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

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.

Emperipolesis-like Invasion of Neoplastic Lymphocytes into Hepatocytes in Feline T-cell Lymphoma

2011 ◽  
Vol 144 (4) ◽  
pp. 312-316 ◽  
Author(s):  
M. Suzuki ◽  
Y. Kanae ◽  
Y. Kagawa ◽  
N. Ano ◽  
K. Nomura ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Lymphoma ◽  
T Cell Lymphoma ◽  
Neoplastic Lymphocytes

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

2008 ◽  
Vol 53 (2) ◽  
pp. 234-236 ◽  
Author(s):  
S-S Chuang ◽  
Y-L Liao ◽  
H Liu ◽  
S-H Lin ◽  
P-P Hsieh ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Lymphoma ◽  
Intraepithelial Lymphocytes ◽  
T Cell Lymphoma ◽  
The West

The Intracellular Intensity of CD3 on Aberrant Intraepithelial Lymphocytes Is a Prognostic Factor of the Progression to Overt Lymphoma in Refractory Celiac Disease Type II (Pre-Enteropathy-Associated T Cell Lymphoma)

2020 ◽  
Vol 38 (6) ◽  
pp. 490-499 ◽  
Author(s):  
Carlota García-Hoz ◽  
Laura Crespo ◽  
Natalia Lopez ◽  
Ana De Andrés ◽  
Raquel Ríos León ◽  
...  
Keyword(s):  
Celiac Disease ◽  
T Cell ◽  
Cell Lymphoma ◽  
Intraepithelial Lymphocytes ◽  
Disease Type ◽  
T Cell Lymphoma ◽  
Control Group ◽  
Type Ii ◽  
Refractory Celiac Disease ◽  
Single Center Study

<b><i>Background:</i></b> 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<sup>–</sup>) intracytoplasmic CD3-positive (icCD3ε<sup>+</sup>) IELs, and a proportion of &#x3e;20% is diagnostic of RCD-II. There is substantial heterogeneity in the clinical course of RCD-II, and insufficient information on prognostic factors. <b><i>Aim:</i></b> To establish flow cytometric predictors of the clinical evolution of RCD-II, to help guide treatment approaches. <b><i>Patients and Methods:</i></b> 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. <b><i>Results:</i></b> Unexpectedly, the frequency of aberrant sCD3<sup>–</sup> icCD3ε<sup>+</sup> cells at diagnosis did not correlate with histological or clinical affection. However, a higher intensity of icCD3ε<sup>+</sup> staining in the aberrant IELs relative to expression on normal IELs correlated with monoclonality and with worse clinical outcomes. <b><i>Conclusion:</i></b> The ratio of icCD3ε<sup>+</sup> 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.

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

Blood ◽  
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.

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 ◽  
2008 ◽  
Vol 112 (13) ◽  
pp. 5103-5110 ◽  
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.

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

Digestion ◽  
2000 ◽  
Vol 62 (1) ◽  
pp. 60-65 ◽  
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

scholarly journals Intraepithelial Lymphocytosis of the Resection Margin in the Monomorphic Epitheliotropic Intestinal T-Cell Lymphoma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5317-5317
Author(s):  
Mi Hwa Heo ◽  
Hye Ra Jung ◽  
Young Rok Do ◽  
Jung-Sook Ha ◽  
Hyera Kim ◽  
...  
Keyword(s):  
Small Intestine ◽  
T Cell ◽  
Resection Margin ◽  
Conflicts Of Interest ◽  
Cell Lymphoma ◽  
Early Recurrence ◽  
T Cell Lymphoma ◽  
Tissue Array ◽  
Resection Margins ◽  
Intraepithelial Lymphocytosis

Abstract Background: Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) is a disease involving the intestine and is often diagnosed in surgically resected specimens. The disease prognosis of MEITL is fatal because of rapid recurrence and leakage after excision. Recently, in microscopic finding of MEITL, intraepithelial lymphocytosis in mucosa that were grossly intact has been reported. In this study, we evaluated the intraepithelial lymphocytosis of the resection margin to determine the reason for the early recurrence or leakage in MEITL. Materials and Methods: We reviewed the medical records of all patients who were diagnosed with small intestine lymphoma from January 1995 to June 2018 at our medical center. We analyzed a tissue array from 8 patients diagnosed with MEITL. The expression of CD3, CD5, and CD8 were analyzed by immunohistochemistry. Results: A total of 8 cases of small intestine lymphoma were collected in this period. There were three men (37.5%) and five women (mean age 55 years). Two patients died without initiation of chemotherapy. Six patients received chemotherapy after resection of MEITL (4 patients received CHOP regimens, 2 patients received ProMACE-CyBOM regimens), but five patients died within 6 months (mean survival time 4.1 months, range 0.3-12.1 months). Only one patient survived for 5 years. On gross examination, the distance to the resection margin was 7.58 cm (3.8-14.0 cm) on average. Microscopic examination revealed intraepithelial lymphocytosis at least of one of the resected margins in all case. Immunohistochemical staining for CD3, CD5, and CD8 was performed on the resection margins. As a result, severe intraepithelial lymphocytosis accompanied by aberrant loss of CD5 was observed in 6 cases (75%). Conclusion: In the MEITL, an intraepithelial lymphocytosis accompanied by aberrant CD5 loss is frequently observed in the resection margin, even if the resection margin is grossly intact, and there is no clear microscopic involvement of the lymphoma especially on low power. This fact is thought to be related to the early recurrence or leakage of MEITL at the surgical site. Disclosures No relevant conflicts of interest to declare.

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

Cancers ◽  
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.

scholarly journals Epitheliotropic T-cell lymphoma in 2 half-sibling bontebok

2020 ◽  
pp. 104063872098411
Author(s):  
Sierra M. Imanse ◽  
Colleen F. Monahan ◽  
Kimberly A. Thompson ◽  
Judilee C. Marrow ◽  
Sarah M. Corner
Keyword(s):  
T Cell ◽  
Fibrous Material ◽  
Cell Lymphoma ◽  
Abdominal Distension ◽  
Neoplastic Cell ◽  
T Cell Lymphoma ◽  
History Of ◽  
Neoplastic Lymphocytes ◽  
Particle Length ◽  
Half Sibling

We diagnosed epitheliotropic T-cell lymphoma of the forestomachs in 2 aged, half-sibling, zoo-managed bontebok ( Damaliscus pygargus pygargus). One bontebok also had mesenteric lymph node and cutaneous involvement. Both animals had a history of chronic abdominal distension and diminished body condition that resulted in euthanasia. At autopsy, both animals had marked ruminal distension with diffusely blunted ruminal papillae and reticular crests. In case 1, there was an increased amount and particle length of the ruminoreticular fibrous material with scant fluid, and a 2-cm diameter focus of cutaneous crusting adjacent to a mammary teat. In case 2, the rumen and reticulum were fluid-distended with decreased fibrous material. Histologically in case 1, the rumen, reticulum, omasum, and skin had intraepithelial nests and sheets of neoplastic small lymphocytes; in case 2, the rumen and reticulum had a similar neoplastic cell population. Immunohistochemically, neoplastic lymphocytes were immunoreactive for CD3 and negative for CD20, confirming the diagnosis of epitheliotropic T-cell lymphoma.

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