, and the middle survival time was 15 months. No different prognosis was found in the three kinds of T-NHL (P = 0.697). Conclusions EATL usually occurs in elder male and jejunum. The diagnosis of EATL needs a lot of information, including clinical history, endoscopy, histomorphology, immunophenotype and EBV-EBER result. EATL has low mobidity and high malignancy, it still lacks impactful therapeutic regimen. Key words: Enteropathy-associated T-cell lymphoma; Pathology, clinical; Immunophenotype; Natural-killer/T-cell lymphoma

Refractory celiac disease and EATL patients show severe malnutrition and malabsorption at diagnosis

Refractory celiac disease type II (RCDII) and EATL (Enteropathy Associated T-cell Lymphoma) are (pre)malignant complications of celiac disease (CD). Data on malnutrition and intestinal absorption is lacking in these patients. Therefore, the aim of the study is to comprehensively assess nutritional status and intestinal absorption capacity of patients with RCDII and EATL, compared with data of newly diagnosed CD patients. Observational study in tertiary care setting in RCDII (n=24, 63.8±8.2y), EATL (n=25, 62.3±5.7y) and CD patients (n=43, 45.6±14.8y). At diagnosis, anthropometry (BMI, unintentional weight loss, fat-free mass index (FFMI), handgrip strength (HGS), nutritional intake, fecal losses and Resting Energy Expenditure (REE)) were assessed. Low BMI (<18.5) was more often observed in RCDII patients than in CD or EATL patients (in 33%, 12% and 12%, respectively, p=0.029). EATL patients more frequently had unintentional weight loss (>10%) than CD or RCDII patients (in 58%, 19% and 39% of patients, respectively; p=0.005/0.082). Energy malabsorption (<85%) was detected in 44% and 33% of RCDII and EATL patients, vs 21.6% in CD (NS). Fecal energy losses were higher in RCDII than in CD patients (589±451 vs 277±137kcal/d, p=0.017). REE was underestimated by predicted-REE with>10% in 60% of RCDII, 89% of EATL, and 38% of CD patients (p=0.006). Low FFMI and HGS were detected in one third and two thirds of all patients, respectively. The nutritional status of patients with RCDII and EATL is inferior compared with untreated naïve CD patients at presentation. Both malabsorption as well as hypermetabolism contribute to malnutrition.

Enteropathy-Associated T-Cell Lymphoma in the U.S.: A Population-Based Study Using Surveillance, Epidemiology, and End Results Program and National Cancer Data Base

Background:Enteropathy-associated T-cell lymphoma (EATL) is a very rare primary intestinal non-Hodgkin lymphoma (NHL) strongly associated with celiac disease. Previous studies suggest that EATL may be more common in Europe and among white population, in which celiac disease is a prevalent condition. However, comparative racial epidemiologic study of EATL in a large population is lacking and clinical studies remain limited to small series. Using two U.S. population databases, we determined the comparative incidences according to race and described the clinical features and outcome of the largest series of EATL reported to date.Methods:Incidence rates (case/1,000,000) were calculated using 2000-2010 data from the Surveillance, Epidemiology, and End Results (SEER) Program and age-adjusted to the U.S. 2000 standard population. Patient level data were obtained from the National Cancer Data Base (NCDB) Participant User File and analyzed for demographic patterns and stage distribution (1998-2011) as well as overall survival (1998-2006). SEER, a program of the U.S. National Cancer Institute, collects cancer incidence and survival data from population-based cancer registries covering approximately 28 percent of the U.S. population. NCDB, a joint program of the American College of Surgeons and the American Cancer Society, is a nationwide oncology outcomes database for more than 1,500 cancer programs in the U.S. and Puerto Rico capturing about 70% of all newly diagnosed cases of cancer in the U.S.Results:In the years 2000-2010, the overall incidence rate of EATL in the U.S. population was 0.111. Asians/Pacific Islanders had a higher incidence rate (0.236) compared to other races (whites [0.101], blacks [0.107], American Indians/Alaska natives [0.128]). The risk ratio of Asians compared to non-Asians was 2.32 (95% CI: 1.39-3.69; P =0.002). From 1998-2011, 515,026 patients were diagnosed with NHL and 337 (0.07%) had EATL. The median age was 64 years (range, 20 -90+ years) and 60% of patients were males. The stage distribution was as follows: I (26.7%), II (16.3%), III (3.3%), IV (29.1%), and unknown (24.6%). The median overall survival (OS) for the entire cohort was 5.9 months. Patients diagnosed in the more recent era (2003-2006) had a better outcome (median OS, 6.6 versus 2.6 months; Figure 1; P = 0.034). Asians/Pacific Islanders had a worse outcome compared to other races (Figure 2; P = 0.031). Multivariable analysis showed the following to be independent factors associated with inferior OS: age >60 years (HR: 1.49; 95% CI: 1.05-2.10), Asians/Pacific Islanders (HR: 2.27; 95% CI: 1.08-4.76), stage III/IV (HR: 3.03; 95%CI: 2.00-4.59), and diagnosis before 2003 (HR: 1.59; 95%CI: 1.10-2.28).Conclusions:Contrary to previous studies, we find that the highest incidence and lowest survival rates of EATL occur among Asians/Pacific Islanders, populations in which celiac disease is not considered to be prevalent. The overall survival of EATL patients has improved over time but remains poor. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Real-world data on prognostic factors and treatment in peripheral T-cell lymphomas: a study from the Swedish Lymphoma Registry

