Enteropathy-associated T-cell Lymphoma Type Research Articles

Flowcytometric data of intermediate-large cell gastrointestinal lymphoma presenting a gross mass in 32 cats - "let them glow in the flow".

Gastrointestinal lymphoma is the most common form of lymphoma in domestic cats. Aggressive phenotypes are much less common but do bear and unfavorable prognosis. Immunophenotyping by flow cytometry (FCM) is not systematically performed in these patients, because of difficulties in the acquisition of suitable sample material from the gastrointestinal tract. A multimodal diagnostic approach is recommended to improve identification of subtypes targeting patient tailored therapeutic strategies. The aim of this prospective study was to present results of multicolor FCM immunophenotyping in surgically removed gastrointestinal mass and relate them with histopathology using the World Health Organization (WHO) classification and clonality PCR testing. Thirty-two patients were included. Eight cats (25%) had gastric, 23 (72%) had intestinal lymphoma and 1 (3%) had gastric/jejunal lymphoma. Intestinal lymphoma sites were represented by 18 small intestinal, 4 ileocaecal, 1 large intestinal. All gastric lymphomas were diffuse large B-cell lymphoma (DLBCL). Small intestinal lymphomas were 10 enteropathy associated T-cell lymphoma type I (EATL I), 2 enteropathy associated T-cell lymphoma type II (EATL II), 2 peripheral T-cell lymphoma (PTCL), 3 DLBCL and one DLBCL+EATL II. The most common small intestinal FCM T-cell phenotype was CD3+CD21- CD4-CD8-CD18+ CD5-CD79- in 7/10 EATL I and one EATL II. The most frequent FCM B-cell phenotype was CD3-CD21+ CD4-CD8-CD18+ CD5-CD79+ in 13/17 DLBCL and the DLBCL+EATL II. Clonality PCR results were positive in 87.5% (28/32) of all cases. No cross-lineage rearrangement was observed. IHC and FCM results agreed in 87.5% (28/32) of all cases. When all 3 methods were combined, consistent results were seen in 75% (24/32). This is the first demonstration of a multicolor FCM approach set in context to the gold standard histopathology and clonality testing results.

Histologic characterization of the major duodenal papilla and association with concurrent biliary, pancreatic, and intestinal pathology in cats.

Conjoining of the major pancreatic duct and common bile duct at the major duodenal papilla (MDP) is suspected to predispose cats to the clinical syndrome of "triaditis." However, microanatomy of the MDP or presence of lesions at the MDP has not been assessed in cats with or without triaditis. The aims of this study were to characterize feline MDP histomorphology and to identify associations between MDP anatomy/disease and the presence of biliary, pancreatic, or intestinal inflammation or neoplasia. Histologic assessment was prospectively performed on the MDP, duodenum, jejunum, ileum, liver, and pancreas from 124 client-owned cats undergoing postmortem examination. The majority of cats (104/124, 84%) had a complex ductular network at the MDP, with no distinction between pancreatic and common bile ducts. Lymphoid aggregates at the MDP were common (63/124, 51%). Inflammation of the MDP (MDPitis) was present in 35 of 124 cats (28%) and was often concurrent with cholangitis, pancreatitis, or enteritis (32/35, 91%), but was only associated with enteritis (19/35, 54%, P < .05). Triaditis was less common (19/124, 15%), but was associated with both conjoined MDP anatomy (19/19, 100%, P < .05) and MDPitis (12/19, 63%, P < .05). Neoplasia was present in 37 of 124 cats (29%), with lymphoma (28/37, 78%) predominating. Enteropathy-associated T-cell lymphoma type 2 (EATL2) was most common (n = 16/37, 43%) and was associated with triaditis and MDPitis (P < .05). These findings suggest that anatomy, immune activation, and/or inflammation of the MDP may play a role in the pathogenesis of triaditis. Further studies are needed to elucidate the relationships between triaditis, MDPitis, and EATL2.

Classificação do linfoma em gatos e sua relação com a detecção do DNA pró-viral do vírus da leucemia felina

ABSTRACT: In this retrospective and prospective study, histopathological and immunohistochemical analyses of 62 cases of lymphomas in cats were performed to classify the anatomic forms and subtypes, according to the WHO guidelines, and correlate it to FeLV proviral DNA detected using PCR. The most common anatomical form was gastrointestinal (40.3%, 25/62), followed by multicentric (29%, 18/62), mediastinal (17.7%, 11/62) and extranodal (12,9%, 8/62). Among the lymphoma subtypes, diffuse large B-cell lymphoma (DLBCL) (30.6%, 19/62) was the most commonly diagnosed followed by peripheral T-cell lymphoma (PTCL) (29%, 18/62) and enteropathy associated T-cell lymphoma type 2 (14.5%, 9/62). DNA extraction from paraffin-embedded neoplastic tissue was obtained in 28 cases and FeLV proviral DNA was detected by PCR, in 23 of these. Of the cases presenting with FeLV proviral DNA, nine (32%) were of the multicentric form, five (22%) of the mediastinal and extranodal forms and four (17%) of the gastrointestinal form. The most frequent subtypes with FeLV proviral DNA, independent of the anatomical form, were DLBCL (39.1%, 9/23) and PTCL (34.7%, 8/23). The presence of the FeLV proviral DNA in 23 cats of this study, probably had association with the multicentric form of lymphoma and higher occurrence in the DLBCL and PTCL subtypes.

