The phenotype of intraepithelial lymphocytes in Taiwanese enteropathy-associated T-cell lymphoma is distinct from that of the West

Background: Refractory celiac disease type II (RCD-II) is a very rare yet severe complication of celiac disease (CD) with a 50% rate of progression to Enteropathy-associated T-cell lymphoma (EATL). Timely diagnosis and treatment of RCD-II is of the essence and requires the identification of a population of frequently clonal, phenotypically aberrant intraepithelial lymphocytes (IELs). Flow Cytometry of intestinal IELs is the recommended method to identify the aberrant surface CD3-negative (sCD3–) intracytoplasmic CD3-positive (icCD3ε+) IELs, and a proportion of >20% is diagnostic of RCD-II. There is substantial heterogeneity in the clinical course of RCD-II, and insufficient information on prognostic factors. Aim: To establish flow cytometric predictors of the clinical evolution of RCD-II, to help guide treatment approaches. Patients and Methods: Retrospective single-center study of clinical and immunological features of 6 RCD-II patients and a control group, both identified from a 2,000-patient cohort over 16 years. IEL subset frequencies and the intensity of staining for surface (s) and intracytoplasmic (ic) CD3ε+ on IEL subsets were quantified and correlated with the clinical outcome. Results: Unexpectedly, the frequency of aberrant sCD3– icCD3ε+ cells at diagnosis did not correlate with histological or clinical affection. However, a higher intensity of icCD3ε+ staining in the aberrant IELs relative to expression on normal IELs correlated with monoclonality and with worse clinical outcomes. Conclusion: The ratio of icCD3ε+ on aberrant IELs vs. normal IELs appears to be a useful indicator of prognosis at the time of diagnosis, and may represent a novel tool in the follow-up of RCD-II patients after therapy.

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Bortezomib Restores Defective Apoptosis by Upregulation of Noxa in Enteropathy-Associated T-Cell Lymphoma

Blood ◽

10.1182/blood.v118.21.2722.2722 ◽

2011 ◽

Vol 118 (21) ◽

pp. 2722-2722

Author(s):

Laura R de Baaij ◽

Marijn Radersma ◽

Jolanda MW van de Water ◽

Kim BJ Groot ◽

Nathalie J Hijmering ◽

...

Keyword(s):

Cell Death ◽

T Cell ◽

Tumor Cells ◽

Cell Lymphoma ◽

Chemotherapy Resistance ◽

Intraepithelial Lymphocytes ◽

T Cell Lymphoma ◽

Caspase 9 ◽

Apoptosis Pathway ◽

Induction Of Apoptosis

Abstract Abstract 2722 Enteropathy-associated T-cell lymphoma (EATL) is a rare intestinal lymphoma that arises from intraepithelial lymphocytes. Clinical outcome of patients with EATL is very poor, due to chemotherapy-resistance and high relapse rates. Therefore, new therapeutic options for EATL are urgently needed. Studies in other types of lymphoma have shown that inhibition of apoptosis may cause chemotherapy-resistance and that restoration of defective apoptosis can induce cell death in these lymphomas. Preliminary data in EATL samples have demonstrated an increased expression of a fraction of NF-κB target genes, suggesting upregulation of NF-κB activity in EATL tumor cells. NF-κB activity can be inhibited by the proteasome inhibitor bortezomib resulting in induction of apoptosis. In the present study, we evaluated if apoptosis is inhibited in EATL cells and if Bortezomib can restore apoptosis in EATL cells. Laser-capture microdissection was applied to 16 fresh frozen EATL samples to obtain purified tumor cells for RNA isolation. Intraepithelial lymphocytes (IEL) of healthy controls were obtained from fresh duodenal biopsies and isolated by cell sorting. RT-MLPA analysis revealed that the pro-apoptotic BH3-only gene Noxa was significantly downregulated in most EATL samples compared to healthy donor IEL. Induction with etoposide resulted in caspase-9 mediated apoptosis in EATL cells with relatively high Noxa expression, whereas in EATL cells with low Noxa expression no apoptosis was induced, suggesting an inhibition in the intrinsic apoptosis pathway. Treatment with Bortezomib resulted in induction of apoptosis in EATL cells. The lethal dose (LD50) varied between 7.5 nM and 15 nM. Bortezomib induced cell death in EATL cells was caspase-9 mediated. mRNA and protein expression analysis showed upregulation of Noxa after incubation with bortezomib. In conclusion, our study showed that bortezomib induces apoptosis by upregulation of Noxa in EATL cells. Bortezomib therefore may be a potential drug in the treatment of patients with EATL. Disclosures: No relevant conflicts of interest to declare.