AbstractPeripheral T-cell lymphomas (PTCLs) are rare lymphomas with mostly poor outcome with current treatment. The addition of etoposide to cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) and upfront consolidation with autologous stem cell transplantation (auto-SCT) have shown promising results but have never been tested in randomized trials. As a complement to retrospective analyses of clinical trials, we aimed at analyzing prognostic factors and outcome in an unselected, population-based cohort. Through the Swedish Lymphoma Registry, we identified 755 PTCL patients diagnosed during a 10-year period. In addition to International Prognostic Index factors, male gender was associated with an adverse overall survival (OS) (hazard ratio [HR], 1.28; P = .011) and progression-free survival (PFS) (HR, 1.26; P = .014). In an intention-to-treat analysis in 252 nodal PTCL and enteropathy-associated T-cell lymphoma patients (excluding anaplastic lymphoma kinase–positive anaplastic large cell lymphoma), upfront auto-SCT was associated with a superior OS (HR, 0.58; P = .004) and PFS (HR, 0.56; P = .002) compared with patients treated without auto-SCT. The addition of etoposide to CHOP resulted in superior PFS in patients ≤60 years (HR, 0.49; P = .008). This study is the largest population-based PTCL cohort reported so far and provides important information on outcome in PTCL outside the setting of clinical trials.

PP081-SUN: Nutritional Status of RCDII and EATL Patients is Poor Compared to Newly Diagnosed Coeliac Disease Patients

Rationale: A minority of newly diagnosed coeliac disease (CD) patients does not show clinical improvement or relapse upon a strict gluten free diet and might suffer from Refractory Coeliac DiseaseII (RCDII) or Enteropathy Associated T-cell Lymphoma (EATL). We aimed to comprehensively assess nutritional status and intestinal absorption capacity in RCDII, EATL and CD patients, at first presentation. Methods: Nutritional status was assessed by antropom-etry, BMI (

Autologous Stem Cell Transplantation (ASCT) for Enteropathy-Associated T-Cell Lymphoma (EATL): Final Analysis of a Retrospective Study On the Behalf of Lymphoma Working Party (LWP) of the European Group for Blood and Marrow Transplantation (EBMT).

AbstractAbstract 3105▪▪This icon denotes a clinically relevant abstract Background:EATL is a rare subtype of peripheral T-cell lymphomas characterized by primarily intestinal localization and a frequent association with celiac disease. The prognosis is considered to be poor with conventional chemotherapy. Limited data is available on the efficacy of ASCT in this lymphoma subtype. Primary objectivewas to study the outcome of ASCT as a consolidation or salvage strategy for EATL. The primary endpoint was overall survival (OS) and progression-free survival (PFS). Eligible patients were > 18 years who had received ASCT between 2000–2010 for EATL that was confirmed by review of written histopathology reports, and had sufficient information on disease history and follow-up available. The search strategy used the EBMT database to identify patients potentially fulfilling the eligibility criteria. An additional questionnaire was sent to individual transplant centres to confirm histological diagnosis (histopathology report or pathology review) as well as updated follow-up data. Patients and transplant characteristics were compared between groups using X2 test or Fisher’s exact test for categorical variables and t-test or Mann-Whiney U-test for continuous variables. OS and PFS were estimated using the Kaplan-Meier product-limit estimate and compared by the log-rank test. Estimates for non-relapse mortality (NRM) and relapse or progression were calculated using cumulative incidence rates to accommodate competing risk and compared to Gray’s test. Results:Altogether 138 patients were identified. Updated follow-up data was received from 74 patients (54 %) and histology report from 54 patients (39 %). In ten patients the diagnosis of EATL could not be adequately verified. Thus the final analysis included 44. There were 24 males and 20 females with a median age of 56 (35–72) years at the time of transplant. Twenty-five patients (57 %) had a history of celiac disease. Disease stage was I in nine patients (21 %), II in 14 patients (33 %) and IV in 19 patients (45 %). Twenty-four patients (55 %) were in the first CR or PR at the time of transplant. BEAM was used as a high-dose regimen in 36 patients (82 %) and all patients received peripheral blood grafts. The median follow-up for survivors was 46 (2–108) months from ASCT. Three patients died early from transplant-related reasons translating into a 2-year non-relapse mortality of 7 %. Relapse incidence at 4 years after ASCT was 39 %, with no events occurring beyond 2.5 years after ASCT. PFS and OS were 54 % and 59 % at four years, respectively. There was a trend for better OS in patients transplanted in the first CR or PR compared to more advanced disease status (70 % vs. 43 %, p=0.053). Of note, patients with a history of celiac disease had superior PFS (70 % vs. 35 %, p=0.02) and OS (70 % vs. 45 %, p=0.052) whilst age, gender, disease stage, B-symptoms at diagnosis or high-dose regimen were not associated with OS or PFS. Conclusions:This study shows for the first time in a larger patient sample that ASCT is feasible in selected patients with EATL and can yield durable disease control in a significant proportion of the patients. Patients transplanted in first CR or PR appear to do better than those transplanted later. ASCT should be considered in EATL patients responding to initial therapy. Disclosures:No relevant conflicts of interest to declare.