Proliferation Activity in Canine Gastrointestinal Lymphoma

Gastrointestinal lymphomas are uncommon in dogs and little is known about their distinct subtypes or proliferation rate. The aim of this study was to stratify 33 canine gastrointestinal lymphoma samples according to the latest World Health Organization classification and to determine the Ki67 proliferation index by manual counting, digital image analysis and visual estimation. The Ki67 index was then correlated with subtype, immunophenotype, mitotic index, grade and tumour location. The mitotic index correlated positively with the Ki67 index. A significantly higher number of Ki67-positive cells was found in enteropathy-associated T-cell lymphoma type I and in diffuse large B-cell lymphoma compared with enteropathy-associated T-cell lymphoma type II. There was also a significant difference in Ki67 immunolabelled cells between grade 1 and grade 2 lymphomas. Moderate agreement was found between the Ki67 index as obtained by manual counting and visual estimation, but there was strong agreement between manual counting and digital image analysis. The user-friendly digital imaging system used in this study could have potential for future determination of the Ki67 index in lymphoid neoplasms.

Equine Intestinal Lymphoma: Clinical-Pathological Features, Immunophenotype, and Survival

Lymphoma is the most common intestinal neoplasm in horses, but its clinical-pathological features are poorly characterized. Primary intestinal lymphoma was diagnosed in 20 horses on biopsy samples and further confirmed by postmortem examination in 16 cases. Lymphoma was found in the small intestine in 12 of 20 (60%), in the colon in 5 of 20 (25%), and in both small and large intestines in 3 of 20 (15%) cases. Gross findings included thickening of the intestinal wall (45%), mural nodules or masses (30%), and both thickening and nodules (10%). Cases were classified according to the human World Health Organization classification as enteropathy-associated T-cell lymphoma (EATL) type 1 (40%), EATL type 2 (45%), and T-cell-rich large B-cell lymphoma (TCRLBCL) (15%). With respect to histologic grade, 70% of cases were grade 1 and 30% were grade 2. Of EATLs, the infiltrate was mucosal only (12%), mucosal and submucosal (53%), or transmural (35%). EATL1 was submucosal to transmural (2/8 and 6/8), EATL2 was mucosal to submucosal (3/9 and 6/9), and TCRLBCL was always transmural. Epitheliotropism was present in most EATLs and characterized by single-cell infiltrates within the epithelium in EATL1 and intraepithelial clusters or plaques in EATL2. Median survival was 25 days for EATL1, 90 days for EATL2, and 187.5 days for TCRLBCL; differences were not statistically significant. Of the EATLs, grade 1 had a median survival of 60 days and grade 2 had a median survival of 25 days; differences were not statistically significant.

Anaplastic Large T-Cell Lymphoma in the Intestine of Dogs.

Anaplastic large T-cell lymphoma (ALTCL) is a rare subtype of non-Hodgkin T-cell lymphoma that occasionally occurs in the gastrointestinal tract of humans. Enteropathy-associated T-cell lymphoma (EATL) type 1 is the most common type of intestinal lymphoma in dogs, and ALTCL has not previously been reported in the intestinal tract of dogs. Thirteen dogs with intestinal masses diagnosed as intestinal lymphoma with anaplastic morphology were reviewed. Clinical data, including treatment protocols, were available for 11 cases. Immunohistochemistry for CD3, CD20, and CD30 was performed for all cases in addition to PCR for Antigen Receptor Rearrangements (PARR) for assessment of clonality. Eight (62%) of the cases presented with intestinal perforation, and all cases had 1 or more masses arising from the small intestine. Histologically, all cases were characterized by transmural infiltrates of large, CD3-positive and frequently CD30-positive cells. Neoplastic T cells had marked anisocytosis and anisokaryosis, prominent nucleoli, and occasionally indented to reniform nuclei. There was abundant necrosis and inflammation with occasional vascular invasion within neoplastic masses. All cases had a monoclonal T-cell receptor γ gene rearrangement. The median survival time was 5 days, with 1 dog surviving 2 years after the initial diagnosis. ALTCL can occur as an aggressive transmural lymphoma in the gastrointestinal tract of dogs and commonly causes intestinal perforation. ALTCL can be differentiated from EATL type 1 and might have implications for accurate prognostication and selection of therapeutic options in the future.

Immunohistochemical Profiling of Canine Intestinal T-Cell Lymphomas.

