Monomorphic epitheliotropic intestinal T-cell lymphoma

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Haematolymphoid Tumours (WHO Classification, 5th ed.)

editContent Update To WHO 5th Edition Classification Is In Process; Content Below is Based on WHO 4th Edition Classification
This page was converted to the new template on 2023-12-07. The original page can be found at HAEM4:Monomorphic Epitheliotropic Intestinal T-cell Lymphoma.

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Primary Author(s)*

Derick Okwan-Duodu MD, PhD; Sumire Kitahara, MD

WHO Classification of Disease

Structure Disease
Book Haematolymphoid Tumours (5th ed.)
Category T-cell and NK-cell lymphoid proliferations and lymphomas
Family Mature T-cell and NK-cell neoplasms
Type Intestinal T-cell and NK-cell lymphoid proliferations and lymphomas
Subtype(s) Monomorphic epitheliotropic intestinal T-cell lymphoma

Definition / Description of Disease

  • Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) is a primary intestinal T-cell lymphoma derived from intraepithelial lymphocytes that, unlike enteropathy-associated T-cell lymphoma, is not clearly associated with celiac disease

Synonyms / Terminology

  • Formerly and no longer referred to as type II enteropathy-associated T-cell lymphoma (EATL)

Epidemiology / Prevalence

  • More prevalent in Asian and Hispanic/indigenous population
  • < 1 per 1,000,000

Clinical Features

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Signs and Symptoms EXAMPLE: Asymptomatic (incidental finding on complete blood counts)

EXAMPLE: B-symptoms (weight loss, fever, night sweats)

EXAMPLE: Fatigue

EXAMPLE: Lymphadenopathy (uncommon)

Laboratory Findings EXAMPLE: Cytopenias

EXAMPLE: Lymphocytosis (low level)


editv4:Clinical Features
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  • Abdominal pain
  • Weight loss
  • Diarrhea
  • Long-standing history of malabsorption is atypical

Sites of Involvement

  • Small Intestine (jejunum > ileum) > large intestine > stomach

Morphologic Features

  • Monomorphic small- to medium-sized neoplastic cells
  • Uniformly round and regular nuclei
  • Finely dispersed chromatin
  • Inconspicuous nucleoli
  • Abundant rim of pale cytoplasm

Immunophenotype

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Finding Marker
Positive (universal) EXAMPLE: CD1
Positive (subset) EXAMPLE: CD2
Negative (universal) EXAMPLE: CD3
Negative (subset) EXAMPLE: CD4


editv4:Immunophenotype
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Postive: CD3, CD8, CD56, TCR gamma > TCR beta, TIA1, CD20 in 20% of cases, MATK in >80% of neoplastic cells helps distinguish from EATL, SYK [1] (distinguishes from EATL), NKP46

Variably positive between cases: granzyme B, perforin

Negative: CD5, EBV/EBER

INCORPORATE INTO TABLE

Chromosomal Rearrangements (Gene Fusions)

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Chromosomal Rearrangement Genes in Fusion (5’ or 3’ Segments) Pathogenic Derivative Prevalence Diagnostic Significance (Yes, No or Unknown) Prognostic Significance (Yes, No or Unknown) Therapeutic Significance (Yes, No or Unknown) Notes
EXAMPLE: t(9;22)(q34;q11.2) EXAMPLE: 3'ABL1 / 5'BCR EXAMPLE: der(22) EXAMPLE: 20% (COSMIC)

EXAMPLE: 30% (add reference)

Yes No Yes EXAMPLE:

The t(9;22) is diagnostic of CML in the appropriate morphology and clinical context (add reference). This fusion is responsive to targeted therapy such as Imatinib (Gleevec) (add reference).


editv4:Chromosomal Rearrangements (Gene Fusions)
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  • N/A
  • No consistent gene fusion reported


editv4:Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications).
Please incorporate this section into the relevant tables found in:
  • Chromosomal Rearrangements (Gene Fusions)
  • Individual Region Genomic Gain/Loss/LOH
  • Characteristic Chromosomal Patterns
  • Gene Mutations (SNV/INDEL)
  • Diagnosis
    • Because of non-specific findings, careful clinical history, along with immunophenotype and morphology, is necessary to arrive at diagnosis
IHC Significance Note
SYK Possible role in diagnosis (inclusion) Strongly diagnostic[1]
CD56 Possible role in diagnosis (inclusion) Contrasts with majority of EATL
EBV Possible role in diagnosis (exclusion) Strongly associated with extranodal NK/T- cell lymphoma, but negative in MEITL
MATK Possible role in diagnosis (inclusion) If present in >80% of tumor cells, helps distinguish from EATL
Gamma delta TCR Possible role in diagnosis (inclusion) Much more frequent in MEITL compared to EATL (silent or alpha beta TCR)
  • Prognosis
    • Poor (median survival of 7 months)
    • Resection, chemotherapy combined with autologous stem cell transplantation improves survival [2]
  • Therapeutic Implications
    • Alemtuzumab and single use of brentuximab and romidepsin in adjuvant setting[3]
    • PEG-asparaginase has been considered as option[4]