Serum parameters in the spectrum of coeliac disease: beyond standard antibody testing - a cohort study

BackgroundInvasive techniques are still required to distinguish between uncomplicated and complicated forms of CD.MethodsWe set out to investigate the potential use of novel serum parameters, including IL-6, IL-8, IL-17, IL-22, sCD25, sCD27, granzyme-B, sMICA and sCTLA-4 in patients diagnosed with active CD, CD on a GFD, Refractory coeliac disease (RCD) type I and II, and enteropathy associated T-cell lymphoma (EATL).ResultsIn both active CD and RCDI-II elevated levels of the proinflammatory IL-8, IL-17 and sCD25 were observed. In addition, RCDII patients displayed higher serum levels of soluble granzyme-B and IL-6 in comparison to active CD patients. In contrast, no differences between RCDI and active CD or RCDII were observed. Furthermore, EATL patients displayed higher levels of IL-6 as compared to all other groups.ConclusionsA series of novel serum parameters reveal distinctive immunological characteristics of RCDII and EATL in comparison to uncomplicated CD and RCDI.

Type II enteropathy‐associated T‐cell lymphoma: A multicenter analysis from the Asia Lymphoma Study Group

Enteropathy-associated T-cell lymphoma (EATL) is a rare primary gastrointestinal T-cell lymphoma. A multicenter study from the Asia Lymphoma Study Group identified 38 EATL patients within a 19-year period. All cases were type II EATL. Men were affected twice as common as women, at a median age of 59 (23-89) years. None had a history of celiac disease. The sites of involvement were small bowel and stomach (5%), small bowel (63%), small and large bowel (16%), and large bowel (18%). Common presenting features were bowel perforation (34%), pain (32%), and obstruction (21%). Lymphomas showed monomorphic neoplastic lymphoid infiltrates that were CD3⁺ (100%), CD56⁺ (91%), TIA-1⁺ (96%), CD4⁻CD8⁺ (63%), CD4⁺CD8⁺ (19%), CD4⁻CD8⁻ (16%), and CD4⁺CD8⁻ (3%). Epstein Barr virus was demonstrable in three cases. Despite chemotherapy and/or surgical resection, the overall response and complete response rates were poor at 46% and 38%. The median overall survival (OS) was 7 months and progression-free-survival (PFS) 1 month. Five patients underwent hematopoietic stem cell transplantation all were alive. Age and the prognostic index for peripheral T-cell lymphoma were not prognostically significant. Good performance status was associated with better OS (P = 0.03), and response to initial treatment led to better OS and PFS (P < 0.001).