Human enteropathy-associated T-cell lymphoma (EATL) is classified into 2 distinct subgroups based on their phenotypes (type I and type II). Canine intestinal T-cell lymphoma can be morphologically classified into large and small cell lymphomas (LCL and SCL, respectively). Their association with human EATL or immunohistochemical and biological features has not been well characterized. In this study, the immunohistochemical profiles of 17 cases of LCL and 33 cases of SCL were evaluated with markers used for human EATL classification. Morphologically, LCL was characterized by sheet-like proliferation of large to moderately sized neoplastic lymphocytes, with scant clear cytoplasm and pleomorphic, irregularly shaped nuclei containing distinctive nucleoli and scattered chromatin. In contrast, SCL was characterized by the proliferation of monomorphic small neoplastic lymphocytes, accompanied by infiltration of nonneoplastic plasma cells. Interestingly, 8 cases demonstrated mixed LCL and SCL morphologies. Granular cytoplasmic expression of granzyme B was observed in most LCL and SCL cases. Membranous expression of CD56 was demonstrated in only 2 of 17 LCL and 0 of 33 SCL cases. Coexpression of CD20 by neoplastic T cells was observed in more SCL cases (16/33; 48%) than LCL cases (1/17; 6%). The CD56-positive cells in 2 cases were negative for CD20. Although canine LCL shares common features with human EATL type I, canine SCL cells and human EATL type II differ in their immunophenotype. Canine intestinal T-cell lymphoma had a homogeneous immunophenotype regardless of cell morphology. The findings of this study may indicate large cell transformation of SCL rather than 2 distinct entities.

Tu1263 - Alterations in the Proteomic, Microbiome, and Metabolomic Profile in Cats with Inflammatory Bowel Disease and Enteropathy-Associated T-Cell Lymphoma type 2

Tu1263 - Alterations in the Proteomic, Microbiome, and Metabolomic Profile in Cats with Inflammatory Bowel Disease and Enteropathy-Associated T-Cell Lymphoma type 2

World Health Organisation Classification of Lymphoid Tumours in Veterinary and Human Medicine: a Comparative Evaluation of Gastrointestinal Lymphomas in 61 Cats

To diagnose and classify the various entities of lymphomas, the World Health Organisation (WHO) classification is applied in human as well as in veterinary medicine. We validated the concordance of these classification systems by having a veterinary and human pathologist evaluate gastrointestinal lymphoma tissue from 61 cats. In 59% of all cases, there was a match between their respective diagnoses of the lymphoma subtype. A complete consensus between the two evaluators was obtained for all samples with a diagnosis of diffuse large B-cell lymphoma, T-cell anaplastic large cell lymphoma and extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue. A corresponding diagnosis was also made in the majority of samples with enteropathy associated T-cell lymphoma (EATL) type II, although this subtype in cats has similarities to the 'indolent T-cell lymphoproliferative disorder of the gastrointestinal tract', a provisional entity newly added to the revised human WHO classification in 2016. Very little consensus has been found with cases of EATL type I due to the fact that most did not meetall of the criteria of human EATL I. Hence, the human pathologist assigned them to the heterogeneous group of peripheral T-cell lymphomas (not otherwise specified). Consequently, concrete guidelines and advanced immunophenotyping based on the model of human medicine are essential to differentiate these challenging entities in veterinary medicine.

Significance of clonal rearrangements of lymphocyte antigen receptor genes on the prognosis of chronic enteropathy in 22 Shiba dogs

Shiba dogs are predisposed to chronic enteropathy (CE) and have poorer prognosis than other dog breeds. The objective of this study was to investigate the significance of polymerase chain reaction for antigen receptor rearrangement (PARR) results on clinical findings and prognosis of Shiba dogs with CE. We retrospectively collected data on 22 Shiba dogs diagnosed as having CE. Fifty-nine percent of the dogs had clonality-positive results on PARR analysis. Furthermore, on histopathology, epitheliotropic behavior of small lymphocytes of the intestinal mucosa was observed significantly more frequently in dogs with clonal rearrangement of antigen receptor genes (P=0.027). The median overall survival time of clonality-positive dogs was 48 days (range, 4–239 days), compared to 271 days (range, 45–1,316+ days) in clonality-negative dogs. The median overall survival time of epitheliotropism-positive dogs was 76 days (range, 30–349 days) compared to 239 days (range, 4–1,316+ days) for epitheliotropism-negative dogs. Statistical analysis revealed that the clonality-positive result was associated with significantly shorter survival time (P=0.036). In contrast, presence or absence of epitheliotropism had no statistically significant effect on survival time (P=0.223). These cases might appropriately be diagnosed as small T-cell intestinal lymphoma; there are some common clinical and pathogenic features with human enteropathy-associated T-cell lymphoma type 2. The pathogenesis and poor prognosis for Shiba dogs with CE seem to be associated with this type of lymphoma, although further investigation is warranted.

