Enteropathy-Associated T-cell Lymphoma

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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

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]


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)

  • No recurrent gene fusions reported

Characteristic Chromosomal Aberrations / Patterns

  • HLA-DQ2 (HLA-DQA1*0501 and DQB1*02) homozygosity - increased (at least 5-fold) risk for RCD and EATL[9]
  • HLA-DQB1*02 genotype correlated with 5q gain [8]

Genomic Gain/Loss/LOH

Chromosome Number[8][10][11][12][13] 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[14]
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[12]

Gene Mutations (SNV/INDEL)

Gene*[12][15] Function/Oncogene/Tumor Suppressor Gene Frequency[12]
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[12]

Epigenomics (Methylation)

  • SETD2 is a histone H3 lysine 36 methyltransferase (forms H3K37me3)[12]
    • Altered (mostly by loss-of-function mutations) in ~32% of EATL
    • Results in global H3K36 hypomethylation

Genes and Main Pathways Involved

  • Chromatin modifying genes: SETD2, TET2, YLPM1; loss of function mutations[12][16][17][18]
  • JAK-STAT pathway: JAK1, JAK3, STAT3, STAT5B, SOCS1; mutated drivers in this pathway tended to be mutually exclusive[12][16][17][18]
  • RAS/MAPK signaling pathway[12][16][17][18]
  • IL-15 deregulation and disruption of intestinal immune homeostasis[12][16][17][18]
  • Overexpression of genes involved in Interferon-γ signaling[12]

Diagnostic Testing Methods

  • No specific recurrent genetic abnormalities that are diagnostic for EATL[19][20]
  • Clonality can be confirmed by T-cell receptor gene rearrangement studies[19][20]
    • Intraepithelial lymphocytes in type 2 refractory celiac disease show similar gene rearrangement size as EATL[19][20]
  • Chromosomal microarrays may identify genetic abnormalities frequently associated with EATL[19][20]
  • Next generation sequencing may identify genetic abnormalities frequently associated with EATL[19][20]
  • 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[21]

Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)

  • 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][11]
      • SETD2 mutations are common in both EATL (32%)[12] and MEITL (91%)[22]
  • Prognosis
    • In one study, >3 chromosomal imbalance was associated with worse prognosis[11]
  • Therapeutic Implications
    • Recurrent mutations in epigenetic machinery genes - epigenetic modifying drugs may be effective[23]
    • 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[24][25]
    • No FDA-approved targeted therapies currently available[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]

Other Information

  • N/A



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  10. Ak, Baumgärtner; et al. (2003). "High frequency of genetic aberrations in enteropathy-type T-cell lymphoma". PMID 14563952.
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  12. 12.00 12.01 12.02 12.03 12.04 12.05 12.06 12.07 12.08 12.09 12.10 12.11 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)
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  14. 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)
  15. Sh, Swerdlow; et al. (2020). "As the world turns, evolving lymphoma classifications-past, present and future". PMID 31493426.
  16. 16.0 16.1 16.2 16.3 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)
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  19. 19.0 19.1 19.2 19.3 19.4 A, Di Sabatino; et al. (2012). "How I treat enteropathy-associated T-cell lymphoma". PMID 22271451.
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  22. 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)
  23. 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)
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  26. National Comprehensive Cancer Network (January 2021). "NCCN Clinical Practice Guidelines in Oncology: Peripheral T-cell Lymphomas" (PDF).CS1 maint: display-authors (link)
  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)


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