Enteropathy associated T-cell lymphoma and its precursor lesions

Enteropathy Associated T-cell Lymphoma (EATL) is an intestinal tumour of intra-epithelial lymphocytes. Based on morphology, immunohistochemistry and genetic profile EATL can be divided into two groups. EATL type I is a large cell lymphoma which is highly associated with Coeliac Disease (CD) and mostly presents with malabsorption, weight loss and CD-related symptoms. EATL type II consists of small to medium-sized cells and presents often with obstruction or perforation of the small bowel. This type of EATL has no known association with CD. When EATL has been diagnosed a thorough diagnostic work-up is needed. This work-up preferably includes video capsule enteroscopy (VCE), double-balloon enteroscopy (DBE), computed tomography (CT) combined with 18F-fluorodeoxyglucose positron emission tomography scan (18F-FDG-PET scan) if possible and magnetic resonance enteroclysis (MRE). Nowadays, most EATL patients are treated with chemotherapy mostly preceded by resection of the tumour and followed by stem cell transplantation. Despite these therapies outcome of EATL remains very poor with a 5-year survival of 8-20%. In order to improve survival prospective multicentre trials, studying new therapies are needed. The combination of chemotherapy, monoclonal antibodies and/or apoptosis inducing small molecules might be a potential treatment for EATL in the (nearby) future.

M2032 HLA-DQ Typing of Extra-Intestinal T-Cell Lymphomas: Evidence for An Association with Undiagnosed Celiac Disease? a Pilot Study On Anaplastic Large Cell Lymphomas

Introduction: The prevalence of celiac disease (CD) is 0.5-1% in the Western population. As CD is widely underdiagnosed, the majority of CD patients is still untreated and therefore at greater risk of developing complicated CD, including Enteropathy Associated T-cell Lymphoma (EATL). Differentiation between various T-cell lymphomas is difficult because of similar morphology and immunophenotype. The final diagnosis is based on clinical presentation and localisation of the lymphoma. Consequently, T-cell lymphomas in CD patients and T-cell lymphomas in the small bowel are always diagnosed as EATLs. However, 25% of EATLs are located extra-intestinal. The most frequent type of T-cell lymphomas is anaplastic large cell lymphoma (ALCL). ALCLs are either anaplastic lymphoma kinase (ALK) negative or positive. EATLs are always ALK negative. As is the case for most EATLs, ALCLs are CD30 positive. CD and EATL are strongly associated with HLA-DQ2 and/or -DQ8. HLADQ2 and/or -DQ8 expression is found in 98% of CD and EATL patients, compared to 40% in the Western population. Aims and Methods: We investigated whether the frequency of HLA-DQ2 and/or -DQ8 is increased in extra-intestinal ALCLs compared to the general population, in order to determine if extra-intestinal ALCLs might in fact be undiagnosed EATLs. For this purpose, extra-intestinal ALCL samples, ALK-positive and ALK-negative, were collected and DNA was isolated. DQA1 and DQB1 alleles were amplified using PCR. HLA-DQ typing was subsequently performed using a single strand conformation polymorphism / heteroduplex based method (SSCP/HD). Results: So far, 21 anaplastic large-cell lymphomas have been HLA-DQ typed. HLA-DQ2 was present in 10 lymphomas, of which 3 were homozygous. HLA-DQ8 was present in 4 lymphomas, all heterozygous. In total, twelve lymphomas (57%) were HLA-DQ2 and/or -DQ8 positive, indicating only a slightly higher prevalence than in the general population. However, within the subgroup of ALKnegative ALCLs, representing potentially undiagnosed EATLs, 71% was HLA-DQ2 and/or DQ8 positive (p=0.05). Conclusion: The increased prevalence of HLA-DQ2 and/or -DQ8 in ALK-negative ALCLs suggests underdiagnosis of EATL within this group of extra-intestinal T-cell lymphomas.

M2033 Role of Antibodies in the Long Term Follow Up of Patients with Celiac Disease to Predict the Adherence to Gluten-Free Diet

Introduction: The prevalence of celiac disease (CD) is 0.5-1% in the Western population. As CD is widely underdiagnosed, the majority of CD patients is still untreated and therefore at greater risk of developing complicated CD, including Enteropathy Associated T-cell Lymphoma (EATL). Differentiation between various T-cell lymphomas is difficult because of similar morphology and immunophenotype. The final diagnosis is based on clinical presentation and localisation of the lymphoma. Consequently, T-cell lymphomas in CD patients and T-cell lymphomas in the small bowel are always diagnosed as EATLs. However, 25% of EATLs are located extra-intestinal. The most frequent type of T-cell lymphomas is anaplastic large cell lymphoma (ALCL). ALCLs are either anaplastic lymphoma kinase (ALK) negative or positive. EATLs are always ALK negative. As is the case for most EATLs, ALCLs are CD30 positive. CD and EATL are strongly associated with HLA-DQ2 and/or -DQ8. HLADQ2 and/or -DQ8 expression is found in 98% of CD and EATL patients, compared to 40% in the Western population. Aims and Methods: We investigated whether the frequency of HLA-DQ2 and/or -DQ8 is increased in extra-intestinal ALCLs compared to the general population, in order to determine if extra-intestinal ALCLs might in fact be undiagnosed EATLs. For this purpose, extra-intestinal ALCL samples, ALK-positive and ALK-negative, were collected and DNA was isolated. DQA1 and DQB1 alleles were amplified using PCR. HLA-DQ typing was subsequently performed using a single strand conformation polymorphism / heteroduplex based method (SSCP/HD). Results: So far, 21 anaplastic large-cell lymphomas have been HLA-DQ typed. HLA-DQ2 was present in 10 lymphomas, of which 3 were homozygous. HLA-DQ8 was present in 4 lymphomas, all heterozygous. In total, twelve lymphomas (57%) were HLA-DQ2 and/or -DQ8 positive, indicating only a slightly higher prevalence than in the general population. However, within the subgroup of ALKnegative ALCLs, representing potentially undiagnosed EATLs, 71% was HLA-DQ2 and/or DQ8 positive (p=0.05). Conclusion: The increased prevalence of HLA-DQ2 and/or -DQ8 in ALK-negative ALCLs suggests underdiagnosis of EATL within this group of extra-intestinal T-cell lymphomas.