Outcome of Patients with Peripheral T-Cell Lymphoma Undergoing Allogeneic Stem Cell in British Columbia

Background:Peripheral T-cell lymphomas (PTCL) are a rare and heterogeneous group of non-Hodgkin lymphomas (NHLs) that accounts for approximately 10% of all aggressive NHLs in Western countries. The optimal management remains unclear, however, given the poor outcome, allogeneic transplant (allo-SCT) has been integrated into the front-line treatment for some rare extranodal subtypes as well in relapsed/refractory setting. We report our provincial experience of the outcome of patients with PTCL who have undergone allo-SCT at the British Columbia Cancer Agency (BCCA).Methods:The Leukemia/BMT Program of British Columbia database and the BCCA Lymphoid Cancer Database were searched to identify all patients diagnosed with PTCL who have undergone allo-SCT between November 1990 and January 2016. Overall survival and relapse free survival were estimated using the Kaplan-Meier method.Results:We identified 36 cases of PTCL patients who have undergone allogeneic transplant from a median time of 11 months from primary diagnosis (range 4-64) with the following clinical features: median age at transplant was 45 years (range 16-58 years); 24 (67%) were male; 32 (89%) patients had advanced stage disease; 22 (61%) had B-symptoms at diagnosis. Bone marrow involvement detected in 13/34 (38%) patients. Histological diagnosis based on the WHO 2008 classification were: Peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) n=15 (42%); anaplastic large cell lymphoma (ALCL) n=7 (19%) out of which three were ALK positive, angioimmunoblastic T-cell lymphoma (AITL) n=6 (17%), hepatosplenic T-cell lymphoma n=5 (14%), enteropathy associated T-cell lymphoma type I n=1, advanced primary cutaneous gamma-delta T-cell lymphoma n=1 and Sezary syndrome n=1. Ten patients (28%) underwent allo-SCT as part of planned primary therapy after achieving their first remission [6 were in complete remission 1 (CR1) and 4 were in partial remission 1 (PR1)], whereas 26 patients (72%) underwent allo-SCT for relapsed/refractory disease. CHOP was administered in 19 patients (53%) as the primary therapy. 17 (47%) patients received alternative chemotherapy regimen due to patient and/or physician preference. The clinical status at the time of transplantation was CR in 12 patients (33%), relapsed sensitive disease n=10 (28%), relapsed untreated n=5 (14%), partial remission (PR) in 5 (14%), primary progressive disease n=3 (8%) and relapsed resistant disease n=1 (3%).Thirty two patients (89%) underwent myeloablative conditioning, 4 (11%) underwent reduced intensity conditioning (RIC). The conditioning regimens included: cyclophosphamide/TBI n=24 (67%), busulfan/cyclophosphamide n=5 (14%), fludarabine containing reduced intensity n=4 (11%), and other regimens n= 3 (8%). With a median follow-up of alive patients from the time of allo-SCT of 69 months (range 1-186 months). At last follow-up, 17 (47%) patients have died, 6 from disease relapse, 5 from graft vs host disease (GVHD), 2 from regimen related toxicity and 4 from other causes. Nineteen patients (53%) still alive at last follow up post-transplant of which 14 (39%) still in remission. The 5-year event free survival (EFS) and overall survival (OS) from the time of allo-SCT of all patients were 43% and 63%, respectively. For PTCL-NOS the 5-year EFS and OS were 52% and 69%, respectively. Table 1 summarizes the patients' characteristics. Figures 1 and 2 shows the Kaplan-Meier curves for OS and EFS respectively.Conclusion:Allo-SCT can be effective strategy in select patients with relapsed/refractory PTCL and those with high risk histologies in the upfront setting PTCL with an acceptable toxicity. [Display omitted] [Display omitted] [Display omitted] DisclosuresToze:Roche Canada: Research Funding. Sehn:roche/genentech: Consultancy, Honoraria; amgen: Consultancy, Honoraria; seattle genetics: Consultancy, Honoraria; abbvie: Consultancy, Honoraria; TG therapeutics: Consultancy, Honoraria; celgene: Consultancy, Honoraria; lundbeck: Consultancy, Honoraria; janssen: Consultancy, Honoraria. Scott:NanoString Technologies: Patents & Royalties: named inventor on a patent for molecular subtyping of DLBCL that has been licensed to NanoString Technologies. Villa:Lundbeck: Honoraria; Roche: Honoraria, Research Funding; Celgene: Honoraria. Connors:NanoString Technologies: Research Funding; F Hoffmann-La Roche: Research Funding; Bristol Myers Squib: Research Funding; Seattle Genetics: Research Funding; Millennium Takeda: Research Funding. Song:Janssen: Honoraria; Otsuka: Honoraria; Celgene: Honoraria, Research Funding.

