Compendium of Cancer Genome Aberrations

Enteropathy-associated T-cell lymphoma

Revision as of 15:54, 30 November 2023 by Bailey.Glen (talk | contribs)

Haematolymphoid Tumours (5th ed.)

editHAEM5 Conversion Notes
This page was converted to the new template on 2023-11-30. The original page can be found at HAEM4:Enteropathy-Associated T-cell Lymphoma.

Primary Author(s)*

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

Cancer Category / Type

Cancer Sub-Classification / Subtype

Definition / Description of Disease

  • Enteropathy-associated T-cell lymphoma (EATL) is an intestinal T-cell neoplasm closely associated with celiac disease[1]
  • Celiac disease may be diagnosed prior to EATL diagnosis in 20-73% of cases, or both entities may be diagnosed concomitantly in 10-58% of the cases[1]
  • Risk factors include homozygosity for HLA-DQ2 and advanced age[1]

Synonyms / Terminology

  • Historically referred to as enteropathy-associated T-cell lymphoma, type 1, but since "type 2" has been renamed in WHO 2016 as monomorphic epitheliotropic T-cell lymphoma, the word "type" has been dropped from both entities

Epidemiology / Prevalence

  • 0.5-1 in 1 million general population (2-5% in patients with celiac disease, 60-80% in patients with refractory celiac disease type 2)[2][3][4][5][6]
  • > 60% of all cases in intestinal T- cell lymphomas[2][3][4]
  • M:F 1.04:1 to 2.8:1[2][3][4]
  • 6th-7th decade of life[2][3][4]
  • Mostly Caucasian (> 90%)[2][3][4]
  • Uncommon in Asian countries due to low population frequency of celiac HLA risk alleles[2][3][4]

Clinical Features

Put your text here and fill in the table (Instruction: Can include references in the table)

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
The content below was from the old template. Please incorporate above.

Many of the below features are indistiguishable from the presentation of celiac disease, which may delay the diagnosis of EATL. Persistent symptoms following gluten-free diet is highly suggestive of EATL.[3]

Signs & Symptoms

  • Abdominal pain
  • Weight loss
  • Gluten-insensitive diarrhea/malabsorption
  • Bowel obstruction or perforation

Laboratory Findings

  • Anemia
  • Hypoalbuminemia
  • Hemophagocytosis

If there is no prior diagnosis of celiac disease and lymphoma is the initial presentation, the following findings can point towards celiac disease associated EATL:

  • Anti-tissue transglutaminase-2 antibodies or Anti-endomysial antibodies
  • Dermatitis herpetiformis

Sites of Involvement

  • Small intestine (predominantly jejunum and ileum > large intestine and stomach)[3]
  • Metastasis involve intra-abdominal node > bone marrow > lung > liver > skin[3]
  • CNS (rare)[3]

Morphologic Features

  • Pleomorphic medium to large neoplastic lymphoid infiltrate[4]
  • Neighborhood mucosa characterized by villous atrophy and crypt hyperplasia (non-malignant areas of celiac disease)[4]
  • Round or angulated vesicular nuclei[4]
  • Prominent nucleoli[4]
  • Moderate-abundant pale cytoplasm[4]
  • Extensive admixture of inflammatory cells (eosinophils, histiocytes)[4]
  • Angiocentric and angioinvasive features with extensive necrosis[4]

Immunophenotype

Put your text here and fill in the table (Instruction: Can include references in the table)

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


editv4:Immunophenotype
The content below was from the old template. Please incorporate above.
Finding[7][8] Marker
Positive (universal) CD3, CD7
Positive (frequent) CD30 (harbinger of transformation to EATL from RCD2), NKP46 (not seen in IEL of CD or RCD1), CD103,

cytotoxic granule-associated markers (TIA1, granzyme B, perforin)

Negative (frequent) CD4, CD8, CD5, CD56, TCR
Ki-67 high
  • Immunophenotype of intraepithelial lymphocytes (IEL):[7][8]
    • Varies depending on background type 1 or type 2 refractory celiac disease (RCD).
      • Type 1 (RCD1):
        • Milder symptoms with high 5-year survival with low risk of EATL development
        • Flow cytometry: sCD3+, CD8+, CD5+
      • Type 2 (RCD2):
        • Severe symptoms with protein-losing enteropathy leads to malnourishment (BMI < 18); low 5-year survival with increased risk of EATL
        • Flow cytometry: sCD3_, CD8-, CD5-
        • IHC:
          • NKP46: significantly more positive in RCD2 IEL than normal IEL in CD and RCD1; not specific for RCD2 or EATL, can be seen in MEITL; not seen in indolent T-cell LPD of GI tract
          • CD30+ indicates progression to EATL

