Compendium of Cancer Genome Aberrations

HAEM5:Enteropathy-associated T-cell lymphoma: Difference between revisions

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{{DISPLAYTITLE:Enteropathy-associated T-cell lymphoma}}
{{DISPLAYTITLE:Enteropathy-associated T-cell lymphoma}}
 
[[HAEM5:Table_of_Contents|Haematolymphoid Tumours (WHO Classification, 5th ed.)]]
[[HAEM5:Table_of_Contents|Haematolymphoid Tumours (5th ed.)]]


{{Under Construction}}
{{Under Construction}}


<blockquote class="blockedit">{{Box-round|title=HAEM5 Conversion Notes|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]].
<blockquote class="blockedit">{{Box-round|title=Content 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]].
}}</blockquote>
}}</blockquote>


<span style="color:#0070C0">(General Instructions – The main focus of these pages is the clinically significant genetic alterations in each disease type. Use [https://www.genenames.org/ <u>HUGO-approved gene names and symbols</u>] (italicized when appropriate), [https://varnomen.hgvs.org/ 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). 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 </span><u>[[Author_Instructions]]</u><span style="color:#0070C0"> and [[Frequently Asked Questions (FAQs)|<u>FAQs</u>]] as well as contact your [[Leadership|<u>Associate Editor</u>]] or [mailto:CCGA@cancergenomics.org <u>Technical Support</u>])</span>
<span style="color:#0070C0">(General Instructions – The focus of these pages is the clinically significant genetic alterations in each disease type. This is based on up-to-date knowledge from multiple resources such as PubMed and the WHO classification books. The CCGA is meant to be a supplemental resource to the WHO classification books; the CCGA captures in a continually updated wiki-stye manner the current genetics/genomics knowledge of each disease, which evolves more rapidly than books can be revised and published. If the same disease is described in multiple WHO classification books, the genetics-related information for that disease will be consolidated into a single main page that has this template (other pages would only contain a link to this main page). Use [https://www.genenames.org/ <u>HUGO-approved gene names and symbols</u>] (italicized when appropriate), [https://varnomen.hgvs.org/ <u>HGVS-based nomenclature for variants</u>], 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 in a table, click nearby within the table and select the > symbol that appears. 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 </span><u>[[Author_Instructions]]</u><span style="color:#0070C0"> and [[Frequently Asked Questions (FAQs)|<u>FAQs</u>]] as well as contact your [[Leadership|<u>Associate Editor</u>]] or [mailto:CCGA@cancergenomics.org <u>Technical Support</u>].)</span>