Primary Intestinal Malignant Lymphomas Associated With Celiakia – A Pathologist´s Review

Celiakia represents a prototype of chronic antigenic stimulation and autoimmune dysregulation leading to the accumulation of reactive cytotoxic intraepithelial lymphocytes (IEL) and small intestinal mucosal injury. These lymphocytes possess a potential of transformation, gaining an aberrant phenotype and genotype during their clonal expansion. The development of type I enteropathy –associated T-cell lymphoma (EATL) in patients with celiac disease might represent a gradual multistep transformation process starting from the increasing accumulation of IEL, and developing through the refractory celiac disease I and refractory celiac disease II, the last representing probably a lymphoma in situ. These transformational stages of the progressing celiac disease are showing increasing risk of type I EATL development, and decreasing survival of the patients. The whole process of progressing EATL lymphomagenesis resembles the hyperplasia-adenoma-dysplasia-adenocarcinoma sequence of colorectal carcinomas. Similar to the already more understood multistep developmental process from CD to type I EATL, an overt type II EATL lymphoma might represent a final step in a process of progression from IEL, representing the lymphoma precursors. However, the patients with the type II lymphoma show signs of celiakia neither clinically nor morphologically and the pathogenetical link to CD is missing. The lymphomagenesis of EATL type II seems to utilize activation of other pathways than that of type I. The recent data support the attempts to set apart the type II from the EATL category and to rename it.

Enteropathy-Associated T-Cell Lymphoma: A Single Centre Experience

Introduction: Enteropathy-associated T-cell Lymphoma (EATL) is a rare lymphoma of the GI tract accounting for less than 1% of all non-Hodgkin's lymphomas (NHL). EATL type I is seen predominately in patients (pts) from parts of Europe associated with a high incidence of celiac disease; type II is less frequently associated with celiac disease and thus a more worldwide distribution. EATL is difficult to treat with very poor prognosis. The purpose of this study is to understand the epidemiology and outcomes of this rare lymphoma in a North American multicultural setting at a tertiary cancer care centre.Methods: All pts with EATL who were assessed and treated at Princess Margaret Cancer Centre in Toronto, Canada, between January 1, 1996 and January 30, 2015 were retrospectively reviewed with case ascertainmentfrom a pathology database as well as a prospectively populatedlymphoma database. Pathological diagnoses were made according to the WHO classification and central pathology review was undertaken when available. Staging procedures included CT scans and bone marrow biopsy. Simple descriptive statistics were calculated as well as progression-free survival (PFS) and overall survival (OS).Results: 4852 new NHLs were seen for primary treatment at our centre during this time period, of which 287 were T cell lymphomas; 11 had EATL (0.23% of all NHL cases and 3.8% of all T-cell lymphomas). Median age at presentation was 61 years (range 51-85) with the majority being male (64%) (Table 1). All 11 pts presented with abdominal pain from small bowel perforation or obstruction. The most common site of EATL was jejunum (55%). Four pts (36%) had EATL type 1 and three had positive celiac serology. None had a history of celiac disease prior to diagnosis. 46% and 36% of pts presented with a high Ann Arbour stage (stage III or IV) and high Lugano stage (stage III or IV) respectively. No pt had a high ECOG score at presentation. Central pathology review was available for 8 patients (table 1). Interestingly, only 36% of cases had an intermediate-high risk International Prognostic Index (IPI) score of 3 and no pts had a high risk score of 4 or 5. Only one pt had an elevated LDH. All type 1 pts were CD56-, while type 2 pts were all CD8+ and most (86%) were CD56+. Ten pts (91%) received CHOP chemotherapy (one with the addition of etoposide and one of an IL2 receptor antibody) and one pt received palliative therapy. Only 5 of 11 responded to therapy (45%), with 2 patients achieving complete remission. All patients have progressed through treatment or relapsed (6 pts primary refractory and 5 responders), with one late relapse 14 years post response. At relapse, patients often presented with another bowel perforation. Upon relapse, four (36%) pts received salvage chemotherapy and 1 patient received an autologous stem cell transplant but progressed 16 months later and died from his disease. Ten patients (91%) have died, all from lymphoma; one patient (the late relapser) is presently undergoing salvage chemotherapy. Both median PFS and OS for all pts were 7 months. Two year OS and PFS were 18% and 9% respectively. Table 1 provides PFS and OS for EATL type separately.Conclusions: EATL is an aggressive form of lymphoma with unique presentation and very poor prognosis despite frequently presenting with limited disease and low IPI score. In our centre, type II EATL was more common, potentially underlying the multicultural composition of our city. CHOP with or without etoposide remains inadequate therapy for this aggressive lymphoma, and alternative induction regimens are needed. Few patients are stem cell transplant candidates at relapse due to age and poor performance status.Table 1Patient characteristicsFeatureEATL1 (N=4)EATL 2 (N=7)Age (yrs)median (range)65 (55-71)61 (51-85)Gender (%)male1 (25)6 (86)Celiac status (%)positive3(75)0PathologyCD3+4(100)7(100)CD7+3(75)5(71)CD4+/CD8-1(25)0CD4-/CD8+2(50)7(100)CD4-/CD8-1(25)0CD56+06(86)T-cell receptor clonal gene rearrangement1/2(50)4/4(100)Symptoms (%)abdominal pain4(100)7(100)constitutional symptoms3(75)1(17)lymphadenopathy2(50)1(14)bone marrow1 (25)0Primary Location (%)duodenum2 (50)3 (43)jejunum1 (25)5 (71)ileum3 (75)0Monofocal (%)yes3 (75)3 (43)Anne Arbor Staging (%)III or IV2 (50)3 (43)Lugano Staging (%)III or IV2 (50)2 (29)IPI (%)score 3-51(25)3 (43)Response to txCR/CRu/PR1(25)4 (57)PFSmedian (mo)672 year PFS25%0%OSmedian (mo)782 year OS25%14% DisclosuresPrica:Janssen: Honoraria; Celgene: Honoraria. Crump:Celgene: Consultancy; Seattle Genetics: Consultancy; Roche Canada: Consultancy. Kukreti:Celgene: Honoraria; Roche: Honoraria; Lundbeck: Honoraria; Amgen: Honoraria; Janssen Ortho: Honoraria. Kuruvilla:Lundbeck: Honoraria; Karyopharm: Honoraria; Merck: Honoraria; Bristol-Myers Squibb: Honoraria; Janssen: Consultancy, Honoraria; Gilead: Consultancy; Seattle Genetics: Consultancy, Honoraria; Hoffmann LaRoche: Consultancy, Honoraria, Research Funding.

