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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 23-901) 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. [ABSTRACT FROM AUTHOR]

The accumulation of intraepithelial lymphocytes (IELs) is a histopathological feature of canine chronic enteropathy (CE), and IELs are considered the cells of origin of intestinal T-cell lymphoma (ITCL). However, the pathogenic mechanism of IEL activation in CE remains unclear. This study hypothesized that the expression of proinflammatory cytokines, associated with cytotoxic T/NK-cell activation, is upregulated in CE and ITCL, and examined the expression of IFN-γ, IL-2, IL-12p35, IL-12p40, IL-15, and IL-21 and the downstream signal transducers and activators of transcription (STAT) pathway in the duodenal mucosa of dogs without lesions (n = 11; NC), with IEL–CE (n = 19; CE without intraepithelial lymphocytosis), IEL+CE (n = 29; CE with intraepithelial lymphocytosis), and with ITCL (n = 60). Quantitative polymerase chain reaction (PCR) revealed that IFN-γ and IL-21 were higher in IEL+CE than in IEL–CE or NC. Western blot revealed upregulation of STAT1 and STAT3 in IEL+CE. Double-labeling immunohistochemistry revealed a positive correlation between the Ki67 index of CD3+ T-cells and IFN-γ expression levels. Immunohistochemistry revealed a higher ratio of p-STAT1-positive villi in IEL+CE and ITCL than IEL–CE and NC, which positively correlated with IFN-γ expression levels. Among the 60 ITCL cases, neoplastic lymphocytes were immunopositive for p-STAT1 in 28 cases and p-STAT3 in 29 cases. These results suggest that IFN-γ and IL-21 contribute to the pathogenesis of IEL+CE, and IFN-γ may be involved in T-cell activation and mucosal injury in CE. STAT1 and STAT3 activation in ITCL cells suggests a role for the upregulation of the STAT pathway in the pathogenesis of ITCL. [ABSTRACT FROM AUTHOR]

Refractory celiac disease (RCD) and enteropathy-associated T-cell lymphoma (EATL) are rare, yet severe complications of celiac disease (CD). Over the last decades, several studies have addressed the biology and clinical-pathological features of such conditions, highlighting unique disease patterns and recurrent genetic events. Current classification proposals identify two forms of RCD, namely: (i) type 1 RCD (RCD-I), characterized by phenotypically normal intraepithelial lymphocytes (IELs); and (ii) type 2 RCD (RCD-II), featuring phenotypically aberrant IELs. While RCD-I likely represents a glutenindependent dysimmune reaction against small bowel epithelial cells, RCD-II is better considered an in situ aggressive T-cell lymphoma, with high rates of progression to overt EATL. The diagnosis of RCD and EATL is often challenging, due to misleading clinical-pathological features and to significant overlap with several CD-unrelated gastro-intestinal disorders. Similarly, the treatment of RCD and EATL is an unmet clinical need for both gastroenterologists and hematologists. Moving from such premises, this review aims to provide a comprehensive view of RCD and EATL, specifically considering their pathogenesis and the many still open issues concerning their diagnosis and clinical management. [ABSTRACT FROM AUTHOR]

BackgroundCurrent tests for diagnosis and differentiation of lymphoplasmacytic enteritis (LPE) and small cell lymphoma (SCL) in cats are expensive, invasive, and lack specificity. The identification of less invasive, more reliable biomarkers would facilitate diagnosis.ObjectivesTo characterize the mucosal proteome in endoscopically obtained, small intestinal tissue biopsy specimens. We hypothesized that differentially expressed proteins could be identified and serve as biomarker candidates for the differentiation of LPE and SCL in cats.AnimalsSix healthy control cats, 6 cats with LPE, and 8 cats with SCL.MethodsThe mucosal proteome was analyzed using 2-dimensional fluorescence difference gel electrophoresis (2D DIGE) and nanoflow liquid chromatography tandem mass spectrometry. For 5 proteins, results were verified by Western blot analysis.ResultsA total of 2349 spots were identified, of which 9 were differentially expressed with a ≥2-fold change between healthy cats and cats with LPE and SCL (.01 < P