Individual Region Genomic Gain / Loss / LOH

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Chr # Gain / Loss / Amp / LOH Minimal Region Genomic Coordinates [Genome Build] Minimal Region Cytoband Diagnostic Significance (Yes, No or Unknown) Prognostic Significance (Yes, No or Unknown) Therapeutic Significance (Yes, No or Unknown) Notes
EXAMPLE:

7

EXAMPLE: Loss EXAMPLE:

chr7:1- 159,335,973 [hg38]

EXAMPLE:

chr7

Yes Yes No EXAMPLE:

Presence of monosomy 7 (or 7q deletion) is sufficient for a diagnosis of AML with MDS-related changes when there is ≥20% blasts and no prior therapy (add reference).  Monosomy 7/7q deletion is associated with a poor prognosis in AML (add reference).

EXAMPLE:

8

EXAMPLE: Gain EXAMPLE:

chr8:1-145,138,636 [hg38]

EXAMPLE:

chr8

No No No EXAMPLE:

Common recurrent secondary finding for t(8;21) (add reference).

editv4:Genomic Gain/Loss/LOH
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In contrast to EATL, gains at 1q32.2-41 and 5q34-35.5 are reported less commonly. However, one study from Japan[5] described a series a non-celiac associated intestinal T-cell lymphoma with MEITL immunophenotype that demonstrated these gains at a frequency comparable to Western EATL, suggesting more overlap between Western EATL and Asian MEITL than previously thought, requiring additional investigation to further study these observations.

Chromosome Number Gain/Loss/Amp/LOH Region Genes Prevalence
8q gain q24 MYC 25-38%
9q gain q22.31;q33.2; q34.3-13 PPP6C, ASS1,CARD9 75%
1q gain q32.2-44 CKS1B 50%
5q gain q34 38%
8p gain p11.23 63%
4p gain p15.1 63%
7q gain q34 63%
12p gain p13.31 ETV6
7p loss p14.1 MAFK 75%
8p loss p23.3-p11.21 38%
16q loss 50%


editUnassigned References
The following referenees were placed in the header. Please place them into the appropriate locations in the text.

[6][5]

Characteristic Chromosomal Patterns

Put your text here (EXAMPLE PATTERNS: hyperdiploid; gain of odd number chromosomes including typically chromosome 1, 3, 5, 7, 11, and 17; co-deletion of 1p and 19q; complex karyotypes without characteristic genetic findings; chromothripsis. Do not delete table.)

Chromosomal Pattern Diagnostic Significance (Yes, No or Unknown) Prognostic Significance (Yes, No or Unknown) Therapeutic Significance (Yes, No or Unknown) Notes
EXAMPLE:

Co-deletion of 1p and 18q

Yes No No EXAMPLE:

See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference).

editv4:Characteristic Chromosomal Aberrations / Patterns
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  • No pathognomonic aberrations/patterns described, but multiple genomic gains and losses are frequent

Gene Mutations (SNV / INDEL)

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Gene; Genetic Alteration Presumed Mechanism (Tumor Suppressor Gene [TSG] / Oncogene / Other) Prevalence (COSMIC / TCGA / Other) Concomitant Mutations Mutually Exclusive Mutations Diagnostic Significance (Yes, No or Unknown) Prognostic Significance (Yes, No or Unknown) Therapeutic Significance (Yes, No or Unknown) Notes
EXAMPLE: TP53; Variable LOF mutations

EXAMPLE:

EGFR; Exon 20 mutations

EXAMPLE: BRAF; Activating mutations

EXAMPLE: TSG EXAMPLE: 20% (COSMIC)

EXAMPLE: 30% (add Reference)

EXAMPLE: IDH1 R123H EXAMPLE: EGFR amplification EXAMPLE:  Excludes hairy cell leukemia (HCL) (add reference).


Note: A more extensive list of mutations can be found in cBioportal (https://www.cbioportal.org/), COSMIC (https://cancer.sanger.ac.uk/cosmic), ICGC (https://dcc.icgc.org/) and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.


editv4:Gene Mutations (SNV/INDEL)
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Gene* Mutation Oncogene/Tumor Suppressor/Other Presumed Mechanism (LOF/GOF/Other; Driver/Passenger) Prevalence (COSMIC/TCGA/Other)
SETD2 mutation and/or deletion Tumor Suppressor LOF frameshift indels or nonsense mutation 43% -93%
STAT5B Oncogene GOF up to 63%
JAK3 Oncogene GOF 46%

*Specific mutations in these genes can be found elsewhere (COSMIC, cBioPortal)


editUnassigned References
The following referenees were placed in the header. Please place them into the appropriate locations in the text.