Genomic and immunohistochemical profiles of enteropathy-associated T-cell lymphoma in Japan

Enteropathy-associated T-cell lymphoma (EATL) is a rare primary T-cell lymphoma of the digestive tract. EATL is classified as either Type I, which is frequently associated with and thought to arise from celiac disease and is primarily observed in Northern Europe, and Type II, which occurs de novo and is distributed all over the world with predominance in Asia. The pathogenesis of EATL in Asia is unknown. We aimed to clarify the histological and genomic profiles of EATL in Japan in a homogeneous series of 20 cases. The cases were characterized by immunohistochemistry, high-resolution oligonucleotide microarray, and fluorescence in situ hybridization (FISH) at five different loci: 1q21.3 (CKS1B), 6q16.3 (HACE1), 7p22.3 (MAFK), 9q33.3 (PPP6C), and 9q34.3 (ASS1, CARD9) using formalin-fixed paraffin-embedded sections. The histological appearance of EATL ranged from medium- to large-sized cells in 13 cases (65%), small- to medium-sized cells in five cases (25%), and medium-sized in two cases (10%). The immunophenotype was CD2+ (60%), CD3ɛ+ (100%), CD4+ (10%), CD7+ (95%), CD8+ (80%), CD56+ (85%), TIA-1+ (100%), Granzyme B+ (25%), T-cell receptor (TCR)β+ (10%), TCRγ+ (35%), TCRγδ+ (50%), and double negative for TCR (six cases, 30%). All cases were EBER−. The genomic profile showed recurrent copy number gains of 1q32.3, 4p15.1, 5q34, 7q34, 8p11.23, 9q22.31, 9q33.2, 9q34.13, and 12p13.31, and losses of 7p14.1. FISH showed 15 patients (75%) with a gain of 9q34.3 with good correlation with array comparative genomic hybridization. EATL in Japan is characterized by non-monomorphic cells with a cytotoxic CD8+ CD56+ phenotype similar to EATL Type II. The genomic profile is comparable to EATL of Western countries, with more similarity to Type I (gain of 1q and 5q) rather than Type II (gain of 8q24, including MYC). The 9q34.3 gain was the most frequent change confirmed by FISH irrespective of the cell origin of αβ-T-cells and γδ-T-cells.

Hepatosplenic T-Cell Lymphoma: A Clinicopathologic Review With an Emphasis on Diagnostic Differentiation From Other T-Cell/Natural Killer-Cell Neoplasms.

Hepatosplenic T-cell lymphoma is a rare, aggressive T-cell lymphoma, characterized by hepatosplenic sinusoidal infiltration of monotonous, medium-sized, nonactivated cytotoxic T cells, usually of γ/δ T-cell receptor type. Hepatosplenic T-cell lymphoma occurs more frequently in immunocompromised patients, especially in those receiving long-term immunosuppressive therapy. Patients usually manifest hepatosplenomegaly without lymphadenopathy. The bone marrow is also involved in two-thirds of cases and is often accompanied by circulating lymphoma cells, which, along with anemia and thrombocytopenia, may raise suspicion for acute leukemia. The differential diagnosis includes aggressive natural killer-cell leukemia, T-large granular lymphocytic leukemia, T-lymphoblastic leukemia, enteropathy-associated T-cell lymphoma type II, primary cutaneous γ/δ T-cell lymphoma, other peripheral T-cell lymphomas, myelodysplastic syndrome, and infectious mononucleosis. The diagnosis is usually established from the combination of clinical findings, histologic features, and immunophenotype, although cytogenetic/molecular studies are occasionally needed. Hepatosplenic T-cell lymphoma exhibits a dismal clinical course with a poor response to currently available therapies.

