The Rising Incidence and Poor Outcomes of Enteropathy-Associated T-Cell Lymphoma.

INTRODUCTION: Enteropathy-associated T-cell lymphoma (EATL) is associated with celiac disease. With the rising prevalence of celiac disease, we hypothesized that the prevalence of EATL is also increasing. METHODS: We used the Surveillance, Epidemiology, and End Results database, which is a population-based US cancer surveillance program. We used the ICD-0-3 code 9717/3 to identify patients with EATL diagnosed between 2000 and 2020. Incidence rates were calculated using the SEER*Stat software, and annual percent change was calculated using the Joinpoint software. Log-rank tests were used to evaluate for significant difference in survival curves between groups. A Cox proportional hazards regression model was used for continuous variables and quantifying association strength of predictors. RESULTS: A total of 463 cases of EATL were identified (273 male, 190 female) with a median age of 65 (range 23-90+) years. Most of the cases were at an advanced stage at diagnosis and were treated with a combination of surgery and chemotherapy. The median survival time was 6 months. The 2000-2020 age-adjusted incidence rate per 100,000 people was 0.014, and the incidence increased between 2000 and 2020, with an annual percent change of 2.58 ( P < 0.05). Increased age at diagnosis and lack of treatment had significant impacts on survival while sex, year of diagnosis, race, and time between diagnosis and treatment had no significant impact on survival. DISCUSSION: There was a significant increase in the incidence of EATL in the United States between 2000 and 2020. Survival in this cancer remains poor and unchanged over the past 2 decades.

Patients with enteropathy-associated T-cell lymphoma in the United States from 2000 to 2018: SEER data-base analysis.

BACKGROUND: Enteropathy-Associated T-Cell Lymphoma (EATL) is a rare lymphoma of T-cell origin associated with celiac disease. There is limited evidence in the literature about the incidence and causes of death in patients with EATL. METHODS: We performed a retrospective study through analyzing the Surveillance, Epidemiology, and End Results (SEER) data base to determine the incidence, trends and causes of death of patients with EATL in the U.S from 2000 to 2018. Baseline characteristics with treatment options (surgery, radiotherapy, and chemotherapy), status of patients either alive, dead due to cancer itself or other non-cancerous causes with listing of those non-cancerous causes was retrieved. Sub-group analysis based on sex was also done. Multiple latency periods (<2 year, 2-5, 6-10, 11-15, and more than 15 years) were analyzed following EATL diagnosis. RESULTS: There were 259 EATL patients, majority were aged 70-74 years old (n = 36, 13.9%), predominantly males 155 (59.8%), most common in whites, (76.4%, n = 198), EATL was the only primary tumor in 177 (68.3%) cases, most common site was small bowel at different sites 84 (32.4%) followed by jejunum specifically 57 (22%), majority went for surgical resection (69.9%, n = 181) followed by chemotherapy (47.5%, n = 123), 217 (83.7%) died during follow-up in this study, CONCLUSION: EATL is a rare entity, mostly seen in males, between 70 and 74 years, and mostly originated in the small bowel. With over 80% death in five-year follow up period, EATL patients showed better survival if they underwent chemotherapy. More studies are needed for further understanding of this rare entity.

Enteropathy-Associated T cell Lymphoma.

PURPOSE OF REVIEW: 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. RECENT FINDINGS: 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.

Enfermedad celiaca refractaria: cuando la dieta sin gluten no sana / Refractory celiac disease: when a gluten-free diet does not heal

Presentamos el caso de una mujer de 61 años con antecedentes de enfermedad celiaca desde los 21, que empieza desde hace doce meses con epigastralgias intermitentes postprandiales, alteraciones del hábito intestinal y pérdida de peso. Afirma el cumplimiento estricto de la dieta sin gluten y sin lactosa, comprobándose esto mediante la titulación de anticuerpos, que fueron negativos. Ante esta clínica se realiza una gastroscopia, donde se evidencia atrofia vellositaria y en la biopsia se objetiva una afectación de la mucosa grado Marsh III. Con estas pruebas se alcanza el diagnóstico de enfermedad celiaca refractaria (ECR). La ECR es una entidad rara que padece el 5-8 % de los enfermos celiacos diagnosticados en la edad adulta y que produce un aumento del riesgo de desarrollo de linfoma intestinal. Por tanto, es evidente la importancia de conocerlo y sospecharlo (AU)