Intestinal perforation is described in coeliac disease in the setting of refractoriness or Enteropathy-Associated T-cell Lymphoma (EATL). We report the case of a man with untreated coeliac disease who presented intestinal perforation and was diagnosed with EATL over one year later. [ABSTRACT FROM AUTHOR]

Refractory celiac disease (RCD) and enteropathy-associated T-cell lymphoma (EATL) are rare, yet severe complications of celiac disease (CD). Over the last decades, several studies have addressed the biology and clinical-pathological features of such conditions, highlighting unique disease patterns and recurrent genetic events. Current classification proposals identify two forms of RCD, namely: (i) type 1 RCD (RCD-I), characterized by phenotypically normal intra-epithelial lymphocytes (IELs); and (ii) type 2 RCD (RCD-II), featuring phenotypically aberrant IELs. While RCD-I likely represents a gluten-independent dysimmune reaction against small bowel epithelial cells, RCD-II is better considered an in situ aggressive T-cell lymphoma, with high rates of progression to overt EATL. The diagnosis of RCD and EATL is often challenging, due to misleading clinical-pathological features and to significant overlap with several CD-unrelated gastro-intestinal disorders. Similarly, the treatment of RCD and EATL is an unmet clinical need for both gastroenterologists and hematologists. Moving from such premises, this review aims to provide a comprehensive view of RCD and EATL, specifically considering their pathogenesis and the many still open issues concerning their diagnosis and clinical management.

BackgroundDifferentiation of lymphocytic-plasmacytic enteropathy (LPE) from small cell lymphoma (SCL) in cats can be challenging.Hypothesis/objectiveHistology-guided mass spectrometry (HGMS) is a suitable method for the differentiation of LPE from SCL in cats.AnimalsForty-one cats with LPE and 52 cats with SCL.MethodsThis is a retrospective clinicopathologic study. Duodenal tissue samples of 17 cats with LPE and 22 cats with SCL were subjected to HGMS, and the acquired data were used to develop a linear discriminate analysis (LDA) machine learning algorithm. The algorithm was subsequently validated using a separate set of 24 cats with LPE and 30 cats with SCL. Cases were classified as LPE or SCL based on a consensus by an expert panel consisting of 5-7 board-certified veterinary specialists. Histopathology, immunohistochemistry, and clonality testing were available for all cats. The panel consensus classification served as a reference for the calculation of test performance parameters.ResultsRelative sensitivity, specificity, and accuracy of HGMS were 86.7% (95% confidence interval [CI]: 74.5%-98.8%), 91.7% (95% CI: 80.6%-100%), and 88.9% (95% CI: 80.5%-97.3%), respectively. Comparatively, the clonality testing had a sensitivity, specificity, and accuracy of 85.7% (95% CI: 72.8%-98.7%), 33.3% (95% CI: 14.5%-52.2%), and 61.5% (95% CI: 48.3%-74.8%) relative to the panel decision.Conclusions and clinical importanceHistology-guided mass spectrometry was a reliable technique for the differentiation of LPE from SCL in duodenal formalin-fixed paraffin-embedded samples of cats and might have advantages over tests currently considered state of the art.

Abstract A 48‐year‐old female patient presented with longstanding unrecognized celiac disease (CD), a family history of CD, and a short duration of alarming symptoms. The diagnostic evaluation revealed the concomitant presence of small and large bowel ulcers raised a dilemma about differential diagnosis in her case. Pathologic examination of tissue specimens from the jejunal ulcer led to the diagnosis of enteropathy‐associated T‐cell lymphoma. In recent years, the availability of modern cross‐sectional imaging and endoscopy modalities has dramatically improved the detection and characterization of small bowel lesions. Characterization of small bowel ulcers by endoscopy and radiology imaging in a patient with suspected complicated CD (CCD) needs to be made in conjunction with all clinical factors, as there is a wide overlap of the possible etiologic factors. Enteropathy‐associated T‐cell lymphoma is a highly aggressive T‐cell lymphoma with a poor prognosis, since early diagnosis and appropriate treatment may be delayed due to nonspecific clinical and endoscopic presentation. Therefore, it is crucial to timely recognize patients with suspected CCD and properly navigate diagnostic imaging tools, acquire adequate biopsy, and perform immunophenotyping to set early diagnosis in patients with diffuse intestinal ulcers and CD.