Cross Lineage Rearrangement in Feline Enteropathy-Associated T-cell Lymphoma.

Feline enteropathy-associated T-cell lymphoma (EATL) type II is characterized by infiltration of the small intestinal mucosa with small T-cells with variable epitheliotropism and is often difficult to differentiate from inflammation. Polymerase chain reaction (PCR) to assess antigen receptor rearrangements (PARR) amplifies the T- (T-cell receptor gamma, TCRG) or B-cell (immunoglobulin heavy chain, IGH) antigen receptor genes and is used to differentiate EATL from inflammation. However, PARR does not determine lymphocyte phenotype, and clonal rearrangement of either or both the TCRG or IGH genes may be detected in neoplastic T-cells. The purpose of this study was to determine the incidence of cross lineage rearrangement in feline EATL type II. Using a diagnostic algorithm combining histology, immunohistochemistry, and PARR testing, 8 of 92 cases diagnosed as EATL type II at Michigan State University between January 2013 and June 2014 showed cross lineage rearrangement (8.7%). PARR for the IGH gene facilitates the diagnosis of cases histologically highly suggestive of EATL type II in which polyclonal rearrangement of the TCRG gene is detected.

Clinicopathologic features of primary colonic enteropathy-associated T cell lymphoma type II in an elderly Asian male with diarrhea

A 76-year-old Asian man with a 6-month history of intractable watery diarrhea proceeded to colonoscopic examination that revealed diffusely dull-appearing colonic mucosa with focal areas of superficial ulceration. Mucosal biopsies demonstrated a neoplastic population of monomorphous small-to-intermediate-sized CD8+/CD56+ cytotoxic T cells that densely infiltrated the surface epithelium and crypts in a near pan-colonic distribution without tumor formation. Clinical staging revealed no disease elsewhere. The patient was treated aggressively with chemotherapy but died from disease five and a half months after presentation. In all likelihood, the patient had primary colonic involvement by enteropathy-associated T cell lymphoma (EATL) type II, a rare and aggressive extranodal non-Hodgkin lymphoma that occurs more commonly in Asians in whom celiac disease is infrequent. Widespread colonic disease in the absence of a mass-forming infiltrate has not been characterized in EATL type II and highlights an expanded clinical and pathological spectrum of the disease.

Enteropathy-Associated T-Cell Lymphoma Type I, But Not Refractory Celiac Disease, Strongly Expresses CD30 and Might Benefit From Brentuximab Vedotin

