Case Of Enteropathy-associated T-cell Lymphoma Research Articles

Incidence and Outcomes of Neutropenia in Patients with Celiac Disease- a Consecutive Analysis of 1729 Patients

▪Background: Celiac disease (gluten sensitive enteropathy) is a systemic disease with hematological manifestations including; iron deficiency anemia, vitamin B12 and folate deficiency, leukopenia/neutropenia, hyposplenism, venous thromboembolism, and the enteropathy associated T cell lymphoma (E-TCL). Leukopenia/neutropenia is rare, and can result from folate or copper deficiency, but in many cases remains idiopathic. The consequences of neutropenia and neutrophil responses to a gluten free diet are not well described. We carried out this study to assess the incidence and outcomes of neutropenia in patients with celiac disease.Methods: The Mayo clinic celiac disease database (n=1729) was retrospectively analyzed for all patients with a confirmed diagnosis of celiac disease that had leukopenia (<3.5 x10(9)/L) and/or neutropenia (<1.5 x 10(9)/L). The diagnosis of celiac disease was established by positive tissue transglutaminase antibodies (TTG) and confirmatory small bowel biopsy findings. Additional causes of neutropenia such as copper and folate deficiency, drugs, benign ethnic and cyclic neutropenia, chemotherapy, hematological malignancies, combined variable immunodeficiency (CVID), and autoimmune diseases were meticulously excluded. Data abstracted included demographics, temporal association with diagnosis, nadir counts, associated hematological findings, relationship with infections, the use and effect of G-CSF, response to gluten free diet and survival outcomes.Results: 21(1.2%) of 1729 cases screened had idiopathic-celiac related neutropenia; 17 (81%) Caucasian, 15 (48%) females. In 12(57%) patients the neutropenia preceded or occurred near the time of the diagnosis of celiac disease, while in 7 (33.3%) it occurred subsequently. In 2 cases the temporal association could not be established. The median age at diagnosis of celiac disease was 46 years (10-67) and the median follow up for this group was 41.7 months (0-207.3). At last follow up 1 (4.8%) death has been documented; 0 from infectious complications, with no cases of E-TCL. The median laboratory values at diagnosis of celiac disease were available in 11 (52%) patients and included; hemoglobin 12.9 g/dL (10.5-16.8), MCV 91.5 fl (79.6-102.8), WBC 3.2 x109/L (2.3-5.2), ANC 1.29x109/L (0.33-3.24), ALC 1.34x109/L (0.75-2.17), AMC 0.39x109/L (0.15-0.71), and platelet counts 225x109/L (168-711). Anti-granulocyte antibodies were assessed in 7 patients and were negative in all cases. None of these patients had coexistent hyposplenism and three cases of neutropenia that occurred in the setting of celiac disease and CVID were excluded. In 15 (71%) patients the neutropenia was incidentally detected during routine laboratory work and in 4 (19%) it came to light secondary to infections. Ten (48%) patients had recurrent infections (≥1) as documented by their providers, including 7 with sinopulmonary infections, 1 with urinary tract infections, and 1 with skin and soft tissue infections. Additional immunological assessments were not available in these patients.Three (14%) patients had an ANC <500 (significant neutropenia); of which 2 had recurrent sinopulmonary infections. The third patient remained largely asymptomatic. Two of the 3 patients received G-CSF support during infections and responded adequately (ANC improvement > 1 x 10(9)/L). The ANC in patients in this cohort did not correlate with severity of infections. Five (23%) of 21 patients had improvement in neutrophil counts after adopting a gluten free diet, while there was no response in 10 and data was unavailable in 6. The median time to ANC response was 14.5 months (10-15.3) and the median increment in ANC was 0.67 x 10(9)/L (0.48-0.98).Conclusions: Celiac disease associated neutropenia, especially significant neutropenia (ANC <500) is a rare occurrence (~1%). It can often pre-date the diagnosis of celiac disease or occur subsequently. It is potentially associated with an increased incidence of infections, with-out good correlation with the severity of neutropenia. Less than half the patients do seem to respond to a gluten free diet. G-CSF responses seem to be adequate and G-CSF can be used in the setting of severe infections. DisclosuresNo relevant conflicts of interest to declare.

Cavitating Mesenteric Lymph Node Syndrome and Enteropathy-Associated T Cell Lymphoma as First Manifestation of Celiac Disease

Celiac disease (CD) is a common systemic disease, affecting about 1.0% of the population. Classical presentation includes malabsorption syndrome and deficiencies of macro-/micronutrients. Patients with undiagnosed CD may be referred to hematologists with different hematologic issues, including anemia, thrombocytosis, thrombocytopenia, leukopenia, venous thromboembolism, hyposplenism, and IgA deficiency. CD imposes an increased risk of various lymphomas, especially intestinal T- and B-cell lymphomas. Enteropathy-associated T-cell lymphoma (EATL) is a rare and aggressive disease with poor prognosis and often fatal complications. Here we present a case of EATL associated with cavitating mesenteric lymph node syndrome as a first manifestation of undiagnosed CD.