Chromosomal Rearrangements (Gene Fusions)

Put your text here and fill in the table

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)
The content below was from the old template. Please incorporate above.
  • No recurrent gene fusions 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
    • No specific recurrent genetic abnormality that is diagnostic for EATL
      • Gain of 1q and 5q more frequent in EATL, whereas 8q24 (MYC) gain is more frequent in MEITL[8][9]
      • SETD2 mutations are common in both EATL (32%)[10] and MEITL (91%)[11]
  • Prognosis
    • In one study, >3 chromosomal imbalance was associated with worse prognosis[9]
  • Therapeutic Implications
    • Recurrent mutations in epigenetic machinery genes - epigenetic modifying drugs may be effective[12]
    • Mutations involved in JAK-STAT signaling pathway - inhibitors of this pathway may be effective
    • Suboptimal response to chemotherapy due to malnutrition, intestinal complications and toxicity and malnutrition
    • CD30+ disease may benefit from brentuximab vedotin (adcetris) as second line with or without stem cell transplant[13][14]
    • No FDA-approved targeted therapies currently available[15]

Individual Region Genomic Gain / Loss / LOH

Put your text here and fill in the table (Instructions: Includes aberrations not involving gene fusions. Can include references in the table. Can refer to CGC workgroup tables as linked on the homepage if applicable.)

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
The content below was from the old template. Please incorporate above.
Chromosome Number[8][16][9][10][17] Gain/Loss/Amp/LOH Region Genes Prevalence
9q gain q22-34 C-ABL1, NOTCH-1, VAV2, CARD9 40-71%
16q loss 12.1 CLYD 23%
1q gain q22-44 CKS1B 30%
5q gain q33.3–34 UBLCP1, IRGM-1 17%-30%
9p LOH p21 CDKN2A/B (p16) 36%; possibly more common in (5 of 9) cases with large cells[18]
7q gain q11.21-q36.1 NSUN5 24%
8p loss p23.3-p11.21 20-30%
8q gain q24 MYC 25-27%
13q loss RB 24%
17p loss p12-13.2 TP53 23%
  • Most copy number alterations are large arm level alterations; no focal gene level alterations reach statistical significance[10]


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)

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
The content below was from the old template. Please incorporate above.
  • HLA-DQ2 (HLA-DQA1*0501 and DQB1*02) homozygosity - increased (at least 5-fold) risk for RCD and EATL[19]
  • HLA-DQB1*02 genotype correlated with 5q gain [8]

Gene Mutations (SNV / INDEL)

Put your text here and fill in the table (Instructions: This table is not meant to be an exhaustive list; please include only genes/alterations that are recurrent and common as well either disease defining and/or clinically significant. Can include references in the table. For clinical significance, denote associations with FDA-approved therapy (not an extensive list of applicable drugs) and NCCN or other national guidelines if applicable; Can also refer to CGC workgroup tables as linked on the homepage if applicable as well as any high impact papers or reviews of gene mutations in this entity.)

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)
The content below was from the old template. Please incorporate above.
Gene*[10][20] Function/Oncogene/Tumor Suppressor Gene Frequency[10]
SETD2 Tumor suppressor gene 32%
YLPM1 Tumor suppressor gene 22%
TET2 Tumor suppressor gene 14%
STAT5B Oncogene 29%
JAK1 Oncogene 23%
JAK3 Oncogene 23%
STAT3 Oncogene 16%
SOCS1 Tumor suppressor gene 7%
NRAS Oncogene 10%
KRAS Oncogene 6%
TP53 Tumor suppressor gene 10%
BCL11B Tumor suppressor gene 13%
BRIP1 Tumor suppressor gene 16%
TERT Oncogene 17%
BBX Cell cycle transcription factor 16%
DAPK3 Apoptosis 10%
PRDM1 Interferon-related transcription factor 9%

*The specific mutations in these genes may be found elsewhere (COSMIC, cBioPortal)

  • PRDM1 and DAPK3, followed by STAT3 and STAT5B, are the most common mutually exclusive gene pairs[10]

Epigenomic Alterations

  • SETD2 is a histone H3 lysine 36 methyltransferase (forms H3K37me3)[10]
    • Altered (mostly by loss-of-function mutations) in ~32% of EATL
    • Results in global H3K36 hypomethylation

Genes and Main Pathways Involved

Put your text here and fill in the table (Instructions: Can include references in the table.)