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Defective synthesis or association of T-cell receptor chains underlies loss of surface T-cell receptor–CD3 expression in enteropathy-associated T-cell lymphoma

Blood ◽

10.1182/blood-2008-04-150748 ◽

2008 ◽

Vol 112 (13) ◽

pp. 5103-5110 ◽

Cited By ~ 28

Author(s):

Jennifer M. L. Tjon ◽

Wieke H. M. Verbeek ◽

Yvonne M. C. Kooy-Winkelaar ◽

Binh H. Nguyen ◽

Arno R. van der Slik ◽

...

Keyword(s):

Celiac Disease ◽

T Cell ◽

Cell Surface ◽

Cell Line ◽

T Cell Receptor ◽

Cell Lymphoma ◽

Cell Receptor ◽

Intraepithelial Lymphocytes ◽

T Cell Lymphoma ◽

Cell Surface Expression

Abstract Enteropathy-associated T-cell lymphoma, an often fatal complication of celiac disease, can result from expansion of aberrant intraepithelial lymphocytes in refractory celiac disease type II (RCD II). Aberrant intraepithelial lymphocytes and lymphoma cells are intracellularly CD3ϵ+ but lack expression of the T-cell receptor (TCR)–CD3 complex on the cell surface. It is unknown what causes the loss of TCR-CD3 expression. We report the isolation of a cell line from an RCD II patient with the characteristic phenotype of enteropathy-associated T-cell lymphoma. We demonstrate that in this cell line the TCR-α and -β chains as well as the CD3γ, CD3δ, CD3ϵ, and ζ-chains are present intracellularly and that assembly of the CD3γϵ, CD3δϵ, and ζζ-dimers is normal. However, dimerization of the TCR chains and proper assembly of the TCR-CD3 complex are defective. On introduction of exogenous TCR-β chains, but not of TCR-α chains, assembly and functional cell surface expression of the TCR-CD3 complex were restored. Defective synthesis of both TCR chains was found to underlie loss of TCR expression in similar cell lines isolated from 2 additional patients. (Pre)malignant transformation in RCD II thus correlates with defective synthesis or defective association of the TCR chains, resulting in loss of surface TCR-CD3 expression.

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ADULT T-CELL LYMPHOMA-LEUKAEMIA IN BLACKS FROM THE WEST INDIES

The Lancet ◽

10.1016/s0140-6736(82)92200-0 ◽

1982 ◽

Vol 319 (8273) ◽

pp. 639-643 ◽

Cited By ~ 371

Author(s):

D Catovsky ◽

M Rose ◽

A.W.G Goolden ◽

J.M White ◽

G Bourikas ◽

...

Keyword(s):

T Cell ◽

West Indies ◽

Cell Lymphoma ◽

T Cell Lymphoma ◽

The West

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Immunophenotyping of intraepithelial lymphocytes in canine chronic enteropathy and intestinal T-cell lymphoma using endoscopic samples

Veterinary Pathology ◽

10.1177/03009858211057220 ◽

2021 ◽

pp. 030098582110572

Author(s):

Kazuhiro Kojima ◽

James K. Chambers ◽

Ko Nakashima ◽

Yuko Goto-Koshino ◽

Kazuyuki Uchida

Keyword(s):

T Cell ◽

Cell Lymphoma ◽

Intraepithelial Lymphocytes ◽

T Cell Lymphoma ◽

Double Labeling ◽

Chronic Enteropathy ◽

High Proliferative Activity ◽

Neoplastic Lymphocytes ◽

Mass Lesions ◽

Intraepithelial Lymphocytosis

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.