Refractory celiac disease (RCeD) is a rare complication of celiac disease (CeD) with a severe prognosis. We describe a cohort of patients with RCeD, their clinical and histological features at diagnosis, after therapy and at lymphoma onset, and the rate and causes of death over a 17-year follow-up. We retrospectively enrolled RCeD-I and RCeD-II patients attending our center between January 2002 and October 2019. Medical data were collected at diagnosis and during monitoring. Response to therapy, changes in RCeD molecular markers, number of hospitalizations, discharge diagnosis, and cause and date of death were evaluated. The control cohort consisted of 1015 responsive CeD patients. Compared with RCeD-I, RCeD-II more frequently exhibits diarrhea (83 vs 64%), anemia (61 vs 50%), hypoalbuminemia (70 vs 21%), parenteral nutrition need (48 vs 7%), ulcerative jejuno-ileitis (7 vs 39%), and extended small intestinal atrophy (62 vs 21%). One RCeD-I and six RCeD-II patients developed lymphoma. Ten RCeD-II patients died, four from lymphoma progression. Among RCeD-II patients, atrophy extension was the only parameter correlated with hypoalbuminemia and mortality. Clinical severity, response to therapy, and mortality differ between RCeD-I and RCeD-II. Atrophy extension, evaluated at capsule endoscopy, was associated with disease severity and mortality. [ABSTRACT FROM AUTHOR]

The Asian small-clawed otter (Aonyx cinereus) is an endangered species that is common in zoologic collections. A 17-y-old female Asian small-clawed otter under human care, with a clinical history of chronic renal disease, was euthanized because of deteriorating health. Histologically, the jejunal wall was infiltrated by a monomorphic population of small neoplastic lymphocytes that expanded the lamina propria of the villi and crypts, and on rare occasions invaded the submucosa. The tumor was composed of T cells (CD3+) with a proliferation index of 16%. Based on the World Health Organization (WHO) Classification of Hematopoietic Neoplasms in Domestic Animals, this lymphoma was classified as an enteropathy-associated T-cell lymphoma (EATL) type 2. We also present here a review of the literature on intestinal lymphoma in the subfamily Lutrinae (otters). [ABSTRACT FROM AUTHOR]

Methods: In this retrospective study, we investigated the endoscopic and clinical features of patients with EATLs at a tertiary center, from January 2008 to October 2020. Results: From a total of 248 patients with primary intestinal lymphoma, only 11 patients were finally diagnosed with EATLs, all of which were EATL type II. Men were affected twice as commonly as women. The median patient age was 47 years. The most common initial symptom was diarrhea (63.6%). Five patients (45.4%) were at late stage (IV) at diagnosis. The endoscopic appearances were classified into four distinct types: ulcerative type (54.5%), epithelial mass type (18.2%), diffuse infiltration type (9.1%), and nodular type (18.2%). The small bowel was the most common site of involvement (72.7%). The initial endoscopic impression of lymphoma was made in only 3 patients (27.3%). Only 4 patients (36.4%) were histologically confirmed as having EATLs based on the initial biopsy specimen. Five patients (45.5%) received emergency surgery. The median overall survival (OS) was 8 months. The use of chemotherapy and the absence of emergency surgery were associated with a significantly better median OS (P < 0.05). Conclusions: EATL may show various endoscopic appearances, and its prognosis is poor. Endoscopists should obtain more knowledge of EATL in order to make an early diagnosis.