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
The content below was from the old template. Please incorporate above.
  • Chromatin modifying genes: SETD2, TET2, YLPM1; loss of function mutations[10][21][22][23]
  • JAK-STAT pathway: JAK1, JAK3, STAT3, STAT5B, SOCS1; mutated drivers in this pathway tended to be mutually exclusive[10][21][22][23]
  • RAS/MAPK signaling pathway[10][21][22][23]
  • IL-15 deregulation and disruption of intestinal immune homeostasis[10][21][22][23]
  • Overexpression of genes involved in Interferon-γ signaling[10]

Genetic Diagnostic Testing Methods

  • No specific recurrent genetic abnormalities that are diagnostic for EATL[24][25]
  • Clonality can be confirmed by T-cell receptor gene rearrangement studies[24][25]
    • Intraepithelial lymphocytes in type 2 refractory celiac disease show similar gene rearrangement size as EATL[24][25]
  • Chromosomal microarrays may identify genetic abnormalities frequently associated with EATL[24][25]
  • Next generation sequencing may identify genetic abnormalities frequently associated with EATL[24][25]
  • Morphology and immunophenotyping
    • Cut-off value of 20% aberrant intraepithelial lymphocytes (cytoplasmic CD3+, surface CD3−, CD7+, CD103+, CD8−, CD4−) to distinguish from refractory celiac disease[26]

Familial Forms

  • While there is a genetic predisposition of those with HLA-DQ2 or HLA-DQ8 to develop celiac disease and EATL is a complication of celiac disease, familial forms of EATL are not described.
    • HLA-DQ2 (HLA-DQA1*0501 and DQB1*02) homozygosity - increased (at least 5-fold) risk for RCD and EATL[27]
    • HLA-DQB1*02 genotype correlated with 5q gain [28]