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Refractory Sprue Syndrome with Clonal Intraepithelial Lymphocytes Evolving into Overt Enteropathy-Type Intestinal T-Cell Lymphoma

Digestion ◽

10.1159/000007779 ◽

2000 ◽

Vol 62 (1) ◽

pp. 60-65 ◽

Cited By ~ 28

Author(s):

Severin Daum ◽

Michael Hummel ◽

Dajana Weiss ◽

Michael Peters ◽

Bertram Wiedenmann ◽

...

Keyword(s):

T Cell ◽

Cell Lymphoma ◽

Intraepithelial Lymphocytes ◽

T Cell Lymphoma ◽

Refractory Sprue

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Monomorphic Epitheliotropic Intestinal T-Cell Lymphoma in Asia Frequently Shows SETD2 Alterations

Cancers ◽

10.3390/cancers12123539 ◽

2020 ◽

Vol 12 (12) ◽

pp. 3539

Author(s):

Sakura Tomita ◽

Yara Yukie Kikuti ◽

Joaquim Carreras ◽

Rika Sakai ◽

Katsuyoshi Takata ◽

...

Keyword(s):

T Cell ◽

Cell Lymphoma ◽

Suppressor Gene ◽

Intraepithelial Lymphocytes ◽

T Cell Lymphoma ◽

Targeted Next Generation Sequencing ◽

Genome Copy Number ◽

Signaling Activation ◽

Aggressive Clinical Course ◽

Next Generation Sequencing Ngs

Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) is a rare primary T-cell lymphoma of the digestive tract derived from intraepithelial lymphocytes and characterized by an aggressive clinical course. In this study, nine cases of Japanese MEITL were analyzed by targeted Next Generation Sequencing (NGS) and immunohistochemistry and were integrated with previously reported whole-genome copy number microarray-based assay data. The highlight of our findings is that all cases showed alterations of the tumor suppressor gene SETD2 by mutations and/or loss of the corresponding 3p21 locus. We also demonstrated that all cases showed mutations in one or more genes of JAK/STAT pathway. Therefore, the combination of epigenetic deregulation and cell signaling activation represent major oncogenic events in the pathogenesis of MEITL in Asian MEITL, similar to Western MEITL.

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Enteropathy-Associated T-Cell Lymphoma: Improving Treatment Strategies

Digestive Diseases ◽

10.1159/000369542 ◽

2015 ◽

Vol 33 (2) ◽

pp. 231-235 ◽

Cited By ~ 20

Author(s):

P. Nijeboer ◽

G. Malamut ◽

C.J. Mulder ◽

N. Cerf-Bensussan ◽

D. Sibon ◽

...

Keyword(s):

T Cell ◽

Coeliac Disease ◽

Cell Lymphoma ◽

Tumour Size ◽

Treatment Strategies ◽

Intraepithelial Lymphocytes ◽

T Cell Lymphoma ◽

Severe Malnutrition ◽

High Dose ◽

High Association

Enteropathy-associated T-cell lymphoma (EATL) is a rare and usually rapidly fatal intestinal T-cell non-Hodgkin lymphoma. It arises from intraepithelial lymphocytes and has a high association with coeliac disease. The high mortality of EATL is associated not only with the very aggressive and often chemotherapy-refractory nature of the lymphoma. The poor condition of patients due to prolonged and severe malnutrition compromises the ability to deliver chemotherapy. There are no standardized treatment protocols, and the optimal therapy for EATL remains unclear. The primary step of treatment consists of local debulking, preferably as early as possible after EATL diagnosis. Morbidity and mortality seem to rise with advanced stages of disease due to tumour size progression, worse nutritional status and a higher risk of emergency surgery due to perforation. Standard induction therapy for EATL is anthracycline-based chemotherapy, preferably resumed between 2 and 5 weeks after surgery (depending on clinical condition). Intensification of therapy using high-dose chemotherapy followed by consolidation with BEAM and autologous stem cell transplantation is associated with better outcome. Notably, this treatment strategy has only been applied in patients eligible for this aggressive regimen which might reflect selection bias. Unfortunately, prognosis of EATL remains poor; 5-year survival varies from 8 to 60% depending on the eligibility to receive additional steps of therapy. New treatment strategies are urgently needed for a better prognosis of this lethal complication of coeliac disease. Brentuximab vedotin (anti-CD30) might be promising when added to conventional chemotherapy and is suggested as upfront treatment in EATL.

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