We present the case of a 61-year-old woman with celiac disease since age 21, who starts 12 months ago with intermittent postprandial epigastralgia, altered bowel habit and weight loss. The patient affirms the strict observance of the gluten and lactose free diet, which is confirmed by negative antibody titration analysis. Due to these symptoms, a gastroscopy is performed in which an atrophy of the villous architecture is detected. A Marsh grade III mucosa damage is also found in the biopsy, being diagnosed of refractory celiac disease (RCD). RCD is a rare entity present in 5-8% of all celiac patients diagnosed in adulthood; it produces an increased risk of intestinal T-cell lymphoma, this is why it is important to know and suspect this disease (AU)

A large variety of clinical features and concomitant disorders in celiac disease - A cohort study in the Netherlands.

BACKGROUND AND AIMS: Celiac disease (CeD) is a gluten triggered, immune-mediated disease of the small intestine. Few clinical cohort descriptions are available, despite the diverse clinical picture. This study provides an overview of a large Dutch CeD cohort focusing on presenting symptoms, co-occurrence of immune mediated diseases (IMD) and malignancies. METHODS: We performed a retrospective study in a Dutch university and a non-university medical hospital and included only biopsy proven (≥Marsh type 2 classification) CeD patients. RESULTS: 412 patients were included, selected from 9468 small-bowel biopsy pathology reports and financial codes. Classical symptoms were present in approximately one third of the cohort (diarrhea (37.4%), fatigue (35.0%), weight loss (31.6%), abdominal pain (33.3%)). Atypical symptoms as constipation (10.4%) and reflux (12.4%) were reported as well. 11.7% was diagnosed without reported symptoms. In 25.2% concomitant IMD occurred (most prevalent: type 1 diabetes mellitus (4.9%), microscopic colitis (4.9%), immune mediated-thyroid disease (4.1%)). CeD patients with a concomitant IMD were diagnosed at a significantly higher age compared to those without (P=0.002). Malignancies occurred in 53 cases (12.9%), including eight Enteropathy Associated T-cell Lymphomas. CONCLUSION: This is the first study describing a CeD cohort in such detail in the Netherlands and highlights the clinical heterogeneity and importance of screening for concomitant diseases in CeD.

Low incidence but poor prognosis of complicated coeliac disease: a retrospective multicentre study.

BACKGROUND: Coeliac disease is a chronic enteropathy characterized by an increased mortality caused by its complications, mainly refractory coeliac disease, small bowel carcinoma and abdominal lymphoma. Aim of the study was to study the epidemiology of complications in patients with coeliac disease. METHODS: Retrospective multicenter case-control study based on collection of clinical and laboratory data. The incidence of complicated coeliac disease was studied among coeliac patients directly diagnosed in four Italian centres. Patients referred to these centres after a diagnosis of coeliac disease and/or complicated coeliac disease in other hospitals were therefore excluded. RESULTS: Between 1/1999 and 10/2011, 1840 adult coeliac patients were followed up for 7364.3 person-years. Fourteen developed complications. Since five patients died, at the end of the observation period (10/2011), the prevalence of complicated coeliac disease was 9/1835 (1/204, 0.49%, 95% CI 0.2-0.9%). The annual incidence of complicated coeliac disease in the study period was 14/7364 (0.2%, 95% CI 0.1-0.31%). Although complications tend to occur soon after the diagnosis of coeliac disease, Kaplan-Meier curve analysis showed that they can actually occur at any time after the diagnosis of coeliac disease. CONCLUSIONS: Complications of coeliac disease in our cohort were quite rare, though characterised by a very high mortality.

2D ultrasonography and contrast enhanced ultrasound for the evaluation of cavitating mesenteric lymph node syndrome in a patient with refractory celiac disease and enteropathy T cell lymphoma.