Flow cytometric determination of aberrant intra-epithelial lymphocytes predicts T-cell lymphoma development more accurately than T-cell clonality analysis in Refractory Celiac Disease

Background: Refractory celiac disease (RCD) patients with aberrant, often clonal, intraepithelial T-cells are at high risk for development of enteropathy associated T-cell lymphoma (EATL). Early detection of those patients that actually develop EATL is of utmost importance for curative intervention. Aim: First, to establish an optimal cut-off value for the percentage of aberrant lymphocytes, previously determined based on clinical observations, via reference ranges for aberrant T-cells in the duodenal mucosa of celiac disease patient and control groups. Secondly, to compare aberrancy with intestinal T-cell clonality as a prognostic parameter for EATL development in RCD. Methods: Immunophenotyping using flow cytometry was performed on small intestinal biopsy-derived lymphocytes, obtained from distinct celiac disease (CD) patient and control groups ( N = 167 in total). T-cell clonality in duodenal biopsy specimens was assessed by PCR in RCD, ulcerative jejunitis and EATL patients ( N = 31 in total). Results: In 95% of non-refractory CD patients, the highest percentage aberrant T-cells was 20%. Using this cut-off value, EATL development was exclusively seen in RCD with more than 20% aberrant T-cells (median 52% aberrant T-cells, range 27–94%). When compared with T-cell clonality analysis, > 20% aberrancy showed a much higher negative predictive value and sensitivity (both 100%) for EATL development in RCD patients than T-cell clonality analysis (respectively 75% and 78%). Conclusions: Quantification of aberrant T-cells by flow cytometry is preferable to T-cell clonality analysis for identification of RCD patients at risk for EATL development. A cut-off value of 20% is of use in risk stratification, therapeutic options and subsequent follow-up of RCD patients.

The MYO9B Gene Is a Strong Risk Factor for Developing Refractory Celiac Disease

Celiac disease (CD) is associated with HLA-DQ2 and HLA-DQ8 and has been linked to genetic variants in the MYO9B gene on chromosome 19. HLA-DQ2 homozygosity is associated with complications of CD such as refractory celiac disease type II (RCD II) and enteropathy-associated T-cell lymphoma (EATL). We investigated whether MYO9B also predisposes to RCD II and EATL. Genotyping of MYO9B and molecular HLA-DQ2 typing were performed on 62 RCD II and EATL patients, 421 uncomplicated CD patients, and 1624 controls. One single nucleotide polymorphism in MYO9B showed a significantly different allele distribution in RCD II and EATL patients compared with controls (P = .00002). The rs7259292 T allele was significantly more frequent in RCD II and EATL patients compared with CD patients (P = .0003; odds ratio [OR], 3.61; 95% confidence interval [CI], 1.78-7.31). The frequency of the haplotype carrying the T allele of this single nucleotide polymorphism was significantly increased in RCD II and EATL patients (11%), compared with controls (2%) and CD patients (3%) (OR, 6.76; 95% CI, 3.40-13.46; P = 2.27E-09 and OR, 4.22; 95% CI, 1.95-9.11; P = .0001, respectively). Both MYO9B rs7259292 and HLA-DQ2 homozygosity increase the risk for RCD II and EATL to a similar extent when compared with uncomplicated CD patients (OR, 4.3; 95% CI, 1.9-9.8 and OR, 5.4; 95% CI, 3.0-9.6, respectively), but there was no evidence for any interaction between these 2 risk factors. We show that both MYO9B and HLA-DQ2 homozygosity might be involved in the prognosis of CD and the chance of developing RCD II and EATL.