Background & Aims: Refractory celiac disease type II (RCDII) is a rare indolent lymphoma in the small intestine characterized by a clonally expanded intraepithelial intracellular CD3+surfaceCD3-CD7+CD56- aberrant cell population. However, RCDII pathogenesis is ill-defined. Here, we aimed at single-cell characterization of the innate and adaptive immune system in RCDII. Methods: Paired small intestinal and blood samples from 12 RCDII patients and 6 healthy controls were assessed by single-cell mass cytometry with a 39–cell surface marker antibody panel, designed to capture heterogeneity of the innate and adaptive immune system. A second single-cell mass cytometry panel that included transcription factors and immune checkpoints was used for analysis of paired samples from 5 RCDII patients. Single-cell RNA sequencing analysis was performed on duodenal samples from 2 RCDII patients. Finally, we developed a 40-marker imaging mass cytometry antibody panel to evaluate cell–cell interactions in duodenal biopsy specimens of RCDII patients. Results: We provide evidence for intertumoral and intratumoral cell heterogeneity within the duodenal and peripheral aberrant cell population present in RCDII. Phenotypic discrepancy was observed between peripheral and duodenal aberrant cells. In addition, we observed that part of the aberrant cell population proliferated and observed co-localization of aberrant cells with CD163+ antigen-presenting cells (APCs) in situ. In addition, we observed phenotypic discrepancy between peripheral and duodenal aberrant cells. Conclusions: Novel high-dimensional single-cell technologies show substantial intertumoral and intratumoral heterogeneity in the aberrant cell population in RCDII. This may underlie variability in refractory disease status between patients and responsiveness to therapy, pointing to the need for personalized therapy in RCDII based on patient-specific immune profiles.

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 (

Flow cytometry of intestinal lymphocytes is discussed to be a stronger predictor of enteropathy-associated T-cell lymphoma development in refractory celiac disease than T-cell clonality analysis. To investigate possible associations between clinical characteristics of refractory celiac disease patients and aberrant intraepithelial lymphocytes and to evaluate the accuracy of immunophenotyping for the identification of high-risk refractory celiac disease. Flow cytometry of isolated lymphocytes from duodenal biopsies of controls and celiac disease patients was performed and results were compared to clinical data. Flow cytometry analysis was performed on 42 controls, 37 non-complicated celiac disease and 30 refractory celiac disease cases with or without T-cell receptor clonality. Elevated aberrant intraepithelial lymphocyte counts were significantly associated with severe malabsorption. A 15% cut-off (aberrant lymphocytes among all lymphocytes) had the best discriminatory ability to identify high-risk patients. However, this technique failed to identify some high-risk cases (sensitivity 63%, specificity 100%). The severity of malabsorption was added to the criteria for high-risk refractory celiac disease, improving the correct patients' allocation (sensitivity 100%, specificity 96%). Immunophenotyping of aberrant intraepithelial lymphocytes is a good predictor for high-risk refractory celiac disease. Furthermore, adding the evaluation of malabsorption to the diagnostic assessment of refractory celiac disease optimizes accuracy. [ABSTRACT FROM AUTHOR]

