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]

Immunophenotype

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

Links

References

  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. 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.
  10. Ak, Baumgärtner; et al. (2003). "High frequency of genetic aberrations in enteropathy-type T-cell lymphoma". PMID 14563952.
  11. 11.0 11.1 11.2 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)
  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)
  13. 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)
  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)
  17. 17.0 17.1 17.2 17.3 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)
  18. 18.0 18.1 18.2 18.3 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)
  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.
  20. 20.0 20.1 20.2 20.3 20.4 Sj, Van Weyenberg; et al. (2011). "MR enteroclysis in refractory celiac disease: proposal and validation of a severity scoring system". PMID 21330559.
  21. 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.
  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)
  24. 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)
  25. 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.
  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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