消化管穿孔をきたした腸管症型T細胞性リンパ腫の2例

消化管穿孔をきたした腸管症型T細胞性リンパ腫（enteropathy-associated T-cell lymphoma，以下EATL）の2例を経験した．症例は53歳および74歳のいずれも男性で，穿孔性腹膜炎の術前診断で緊急手術を施行した．穿孔部位は1例は小腸と結腸の多発穿孔であり，もう1例は小腸のみの穿孔であった．いずれも病変部の切除を行ったが，前者は第11病日に死亡し，後者は術後に化学療法を施行できたものの，原病の増悪により術後5カ月で死亡した．本邦報告63例の集計でもEATLは極めて予後不良であったが，わずかに長期生存例も認めた．長期生存を可能にするためには病変の可及的全切除と術後早期の化学療法が必須であると考えられた．

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

Recurrent TET2 mutations in peripheral T-cell lymphomas correlate with TFH-like features and adverse clinical parameters

AbstractInactivating mutations of the Ten-Eleven Translocation 2 (TET2) gene were first identified in myeloid malignancies and more recently in peripheral T-cell lymphomas (PTCLs). In the present study, we investigated the presence of TET2 coding sequence mutations and their clinical relevance in a large cohort of 190 PTCL patients. TET2 mutations were identified in 40 of 86 (47%) cases of angioimmunoblastic T-cell lymphoma (AITL) and in 22 of 58 (38%) cases of peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), but were absent in all other PTCL entities, with the exception of 2 of 10 cases of enteropathy-associated T-cell lymphoma. Among PTCL-NOS, a heterogeneous group of lymphoma-comprising cases likely to derive from Th follicular (TFH) cells similarly to AITL, TET2 mutations were more frequent when PTCL-NOS expressed TFH markers and/or had features reminiscent of AITL (58% vs 24%, P = .01). In the AITL and PTCL-NOS subgroups, TET2 mutations were associated with advanced-stage disease, thrombocytopenia, high International Prognostic Index scores, and a shorter progression-free survival.

A case of enteropathy-associated T-cell lymphoma: diagnosis by flow cytometric immunophenotyping and genome analysis using ascitic fluid

Enteropathy-associated T-cell lymphoma (ETCL) is a primary extranodal T-cell lymphoma arising in the gastrointestinal tract, and is known as a rare and highly aggressive disease with a poor prognosis. The diagnosis of ETCL is usually established by histological examination using resected tumors or biopsy specimens during endoscopic studies. If tumor specimens for histopathological investigation are not available, then such a case might be difficult to accurately diagnose. We report here a case of ETCL which was diagnosed by cytopathology and flow cytometric immunophenotyping using paracentesis fluid without tumor specimens. Immunophenotyping by flow cytometry (FCM) of the ascitic fluid (AF) was invaluable in the final diagnosis of ETCL. Moreover, genetic alterations in the current case were also demonstrated. We emphasize the usefulness of effusion cytology for the expeditious diagnosis of ETCL. In particular, even in cases without tumor specimens, immunophenotyping by FCM using AF can play an important role in the diagnosis of ETCL, and simultaneous genome analysis may be useful to elucidate the biological characteristics of ETCL.

Refractory sprue, coeliac disease, and enteropathy-associated T-cell lymphoma

Adult refractory sprue is a poorly defined disorder. We did a multicentre national study of patients with refractory sprue to characterise their clinical and pathological profile and outcome, and to assess the frequency and prognostic significance of phenotypic and molecular abnormalities in the intraepithelial T-cell population. Patients with severe symptomatic villous atrophy mimicking coeliac disease but refractory to a strict gluten-free diet, and with no initial evidence of overt lymphoma, were diagnosed at gastrointestinal referral centres between 1974 and 1998. Fixed and/or frozen duodenojejunal biopsy samples were reanalysed and immunostained with CD3 and CD8 monoclonal antibodies to find out the phenotype of intraepithelial lymphocytes (IEL). TCRgamma gene rearrangements were assessed on frozen biopsy samples by multiplex fluorescent PCR. There were 21 patients with refractory sprue and 20 controls with coeliacs disease. 16 (84%) of 19 assessed patients had an aberrant intraepithelial lymphoid intestinal population expressing intracytoplasmic CD3 but not surface CD8. Clonal intestinal TCRgamma gene rearrangements were found in 13 (76%) of 17 patients assessed; four (out of 12 assessed) had clonal dissemination to the blood. The 16 patients with an aberrant phenotype all had uncontrolled malabsorption; three subsequently developed overt T-cell lymphoma, and eight died. The three (16%) patients without aberrant clonal IEL made a complete clinical and histological recovery with steroid therapy plus a gluten-free diet. An immunophenotypically aberrant clonal intraepithelial T-cell population (similar to that of most cases of enteropathy-associated T-cell lymphoma) can be found in up to 75% of patients with refractory coeliac sprue; its identification by simple diagnostic techniques represents a marker of poor outcome (including occurrence of overt T-cell lymphoma). We suggest that refractory sprue associated with an aberrant clonal IEL may be the missing link between coeliac disease and T-cell lymphoma and may be classified as cryptic enteropathy-associated T-cell lymphoma.

Phenotyping of T‐cell lymphomas in paraffin sections–which antibodies?

Five antibodies, MT1 (CD43), UCHL1 (CD45RO), OPD4, poly-CD3 and beta F1, were assessed for their reactivity with 50 archival cases of T-cell lymphoma in formalin-fixed paraffin-embedded tissue. All cases had been previously characterized as T-cell lymphomas, and the histological types included 14 cases of small cerebriform lymphoma, six cases of angioimmunoblastic lymphadenopathy-like T-cell lymphoma, four cases of T-zone lymphoma, five cases of pleomorphic small cell lymphoma, 12 cases of pleomorphic medium and large cell lymphoma, four cases of anaplastic large cell lymphoma, two cases of T-lymphoblastic lymphoma and three cases of enteropathy-associated T-cell lymphoma. UCHL1 and MT1 showed reactivity with the highest percentage of cases (94 and 86% respectively) but lack absolute specificity for T-cells, especially in high-grade lymphomas. Poly-CD3 is highly specific for T-cells, and stained neoplastic cells in almost 80% of the cases. beta F1 stained the lowest percentage of cases (40%). UCHL1 and poly-CD3 together identified 98% of cases, and this combination is recommended for the diagnosis of T-cell lymphomas in paraffin sections.