[7][8][9]

Epigenomic Alterations

  • Defective H3K36 trimethylation[8]

Genes and Main Pathways Involved

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Gene; Genetic Alteration Pathway Pathophysiologic Outcome
EXAMPLE: BRAF and MAP2K1; Activating mutations EXAMPLE: MAPK signaling EXAMPLE: Increased cell growth and proliferation
EXAMPLE: CDKN2A; Inactivating mutations EXAMPLE: Cell cycle regulation EXAMPLE: Unregulated cell division
EXAMPLE:  KMT2C and ARID1A; Inactivating mutations EXAMPLE:  Histone modification, chromatin remodeling EXAMPLE:  Abnormal gene expression program
editv4:Genes and Main Pathways Involved
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  • JAK-STAT (most common)
  • RAS
  • P53
  • TERT
  • BBX

Include these in the standard table.


editUnassigned References
The following referenees were placed in the header. Please place them into the appropriate locations in the text.

[7][10]

Genetic Diagnostic Testing Methods

  • Careful clinicopathologic correlation: lack of prior history of celiac disease or histologic features of celiac disease if no prior history known or documented
  • Immunohistochemical evaluation (see Immunophenotype above and Clinical Significance below)
    • Some immunostains not routinely available at commercial labs (e.g. SYK, MATK)

Familial Forms

  • Not described

Additional Information

None

Links

HAEM4:Intestinal T-cell Lymphoma

References

(use the "Cite" icon at the top of the page) (Instructions: Add each reference into the text above by clicking on where you want to insert the reference, selecting the “Cite” icon at the top of the page, and using the “Automatic” tab option to search such as by PMID to select the reference to insert. The reference list in this section will be automatically generated and sorted. If a PMID is not available, such as for a book, please use the “Cite” icon, select “Manual” and then “Basic Form”, and include the entire reference.)

  1. 1.0 1.1 G, Mutzbauer; et al. (2018). "SYK expression in monomorphic epitheliotropic intestinal T-cell lymphoma". PMID 29052597.
  2. P, Nijeboer; et al. (2015). "Treatment response in enteropathy associated T-cell lymphoma; survival in a large multicenter cohort". PMID 25716069.
  3. "Enteropathy-Associated T-Cell Lymphoma". Definitions. Qeios. 2020-02-07.
  4. C, Gentille; et al. (2017). "Use of PEG-asparaginase in monomorphic epitheliotropic intestinal T-cell lymphoma, a disease with diagnostic and therapeutic challenges". doi:10.3332/ecancer.2017.771. PMC 5636209. PMID 29062389.CS1 maint: PMC format (link)
  5. 5.0 5.1 S, Tomita; et al. (2015). "Genomic and immunohistochemical profiles of enteropathy-associated T-cell lymphoma in Japan". PMID 26226842.
  6. Rj, Deleeuw; et al. (2007). "Whole-genome analysis and HLA genotyping of enteropathy-type T-cell lymphoma reveals 2 distinct lymphoma subtypes". PMID 17484883.
  7. 7.0 7.1 Ab, Moffitt; et al. (2017). "Enteropathy-associated T cell lymphoma subtypes are characterized by loss of function of SETD2". doi:10.1084/jem.20160894. PMC 5413324. PMID 28424246.CS1 maint: PMC format (link)
  8. 8.0 8.1 A, Roberti; et al. (2016). "Type II enteropathy-associated T-cell lymphoma features a unique genomic profile with highly recurrent SETD2 alterations". doi:10.1038/ncomms12602. PMC 5023950. PMID 27600764.CS1 maint: PMC format (link)
  9. Ml, Nairismägi; et al. (2016). "JAK-STAT and G-protein-coupled receptor signaling pathways are frequently altered in epitheliotropic intestinal T-cell lymphoma". doi:10.1038/leu.2016.13. PMC 4895162. PMID 26854024.CS1 maint: PMC format (link)
  10. A, Nicolae; et al. (2016). "Mutations in the JAK/STAT and RAS signaling pathways are common in intestinal T-cell lymphomas". doi:10.1038/leu.2016.178. PMC 5093023. PMID 27389054.CS1 maint: PMC format (link)

Notes

*Primary authors will typically be those that initially create and complete the content of a page.  If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the CCGA coordinators (contact information provided on the homepage).  Additional global feedback or concerns are also welcome. *Citation of this Page: “Monomorphic epitheliotropic intestinal T-cell lymphoma”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 09/6/2024, https://ccga.io/index.php/HAEM5:Monomorphic_epitheliotropic_intestinal_T-cell_lymphoma.