IntroductionEnteropathy-associated T-cell lymphoma (EATL) is an intestinal tumor of intraepithelial T lymphocytes. The 2008 WHO classification distinguishes two types of EATL: the first type of EATL (type I), the most frequent (80-90%) is strongly associated with celiac disease (CD) and the HLA-DQ2/DQ8 haplotypes. The tumor cells are CD3+CD8-/+CD4-CD56- and contain cytotoxic granules. In almost all cases, a varying proportion of the tumor cells express CD30. The second type of EATL (type II), the monomorphic form, has a distinct immunophenotype (CD3+CD4-CD8+CD56+). In two types, TCRgamma genes are often clonally rearranged.EATL may be preceded by refractory celiac disease (RCD), corresponding to CD refractory to gluten free diet (GFD). RCD is divided in two types based on the absence (type I) or presence (type II) of abnormal intraepithelial lymphocytes (IEL) showing down-regulation of CD8 and often TCRgamma genes rearrangement. RCD II is now considered as a small cell intraepithelial T-cell lymphoma that could be an intermediate stage between CD and EATL.The aim of the present study was to establish the pattern of CD30 expression in EATL. This could have therapeutic implications with the use of anti-CD30 monoclonal antibody like brentuximab vedotin (BV). MethodsConsecutive adult patients (pts) diagnosed with EATL between 2007 and 2013 in two university hospitals in Paris (Necker University Hospital and Georges Pompidou European Hospital) were eligible for this study. Diagnosis was confirmed after histopathologic and immunohistochemical review. For the purpose of the present study, two expert hematopathologists (V.V. and N.B.) reviewed all EATL and extended the phenotypic analysis to reclassify them according to the 2008 WHO classification. A panel of antibodies directed against CD20, CD3, CD4, CD5, CD8, CD56, granzyme B and ALK1 was used. CD30 staining was performed with Monoclonal Mouse Anti-Human CD30, Clone Ber-H2 (Dako). Consecutive RCDI and RCDII cases with complete phenotype and clonality analyses diagnosed in the same period were used as control. Diagnosis of CD was based on HLA-DQ2/8 typing, detection of celiac specific antibodies and of villous atrophy with increased counts of IEL on normal diet. Pts were further classified in RCDI or II depending on their clinical and histological response to a GFD and the presence of abnormal IEL. ResultsTwenty five adults were diagnosed with EATL on consensus review (median age 53 years [range 34-76], M/F ratio 12/13). Twenty five RCDI pts (median age 51 years [range 16-75], M/F ratio 6/19) and 20 RCDII pts (median age 62 years [range 29-81], M/F ratio 7/13) were used as control. A clinical history of CD was found in 17/20 (85%) evaluable EATL pts. Histological features of CD/RCD were seen in all cases (20/20) of EATL in which the mucosa adjacent to the tumor could be investigated (half of these were RCDII). Primary sites of EATL were small intestine (20/25), mesenteric lymph nodes (3/25), peritoneal nodules (1/25) and spleen (1/25). Phenotypic analysis showed that EATL cases were all WHO type I (25/25). ALK1 was constantly negative.IEL were CD3+ in all 70 cases. CD8 was normally expressed in all RCDI IEL and downregulated in all RCDII IEL and 35% of EATL.In all cases of EATL (25/25), CD30 was strongly expressed by all large tumor cells. In RCDI and II, CD30 was negative in most cases (∼90%), and was rarely expressed by dispersed atypical lymphocytes (IEL or in lamina propria) in some cases.TCRgamma genes were clonally rearranged in 11/14 (79%) EATL, 3/25 (12%) RCDI and 18/20 (90%) RCDII.Based on these results, we initiated in 2012 a pilot study combining BV with chemotherapy followed by autologous stem-cell transplantation (ASCT) as frontline treatment of EATL. Five pts have currently been treated. The associated chemotherapy regimen was IVE/MTX (Sieniawski M, Blood 2010) for the first two pts. After presentation at ASH 2012 Annual Meeting of preliminary results of a phase 1 study combining BV with CHP regimen as frontline treatment of systemic ALCL and other CD30-positive mature T–cell and NK–cell lymphomas (Fanale MA, Abstract #60), we replaced IVE/MTX by CHP regimen, and treated 3 other pts. The treatment was well tolerated, and the 5 pts reached CR and underwent ASCT. ConclusionCD30 is strongly expressed in EATL type I. Promising results of the combination of BV with CHP led us to plan a phase 2 study of BV and CHP followed by ASCT as frontline treatment of EATL. Disclosures:Off Label Use: Brentuximab vedotin was used in enteropathy-associated T-cell lymphoma (EATL).

A case of colon perforation due to enteropathy-associated T-cell lymphoma

Enteropathy-associated T-cell lymphoma (EATL) is an extremely rare disease, which is often related to gluten-sensitive enteropathy. It is an uncommon intestinal lymphoma with very poor prognosis and high mortality rate. In the absence of specific symptoms or radiological findings, it is difficult to diagnose early. Major complications of EATL have been known as intestinal perforation or obstruction, and only 5 cases of EATL are reported in South Korea. In this study, we report a case of 71-year-old male with symptoms of diarrhea, which later it progressed into cancer perforation of the colon. The initial colonoscopic findings were normal and computed tomography scan demonstrated a segmental wall thickening of the distal ascending colon with nonspecific multiple small lymphnodes, along the ileocolic vessels, but no signs of mass or obstruction. The histologic findings of resected specimen confirmed EATL type II. Patient expired two weeks after the operation. Therefore, we emphasize the need of random biopsy in the presence of normal mucosa appearance on colonoscopy for the early diagnosis of EATL.

A case of enteropathy-associated T-cell lymphoma (Type I) arising in stomach without refractory celiac disease

Enteropathy-associated T-cell lymphoma (EATL) is a rare peripheral T-cell lymphoma which was classified into 2 types based on histology. EATL is often, but not always, associated with celiac disease. EATL type I is a large cell lymphoma which is more common in frequency and highly associated with celiac disease compared with type II. Jejunum and ileum are the common sites, although EATL can rarely occur in the duodenum, stomach and colon or outside the gastrointestinal tract. We herein presented one case of gastric EATL, which happened in a 73-year-old Chinese male patient. Histologically, the tumor was composed of polymorphic (pleomorphic, anaplastic, immunoblastic) lymphoid cells and numerous inflammatory cells, including histiocytes, neutrophils and eosnophils in the background. The pleomorphic lymphoid cells were diffuse and strongly positive for CD3 and partially positive for CD30, while negative for CD4, CD5, CD8 or CD56. The gastric EATL should be distinguished from other gastric lesions, such as peptic ulcer, poorly-differentiated adenocarcinoma and other types of lymphoma.Virtual slidesThe virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1174320824810970