HAEM5:Enteropathy-associated T-cell lymphoma

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:Enteropathy-Associated T-cell Lymphoma.

(General Instructions – The main focus of these pages is the clinically significant genetic alterations in each disease type. Use HUGO-approved gene names and symbols (italicized when appropriate), HGVS-based nomenclature for variants, as well as generic names of drugs and testing platforms or assays if applicable. Please complete tables whenever possible and do not delete them (add N/A if not applicable in the table and delete the examples); to add (or move) a row or column to a table, click within the table and select the > symbol that appears to be given options. Please do not delete or alter the section headings. The use of bullet points alongside short blocks of text rather than only large paragraphs is encouraged. Additional instructions below in italicized blue text should not be included in the final page content. Please also see Author_Instructions and FAQs as well as contact your Associate Editor or Technical Support)

Primary Author(s)*

• FNU Monika, MBBS
• Andrew Siref, 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)	Enteropathy-associated T-cell lymphoma

Definition / Description of Disease

• Enteropathy-associated T-cell lymphoma (EATL) is an aggressive intestinal T-cell lymphoma more common in patients with celiac disease, especially type II refractory celiac disease (RCDII).
• Most of the EATL cases develop through an intermediate step of RCDII, however it can also arise de novo in patients with celiac disease. 33579790
• RCDII can be defined as failure to respond to a strict gluten-free diet for at least 12 months and is associated with clonal expansion of immunophenotypically an aberrant IELs , { 33707055 }.
• 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
• Risk factors include homozygosity for HLA-DQ2 and advanced age

Synonyms / Terminology

• None

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)
• EATL accounts for 3% of peripheral T-cell lymphomas and represents 66% of all primary intestinal T-cell lymphomas
• More common in regions with a high prevalence of CD, particularly Europe (0.05–0.14 cases per 100 000 population) { 15825131 ; 20197551 ; 18618372 } and the USA (0.016 cases per 100 000 population)
• Extremely rare in Asia due to low population frequency of celiac HLA risk alleles
• > 60% of all cases in intestinal T- cell lymphomas
• M:F 1.04:1 to 2.8:1
• 6th-7th decade of life
• Mostly Caucasian (> 90%)

Clinical Features

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

Signs and Symptoms	Abdominal pain Weight loss Gluten-insensitive diarrhea/malabsorption Bowel obstruction or perforation (50% cases)
Laboratory Findings	Anemia Hypoalbuminemia Hemophagocytosis

• CD can be diagnosed at the time of EATL diagnosis
• Patients with RCD can sometimes present with small-intestinal ulceration (ulcerative jejunitis) { 9250161 ; 10381521 }.

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)
• Dissemination to extra gastrointestinal sites: mesenteric and abdominal lymph nodes > bone marrow, lung, liver or skin { 8583077 ; 23313469 ; 21566094 }.
• Metastases involve intra-abdominal node > bone marrow > lung > liver > skin
• CNS (rare)

Morphologic Features

• Pleomorphic medium to large sized neoplastic lymphoid cells with immunoblastic or anaplastic morphology.
• Angulated vesicular nuclei, prominent nucleoli, and a pale-staining cytoplasm [https://doi.org/10.3390/diagnostics13162629]
• Extensive inflammatory background of histiocytes, eosinophils, small lymphocytes, and plasma cells
• Adjacent mucosa often displays the histological features of active CD, including increased IEL infiltration, crypt hyperplasia, and villous atrophy [https://doi.org/10.3390/diagnostics13162629]
• Angioinvasion and angiodestruction are commonly seen
• Neighborhood mucosa characterized by villous atrophy and crypt hyperplasia (non-malignant areas of celiac disease)
• Round or angulated vesicular nuclei
• Prominent nucleoli
• Moderate-abundant pale cytoplasm
• Extensive admixture of inflammatory cells (eosinophils, histiocytes)
• Angiocentric and angioinvasive features with extensive necrosis

Immunophenotype

• The most common immunophenotypic profile in EATL is given below:

Finding	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, EBER
Ki-67	high

• Approximately 25% of EATLs (primarily de novo EATL) are CD8+, and rare cases express TCRγδ [23313469, 26462278]
• Ki-67 is very low and CD30 is negative in RCDII, their appearance is useful to monitor RCDII progression to EATL and to indicate the need for chemotherapeutic regimens targeting dividing cells, a therapeutic option that is inefficient and even dangerous in RCDII. 33579790

	RCD Type 1	RCD Type 2	EATL
Histopathology	Identical to uncomplicated CD	Moderate/ severe villous atrophy with atypical IELs	Infiltration of medium to large sized pleomorphic IELs
IEL Immunophenotype	Like CD; sCD3+, CD8+

Immunophenotype of intraepithelial lymphocytes (IEL):

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

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. Do not delete table.)

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
9	gain	9q	q22-34				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).
16	loss	16q	12.1				EXAMPLE: Common recurrent secondary finding for t(8;21) (add reference).
1	gain	1q	q22-44
5	gain	5q	q33.3–34
9	LOH	9p	p21
7	gain	7q	q11.21-q36.1
8	loss	8p	p23.3-p11.21
8	gain	8q	q24
13	loss	13q
17	loss	17p	p12-13.2

editv4:Genomic Gain/Loss/LOH

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

Chromosome Number	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
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

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

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
• HLA-DQB1*02 genotype correlated with 5q gain

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 as 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. Do not delete table.)

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
SETD2	TSG	32%
YLPM1	TSG	22%
TET2	TSG	14%
STAT5B	Oncogene	29%
JAK1	Oncogene	23% 48%
JAK3	Oncogene	23%
STAT3	oncogene	16%, 38%
SOCS1	TSG	7%
SOCS3	TSG	8%
NRAS	Oncogene	10%
KRAS	Oncogene	6%
TP53	TSG	10%
BCL11B	TSG	13%
BRIP1	TSG	16%
TERT	Oncogene	17%
BBX	Cell cycle transcription factor	16%
DAPK3	Apoptosis	10%
PRDM1	Interferon-related transcription factor	9%

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.

*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

Epigenomic Alterations

• SETD2 is a histone H3 lysine 36 methyltransferase (forms H3K37me3)
  • 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. Do not delete table.)

Gene; Genetic Alteration	Pathway	Pathophysiologic Outcome
SETD2, TET2, YLPM1; loss of function mutations	Gene regulation	EXAMPLE: Increased cell growth and proliferation
JAK1, JAK3, STAT3, STAT5B, SOCS1	JAK-STAT pathway	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
• JAK-STAT pathway: JAK1, JAK3, STAT3, STAT5B, SOCS1; mutated drivers in this pathway tended to be mutually exclusive
• RAS/MAPK signaling pathway
• IL-15 deregulation and disruption of intestinal immune homeostasis
• Overexpression of genes involved in Interferon-γ signaling

Genetic Diagnostic Testing Methods

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

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
  • HLA-DQB1*02 genotype correlated with 5q gain

Additional Information

• N/A

Links

• HAEM4:Intestinal T-cell Lymphomas
• Monomorphic epitheliotropic 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.)

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 09/6/2024, https://ccga.io/index.php/HAEM5:Enteropathy-associated_T-cell_lymphoma.