BACKGROUND: The cavitating mesenteric lymph node syndrome (CMLNS) is a rare manifestation of celiac disease, with an estimated mortality rate of 50%. Specific infections and malignant lymphoma may complicate its clinical course and contribute to its poor prognosis. Diagnosing the underlying cause of CMLNS can be challenging. This is the first report on contrast enhanced ultrasound (CEUS) findings in enteropathy associated T-cell lymphoma (EATL) complicating CMLNS in a gluten-free compliant patient with persistent symptoms and poor outcome. CASE PRESENTATION: We present the case of a 51-year old Caucasian male patient, diagnosed with celiac disease and CMLNS. Despite his compliance to the gluten-free diet the symptoms persisted and we eventually considered the possible development of malignancy. No mucosal changes suggestive of lymphoma were identified with capsule endoscopy. Low attenuation mesenteric lymphadenopathy, without enlarged small bowel segments were seen on computed tomography. CEUS revealed arterial rim enhancement around the necrotic mesenteric lymph nodes, without venous wash-out. No malignant cells were identified on laparoscopic mesenteric lymph nodes biopsies. The patient died due to fulminant liver failure 14 months later; the histopathological examination revealed CD3/CD30-positive atypical T-cell lymphocytes in the liver, mesenteric tissue, spleen, gastric wall, kidney, lung and bone marrow samples; no malignant cells were present in the small bowel samples. CONCLUSIONS: CEUS findings in EATL complicating CMLNS include arterial rim enhancement of the mesenteric tissue around the cavitating lymph nodes, without venous wash-out. This vascular pattern is not suggestive for neoangiogenesis, as arteriovenous shunts from malignant tissues are responsible for rapid venous wash-out of the contrast agent. CEUS failed to provide a diagnosis in this case.

Risk of intestinal lymphoma in undiagnosed coeliac disease: results from a registered population with different coeliac disease prevalence.

BACKGROUND: Coeliac disease is often undiagnosed, early diagnosis and treatment could be relevant to avoid fearful complications as intestinal lymphoma. Our aim is to estimate the risk of intestinal lymphoma in undiagnosed coeliac patients, evaluating the real incidences and applying different theoretical settings of coeliac prevalence. METHODS: We collected cases of intestinal lymphomas from the Lombardy Cancer Registry and coeliac patients through computerized search of all Pathology Departments; duodenal pathological reports compatible with a Marsh 3 grade were included. The lymphoproliferative risk was calculated for theoretical different settings of coeliac prevalence (from 1:50 to 1:200), relative risks for intestinal lymphomas and compared to the real incidence of the lymphomas in this population. RESULTS: Population consisted in 815,362 inhabitants; during the investigated period of time, 237 intestinal lymphomas and 326 coeliac patients were diagnosed. None of the coeliac patients had lymphoma. In the different scenarios calculated and compared with the real lymphoma incidence the relative risks of undiagnosed celiac disease for gastrointestinal B- and T-cell lymphomas ranges from 1.0 to 2.0 for 1:100 coeliac disease prevalence. CONCLUSIONS: Undiagnosed coeliac patients have no increased risk of developing intestinal lymphoma; population screening programmes, aimed at early diagnosis of lymphoma may not be useful in this setting.

Enteropatía sensible al gluten y dispepsia funcional / Gluten-sensitive enteropathy and functional dyspepsia

La enteropatía sensible al gluten (ESG) cada vez se diagnostica con mayor frecuencia en el adulto, siendo frecuente su presentación con síntomas que en ocasiones se solapan con los de la dispepsia funcional. Se ha descrito una prevalencia de la ESG en la dispepsia entre el 1,2-6,2%, que podría ser superior si se tiene presente todo el espectro de lesiones relacionadas con la sensibilidad al gluten, incluida la enteropatía linfocítica. Un paciente con dispepsia secundaria a ESG podría ser erróneamente diagnosticado de dispepsia funcional, si la endoscopia digestiva alta no se completa con la toma de biopsias de duodeno y se realiza inmunotinción para linfocitos intraepiteliales. Este hecho podría tener importantes consecuencias en términos de morbimortalidad y calidad de vida de los pacientes. En consecuencia, la biopsia de duodeno debería completar el estudio endoscópico del paciente con dispepsia cuando el contexto clínico sugiere una ESG (AU)

Gluten-sensitive enteropathy (GSE) is increasingly diagnosed in adults. The symptoms of this disease can overlap with those of functional dyspepsia. The prevalence of GSE in dyspepsia has been reported to be 1.2-6.2% and could be higher if the entire spectrum of lesions related to gluten sensitivity, including lymphocytic enteropathy, is considered. Patients with dyspepsia secondary to GSE could be mistakenly diagnosed with functional dyspepsia unless upper gastrointestinal endoscopy is completed with duodenal biopsy and immunostaining for intraepithelial lymphocytes. A missed diagnosis could have major consequences in terms of morbidity and mortality and quality of life. Consequently, endoscopic study of patients with dyspepsia should be completed by duodenal biopsy when there are symptoms suggestive of GSE (AU)

Type II enteropathy-associated T-cell lymphoma: a distinct aggressive lymphoma with frequent γδ T-cell receptor expression.