The purpose of this expert review is to summarize the diagnosis and management of refractory celiac disease. It will review evaluation of patients with celiac disease who have persistent or recurrent symptoms, differential diagnosis, nutritional support, potential therapeutic options, and surveillance for complications of this condition. This expert review was commissioned and approved by the American Gastroenterological Association (AGA) Institute Clinical Practice Updates Committee (CPUC) and the AGA Governing Board to provide timely guidance on a topic of high clinical importance to the AGA membership and underwent internal peer review by the CPUC and external peer review through standard procedures of Gastroenterology. These Best Practice Advice (BPA) statements were drawn from a review of the published literature and from expert opinion. Since systematic reviews were not performed, these BPA statements do not carry formal ratings of the quality of evidence or strength of the presented considerations. Best Practice Advice Statements In patients believed to have celiac disease who have persistent or recurrent symptoms or signs, the initial diagnosis of celiac disease should be confirmed by review of prior diagnostic testing, including serologies, endoscopies, and histologic findings. In patients with confirmed celiac disease with persistent or recurrent symptoms or signs (nonresponsive celiac disease), ongoing gluten ingestion should be excluded as a cause of these symptoms with serologic testing, dietitian review, and detection of immunogenic peptides in stool or urine. Esophagogastroduodenoscopy with small bowel biopsies should be performed to look for villous atrophy. If villous atrophy persists or the initial diagnosis of celiac disease was not confirmed, consider other causes of villous atrophy, including common variable immunodeficiency, autoimmune enteropathy, tropical sprue, and medication-induced enteropathy. For patients with nonresponsive celiac disease, after exclusion of gluten ingestion, perform a systematic evaluation for other potential causes of symptoms, including functional bowel disorders, microscopic colitis, pancreatic insufficiency, inflammatory bowel disease, lactose or fructose intolerance, and small intestinal bacterial overgrowth. Use flow cytometry, immunohistochemistry, and T-cell receptor rearrangement studies to distinguish between subtypes of refractory celiac disease and to exclude enteropathy-associated T-cell lymphoma. Type 1 refractory celiac disease is characterized by a normal intraepithelial lymphocyte population and type 2 is defined by the presence of an aberrant, clonal intraepithelial lymphocyte population. Consultation with an expert hematopathologist is necessary to interpret these studies. Perform small bowel imaging with capsule endoscopy and computed tomography or magnetic resonance enterography to exclude enteropathy-associated T-cell lymphoma and ulcerative jejunoileitis at initial diagnosis of type 2 refractory celiac disease. Complete a detailed nutritional assessment with investigation of micronutrient and macronutrient deficiencies in patients diagnosed with refractory celiac disease. Check albumin as an independent prognostic factor. Correct deficiencies in macro- and micronutrients using oral supplements and/or enteral support. Consider parenteral nutrition for patients with severe malnutrition due to malabsorption. Corticosteroids, most commonly open-capsule budesonide or, if unavailable, prednisone, are the medication of choice and should be used as first-line therapy in either type 1 or type 2 refractory celiac disease. Patients with refractory celiac disease require regular follow-up by a multidisciplinary team, including gastroenterologists and dietitians, to assess clinical and histologic response to therapy. Identify local experts with expertise in celiac disease to assist with management. Patients with refractory celiac disease without response to steroids may benefit from referral to a center with expertise for management or evaluation for inclusion in clinical trials. [ABSTRACT FROM AUTHOR]

DUSP22 gene rearrangements are recurrent in systemic and cutaneous ALK-negative anaplastic large cell lymphomas, rarely encountered in other cutaneous CD30+ lymphoproliferations, and typically absent in other peripheral T-cell lymphomas. We report the case of a 51-year-old woman, with longstanding celiac disease and a rapidly enlarging leg ulcer, due to a DUSP22-rearranged CD30+ T-cell lymphoproliferation. Subsequent history revealed an intestinal enteropathy-associated T-cell lymphoma (EATL). Identical monoclonal TR gene rearrangements and mutations in STAT3 and JAK1 typical of EATL were present in the cutaneous and intestinal lesions. No DUSP22 rearrangement was detected in the patient's intestinal tumour, nor in 15 additional EATLs tested. These findings indicate that DUSP22 rearrangements are not entirely specific of ALCLs, may rarely occur as a secondary aberration in EATL, and expand the differential diagnosis of DUSP22-rearranged cutaneous CD30+ lymphoproliferative disorders. [ABSTRACT FROM AUTHOR]