Additional Information

  • N/A

Links

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 1.2 Arber DA, et al., (2017). Acute myeloid leukaemia with recurrent genetic abnormalities, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Arber DA, Hasserjian RP, Le Beau MM, Orazi A, and Siebert R, Editors. IARC Press: Lyon, France, p372-377.
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 Wh, Verbeek; et al. (2008). "Incidence of enteropathy--associated T-cell lymphoma: a nation-wide study of a population-based registry in The Netherlands". PMID 18618372.
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 3.7 3.8 3.9 Aj, Ferreri; et al. (2011). "Enteropathy-associated T-cell lymphoma". PMID 20655757.
  4. ↑ 4.00 4.01 4.02 4.03 4.04 4.05 4.06 4.07 4.08 4.09 4.10 4.11 4.12 J, Delabie; et al. (2011). "Enteropathy-associated T-cell lymphoma: clinical and histological findings from the international peripheral T-cell lymphoma project". PMID 21566094.
  5. ↑ A, Rubio-Tapia; et al. (2010). "Classification and management of refractory coeliac disease". doi:10.1136/gut.2009.195131. PMC 2861306. PMID 20332526.CS1 maint: PMC format (link)
  6. ↑ G, Malamut; et al. (2009). "Presentation and long-term follow-up of refractory celiac disease: comparison of type I with type II". PMID 19014942.
  7. ↑ 7.0 7.1 P, Domizio; et al. (1993). "Primary lymphoma of the small intestine. A clinicopathological study of 119 cases". PMID 8470758.
  8. ↑ 8.0 8.1 8.2 8.3 8.4 Deleeuw, Ronald J.; et al. (2007-05). "Whole-genome analysis and HLA genotyping of enteropathy-type T-cell lymphoma reveals 2 distinct lymphoma subtypes". Gastroenterology. 132 (5): 1902–1911. doi:10.1053/j.gastro.2007.03.036. ISSN 0016-5085. PMID 17484883. Check date values in: |date= (help)
  9. ↑ 9.0 9.1 9.2 A, Zettl; et al. (2002). "Chromosomal gains at 9q characterize enteropathy-type T-cell lymphoma". doi:10.1016/S0002-9440(10)64441-0. PMC 1850794. PMID 12414511.CS1 maint: PMC format (link)
  10. ↑ 10.00 10.01 10.02 10.03 10.04 10.05 10.06 10.07 10.08 10.09 10.10 10.11 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)
  11. ↑ Roberti, Annalisa; et al. (09 07, 2016). "Type II enteropathy-associated T-cell lymphoma features a unique genomic profile with highly recurrent SETD2 alterations". Nature Communications. 7: 12602. doi:10.1038/ncomms12602. ISSN 2041-1723. PMC 5023950. PMID 27600764. Check date values in: |date= (help)
  12. ↑ Zhang, Ping; et al. (2020-11-07). "Epigenetic alterations and advancement of treatment in peripheral T-cell lymphoma". Clinical Epigenetics. 12 (1): 169. doi:10.1186/s13148-020-00962-x. ISSN 1868-7083. PMC PMC7648940 Check |pmc= value (help). PMID 33160401 Check |pmid= value (help).CS1 maint: PMC format (link)
  13. ↑ Sm, Horwitz; et al. (2014). "Objective responses in relapsed T-cell lymphomas with single-agent brentuximab vedotin". doi:10.1182/blood-2013-12-542142. PMC 4425442. PMID 24652992.CS1 maint: PMC format (link)
  14. ↑ Fanale, Michelle A.; et al. (2018-05-10). "Five-year outcomes for frontline brentuximab vedotin with CHP for CD30-expressing peripheral T-cell lymphomas". Blood. 131 (19): 2120–2124. doi:10.1182/blood-2017-12-821009. ISSN 0006-4971. PMC 5946765. PMID 29507077.
  15. ↑ National Comprehensive Cancer Network (January 2021). "NCCN Clinical Practice Guidelines in Oncology: Peripheral T-cell Lymphomas" (PDF).CS1 maint: display-authors (link)
  16. ↑ Ak, Baumgärtner; et al. (2003). "High frequency of genetic aberrations in enteropathy-type T-cell lymphoma". PMID 14563952.
  17. ↑ Tomita, Sakura; et al. (2015-10). "Genomic and immunohistochemical profiles of enteropathy-associated T-cell lymphoma in Japan". Modern Pathology. 28 (10): 1286–1296. doi:10.1038/modpathol.2015.85. ISSN 1530-0285. Check date values in: |date= (help)
  18. ↑ Obermann, E. C.; et al. (2004-02). "Loss of heterozygosity at chromosome 9p21 is a frequent finding in enteropathy-type T-cell lymphoma". The Journal of Pathology. 202 (2): 252–262. doi:10.1002/path.1506. ISSN 0022-3417. PMID 14743509. Check date values in: |date= (help)
  19. ↑ A, Al-Toma; et al. (2006). "Human leukocyte antigen-DQ2 homozygosity and the development of refractory celiac disease and enteropathy-associated T-cell lymphoma". PMID 16527694.
  20. ↑ Sh, Swerdlow; et al. (2020). "As the world turns, evolving lymphoma classifications-past, present and future". PMID 31493426.
  21. ↑ 21.0 21.1 21.2 21.3 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)
  22. ↑ 22.0 22.1 22.2 22.3 G, Malamut; et al. (2010). "IL-15 triggers an antiapoptotic pathway in human intraepithelial lymphocytes that is a potential new target in celiac disease-associated inflammation and lymphomagenesis". doi:10.1172/JCI41344. PMC 2877946. PMID 20440074.CS1 maint: PMC format (link)
  23. ↑ 23.0 23.1 23.2 23.3 Mention, Jean-Jacques; et al. (2003-09). "Interleukin 15: a key to disrupted intraepithelial lymphocyte homeostasis and lymphomagenesis in celiac disease". Gastroenterology. 125 (3): 730–745. doi:10.1016/s0016-5085(03)01047-3. ISSN 0016-5085. PMID 12949719. Check date values in: |date= (help)
  24. ↑ 24.0 24.1 24.2 24.3 24.4 A, Di Sabatino; et al. (2012). "How I treat enteropathy-associated T-cell lymphoma". PMID 22271451.
  25. ↑ 25.0 25.1 25.2 25.3 25.4 Sj, Van Weyenberg; et al. (2011). "MR enteroclysis in refractory celiac disease: proposal and validation of a severity scoring system". PMID 21330559.
  26. ↑ Wh, Verbeek; et al. (2008). "Flow cytometric determination of aberrant intra-epithelial lymphocytes predicts T-cell lymphoma development more accurately than T-cell clonality analysis in Refractory Celiac Disease". PMID 18024205.
  27. ↑ A, Al-Toma; et al. (2006). "Human leukocyte antigen-DQ2 homozygosity and the development of refractory celiac disease and enteropathy-associated T-cell lymphoma". PMID 16527694.
  28. ↑ Deleeuw, Ronald J.; et al. (2007-05). "Whole-genome analysis and HLA genotyping of enteropathy-type T-cell lymphoma reveals 2 distinct lymphoma subtypes". Gastroenterology. 132 (5): 1902–1911. doi:10.1053/j.gastro.2007.03.036. ISSN 0016-5085. PMID 17484883. Check date values in: |date= (help)

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: “Enteropathy-associated T-cell lymphoma”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 11/30/2023, https://ccga.io/index.php/HAEM5:Enteropathy-associated_T-cell_lymphoma.

Retrieved from "https://ccga.io/index.php?title=HAEM5:Enteropathy-associated_T-cell_lymphoma&oldid=13156"