Enteropathy-associated T-cell lymphoma (EATL), an uncommon lymphoma of intestinal intraepithelial T lymphocytes, occurs with a higher frequency in northern Europe due to association with celiac disease. Data on the occurrence of EATL in the Asian population, among whom celiac disease is very rare, are conflicting. This study aimed to characterize EATL encountered in the Chinese population in Hong Kong. Eighteen cases were identified, all fulfilling the criteria of type II rather than classical EATL. The patients, including 13 men and 5 women, had a median age of 62 years. Most presented with small bowel perforation, and there was no history of malabsorption. The clinical course was aggressive, with 14 of 16 patients dying of progressive disease or complications, usually within 1 year. The histologic features were practically identical in all cases. The central zone of the tumor showed ulceration with or without perforation and was characterized by monotonous transmural infiltration of the bowel by small-sized or medium-sized lymphoma cells with few admixed inflammatory cells and no coagulative necrosis. The peripheral zone featured lateral spread of lymphoma cells in the mucosa, accompanied by variable involvement of the submucosa and muscularis. In all cases, there was an intraepithelial lymphocytosis zone contiguous or discontinuous with the peripheral zone, which was characterized by infiltration of the intestinal epithelium by nonatypical small lymphocytes, and not accompanied by other histologic changes of enteropathy. The most common phenotype of the lymphoma cells was CD3+, CD5-, CD4-, CD8+, CD56+, TIA1+, CD30-, and Epstein-Barr virus, and 2 cases showed aberrant expression of CD20. A remarkable finding was that 14 (78%) cases expressed γδ T-cell receptor, and only 6 (33%) expressed αß T-cell receptor (with 3 cases coexpressing both T-cell receptors and 1 case expressing neither). The immunophenotype of the intraepithelial lymphocytes was either discordant (particularly with respect to CD8 and CD56 expressions) or concordant with the lymphoma cells of the corresponding cases. Thus, this study shows that EATL occurring in the Chinese population is exclusively of type II. In contrast to several studies, intraepithelial lymphocytosis can be consistently demonstrated and this component seems to represent a precursor lesion of EATL rather than a manifestation of celiac disease. In view of the differences in epidemiology and clinicopathologic features, we believe it is justified to separate out type II EATL from the EATL category as a distinct form of lymphoma, for which we propose the designation "monomorphic intestinal T-cell lymphoma."

Enteropathy-associated T-cell lymphoma: epidemiology, clinical features, and current treatment strategies.

Enteropathy-associated T-cell lymphoma (EATL) is a rare non-Hodgkin lymphoma of T-cell origin. The recent 2008 World Health Organization classification of hematologic malignancies distinguishes between two types of EATL. The disease is associated with celiac disease, particularly with its late, adult onset. Currently, there are no standardized diagnostic or treatment protocols for EATL, mostly because of its rarity. Historically, the patients have been treated with anthracycline-based chemotherapy with or without surgery. The outcome of patients with EATL treated with these approaches is poor. The reported death rates in the biggest studies are approximately 80-84%, with median progression-free survival (PFS) of 3.4-6.0 months and overall survival of 7.1-10.0 months. The 5-year PFS ranged from 3.2% to 18% and OS from 19.7% to 20%. The results of a novel induction regimen with ifosfamide, etoposide, and epirubicin alternating with intermediate-dose methotrexate followed by autologous stem cell transplantation (ASCT) are more promising, with a 5-year PFS of 52% and OS of 60%. The alternative approach, with a more common induction with cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisone followed by ASCT has also delivered promising results, with a 3-year PFS of 52% and OS of 47%. This review summarizes recently published data on epidemiology and clinical features, as well as standard and novel treatments including high-dose chemotherapy with ASCT and their outcome in EATL.