Thiopurine exposure from inflammatory bowel disease (IBD) treatment had been associated with a higher risk of lymphoproliferative disorders namely peripheral T-cell lymphoma, as early as 2 years after its initiation. We report a rare case of classical or type 1 enteropathy-associated T-cell lymphoma (EATL) with liver metastasis in a longstanding Crohn’s disease 61-year-old patient treated with azathioprine monotherapy. He presented with acute, severe abdominal pain with cholestatic jaundice and pancytopenia. Colonoscopy showed multiple small, superficial ulcers at the terminal ileum and the biopsy taken was reported as classical EATL, an uncommon gastrointestinal non- Hodgkin’s lymphoma with CD2, CD 3, CD 30 and CD 56 positivity and more than 90% Ki67 proliferative index. Computed tomography (CT) 3-phase liver scan suggested liver metastasis. This case highlights the unusual presentation of classical EATL in non-celiac disease patients and its risk association with thiopurine therapy in IBD. [ABSTRACT FROM AUTHOR]

Enteropathy-associated T cell lymphoma (EATL) is a lethal, and the most common, neoplastic complication of celiac disease. Here, we defined the genetic landscape of EATL through whole-exome sequencing of 69 EATL tumors. SETD2 was the most frequently silenced gene in EATL (32% of cases). The JAK-STAT pathway was the most frequently mutated pathway, with frequent mutations in STAT5B as well as JAK1, JAK3, STAT3, and SOCS1 We also identified mutations in KRAS, TP53, and TERT Type I EATL and type II EATL (monomorphic epitheliotropic intestinal T cell lymphoma) had highly overlapping genetic alterations indicating shared mechanisms underlying their pathogenesis. We modeled the effects of SETD2 loss in vivo by developing a T cell-specific knockout mouse. These mice manifested an expansion of γδ T cells, indicating novel roles for SETD2 in T cell development and lymphomagenesis. Our data render the most comprehensive genetic portrait yet of this uncommon but lethal disease and may inform future classification schemes.

Abstract Background Current tests for diagnosis and differentiation of lymphoplasmacytic enteritis (LPE) and small cell lymphoma (SCL) in cats are expensive, invasive, and lack specificity. The identification of less invasive, more reliable biomarkers would facilitate diagnosis. Objectives To characterize the mucosal proteome in endoscopically obtained, small intestinal tissue biopsy specimens. We hypothesized that differentially expressed proteins could be identified and serve as biomarker candidates for the differentiation of LPE and SCL in cats. Animals Six healthy control cats, 6 cats with LPE, and 8 cats with SCL. Methods The mucosal proteome was analyzed using 2‐dimensional fluorescence difference gel electrophoresis (2D DIGE) and nanoflow liquid chromatography tandem mass spectrometry. For 5 proteins, results were verified by Western blot analysis. Results A total of 2349 spots were identified, of which 9 were differentially expressed with a ≥2‐fold change between healthy cats and cats with LPE and SCL (.01 < P

Methods: In this retrospective study, we investigated the endoscopic and clinical features of patients with EATLs at a tertiary center, from January 2008 to October 2020. Results: From a total of 248 patients with primary intestinal lymphoma, only 11 patients were finally diagnosed with EATLs, all of which were EATL type II. Men were affected twice as commonly as women. The median patient age was 47 years. The most common initial symptom was diarrhea (63.6%). Five patients (45.4%) were at late stage (IV) at diagnosis. The endoscopic appearances were classified into four distinct types: ulcerative type (54.5%), epithelial mass type (18.2%), diffuse infiltration type (9.1%), and nodular type (18.2%). The small bowel was the most common site of involvement (72.7%). The initial endoscopic impression of lymphoma was made in only 3 patients (27.3%). Only 4 patients (36.4%) were histologically confirmed as having EATLs based on the initial biopsy specimen. Five patients (45.5%) received emergency surgery. The median overall survival (OS) was 8 months. The use of chemotherapy and the absence of emergency surgery were associated with a significantly better median OS (P < 0.05). Conclusions: EATL may show various endoscopic appearances, and its prognosis is poor. Endoscopists should obtain more knowledge of EATL in order to make an early diagnosis. [ABSTRACT FROM AUTHOR]

Human enteropathy-associated T-cell lymphoma (EATL) is considered to be derived from intraepithelial lymphocytes (IELs); however, the origin of canine intestinal T-cell lymphoma (ITCL) remains unclear. Histological, immunohistochemical, and clonality examinations were performed using endoscopically collected canine duodenum samples of mucosal lesions of chronic enteropathy (CE; 73 cases) and ITCL without transmural neoplastic mass lesions (64 cases). Histopathological examinations revealed the intraepithelial accumulation of lymphocytes (called "intraepithelial lymphocytosis") in 54/73 CE cases (74%) and the epitheliotropism of neoplastic lymphocytes in 63/64 ITCL cases (98%). Immunohistochemically, IELs in CE with intraepithelial lymphocytosis (IEL+CE) were diffusely immunopositive for CD3, with scattered immunopositivity for CD5, CD8, CD20, and granzyme B (GRB). The percentage of CD8+ in CD3+ IELs was significantly lower in IEL+CE than in CE without intraepithelial lymphocytosis (IEL−CE). Double-labeling immunohistochemistry revealed a high percentage of GRB expression in CD8− IEL among IEL+CE. Among 64 ITCL cases, CD3 was immunopositive in 64 (100%), CD5 in 22 (34%), CD8 in 8 (13%), CD20 in 12 (19%), CD30 in 13 (20%), and GRB in 49 (77%). In CD3+ cells, Ki67 immunopositivity was highest in ITCL, intermediate in IEL+CE, and lower in IEL−CE. A clonal TCR gene rearrangement was detected in 1/19 IEL−CE cases (5%), 15/54 IEL+CE (28%), and 38/58 ITCL (66%). These results indicate that the immunophenotype of canine ITCL (CD8−GRB+) is similar to that of the increased IELs in CE. The high proliferative activity and clonality of T cells in IEL+CE suggest that canine ITCL originates from these IELs, similar to human EATL. [ABSTRACT FROM AUTHOR]

Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL), also known as type II enteropathy-associated T-cell lymphoma, is a rare malignant lymphoma of the extranodal lymphoid tissue derived from interepithelial T lymphocytes. MEITL is a primary intestinal T-cell lymphoma with a challenging diagnosis and aggressive progression, and it can invade other extraintestinal sites. In this study, we report four patients diagnosed with MEITL. All patients presented with abdominal pain, and one patient was admitted because of acute intestinal perforation. Two patients presented with unformed defecation and diarrhea. All patients carried the immunophenotypes CD3, CD7, CD8, CD20, and CD56, and the Ki-67 index ranged 60% to 90%. Three cases were analyzed using next-generation sequencing. One case displayed possibly relevant alterations of CREBBP, NOTCH2, SETD2, and STAT5B, and another case exhibited definite alteration of NOTCH1, possibly relevant alterations of CCND1 and DNMT3A, and potentially relevant alterations of HISTH3B, IGLL5, KMT2C, and KRAS. Different chemotherapy regimens were used, but the prognosis was poor. Hence, we illustrated that because of its low incidence, challenging diagnosis, and difficult treatment, further therapeutic improvements are urgently warranted., Competing Interests: Declaration of conflicting interestsThe authors report no conflicts of interest in this work.

The intestinal T-cell lymphomas are a rare group of lymphatic malignancies arising from the gastrointestinal tract. They frequently manifest with non-specific clinical and radiographic findings that may mimic several other disease processes. The most common subtype is linked with refractory coeliac disease and commonly affects the small intestine. We report a case where the diagnosis was uncovered endoscopically in a patient presenting with colonic perforation on a background of long-standing ulcerative colitis. Surgical source control was required prior to considering chemotherapy, which is the usual treatment option in lymphatic malignancies. The case highlights the importance endoscopic evaluation in inflammatory conditions of the colon. [ABSTRACT FROM AUTHOR]