==Primary Author(s)*==
==Primary Author(s)*==
Line 14: Line 13:
*FNU Monika, MBBS
*FNU Monika, MBBS
*Andrew Siref, MD
*Andrew Siref, MD
__TOC__
==Cancer Category / Type==
*HAEM5: Mature T-cell and NK-cell neoplasms
==Cancer Sub-Classification / Subtype==
*Intestinal T-cell and NK-cell lymphoid proliferations and lymphomas / None
==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. <u>33579790</u>'''
*'''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''' <ref name=":5">Govind Bhagat, et al. Enteropathy-associated T-cell lymphoma. In:  WHO Classification of Tumours Editorial Board. Haematolymphoid tumours [Internet]. Lyon (France): International Agency for Research on Cancer; 2024 [cited 2024 July 2]. (WHO classification of tumors series, 5th ed.; vol. 11). Available from: <nowiki>https://tumourclassification.iarc.who.int/chaptercontent/63/224</nowiki> </ref>, { 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<ref name=":5" />
*Risk factors include homozygosity for HLA-DQ2 and advanced age<ref name=":5" />
==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)<ref name=":6">{{Cite journal|last=Wh|first=Verbeek|last2=Jm|first2=Van De Water|last3=A|first3=Al-Toma|last4=Jj|first4=Oudejans|last5=Cj|first5=Mulder|last6=Vm|first6=Coupé|date=2008|title=Incidence of enteropathy--associated T-cell lymphoma: a nation-wide study of a population-based registry in The Netherlands|url=https://pubmed.ncbi.nlm.nih.gov/18618372/|language=en|pmid=18618372}}</ref><ref name=":1">{{Cite journal|last=Aj|first=Ferreri|last2=Pl|first2=Zinzani|last3=S|first3=Govi|last4=Sa|first4=Pileri|date=2011|title=Enteropathy-associated T-cell lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/20655757/|language=en|pmid=20655757}}</ref><ref name=":2">{{Cite journal|last=J|first=Delabie|last2=H|first2=Holte|last3=Jm|first3=Vose|last4=F|first4=Ullrich|last5=Es|first5=Jaffe|last6=Kj|first6=Savage|last7=Jm|first7=Connors|last8=L|first8=Rimsza|last9=Nl|first9=Harris|date=2011|title=Enteropathy-associated T-cell lymphoma: clinical and histological findings from the international peripheral T-cell lymphoma project|url=https://pubmed.ncbi.nlm.nih.gov/21566094/|language=en|pmid=21566094}}</ref><ref>{{Cite journal|last=A|first=Rubio-Tapia|last2=Ja|first2=Murray|date=2010|title=Classification and management of refractory coeliac disease|url=https://pubmed.ncbi.nlm.nih.gov/20332526/|language=en|doi=10.1136/gut.2009.195131|pmc=PMC2861306|pmid=20332526}}</ref><ref>{{Cite journal|last=G|first=Malamut|last2=P|first2=Afchain|last3=V|first3=Verkarre|last4=T|first4=Lecomte|last5=A|first5=Amiot|last6=D|first6=Damotte|last7=Y|first7=Bouhnik|last8=Jf|first8=Colombel|last9=Jc|first9=Delchier|date=2009|title=Presentation and long-term follow-up of refractory celiac disease: comparison of type I with type II|url=https://pubmed.ncbi.nlm.nih.gov/19014942/|language=en|pmid=19014942}}</ref>
*'''EATL accounts for 3% of peripheral T-cell lymphomas and represents 66% of all primary intestinal T-cell lymphomas'''<ref name=":5" />
*'''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<ref name=":6" /><ref name=":1" /><ref name=":2" />'''
*> 60% of all cases in intestinal T- cell lymphomas<ref name=":6" /><ref name=":1" /><ref name=":2" />
*'''M:F 1.04:1 to 2.8:1'''<ref name=":6" /><ref name=":1" /><ref name=":2" />
*'''6th-7th decade of life'''<ref name=":6" /><ref name=":1" /><ref name=":2" />
*Mostly Caucasian (> 90%)<ref name=":6" /><ref name=":1" /><ref name=":2" />


==Clinical Features==
==WHO Classification of Disease==


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.<ref name=":1" />
{| class="wikitable"
{| class="wikitable"
|'''Signs and Symptoms'''
!Structure
|
!Disease
*Abdominal pain
*Weight loss
*Gluten-insensitive diarrhea/malabsorption
*Bowel obstruction or perforation (50% cases)
|-
|-
|'''Laboratory Findings'''
|Book
|
|Haematolymphoid Tumours (5th ed.)
*Anemia
*Hypoalbuminemia
*Hemophagocytosis
|}
 
*'''CD can be diagnosed at the time of EATL diagnosis'''<ref name=":5" />
*'''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)<ref name=":1" />'''
*'''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<ref name=":1" />
*CNS (rare)<ref name=":1" />
 
==Morphologic Features==
 
*Pleomorphic medium to large neoplastic lymphoid infiltrate<ref name=":2" />
*Neighborhood mucosa characterized by villous atrophy and crypt hyperplasia (non-malignant areas of celiac disease)<ref name=":2" />
*Round or angulated vesicular nuclei<ref name=":2" />
*Prominent nucleoli<ref name=":2" />
*Moderate-abundant pale cytoplasm<ref name=":2" />
*Extensive admixture of inflammatory cells (eosinophils, histiocytes)<ref name=":2" />
*Angiocentric and angioinvasive features with extensive necrosis<ref name=":2" />
 
==Immunophenotype==
 
Put your text here and fill in the table <span style="color:#0070C0">(''Instruction: Can include references in the table'') </span>
 
{| class="wikitable sortable"
|-
|-
!Finding!!Marker
|Category
|T-cell and NK-cell lymphoid proliferations and lymphomas
|-
|-
|Positive (universal)||CD3, CD7
|Family
|Mature T-cell and NK-cell neoplasms
|-
|-
|Positive (frequent)||CD30 (harbinger of transformation to EATL from RCD2), NKP46 (not seen in IEL of CD or RCD1), CD103,
|Type
cytotoxic granule-associated markers (TIA1, granzyme B, perforin)
|Intestinal T-cell and NK-cell lymphoid proliferations and lymphomas
|-
|-
|Negative (frequent)||CD4, CD8, CD5, CD56, TCR, EBER
|Subtype(s)
|Enteropathy-associated T-cell lymphoma
|}
 
==Related Terminology==
 
{| class="wikitable"
|+
|Acceptable
|N/A
|-
|-
|Ki-67||high
|Not Recommended
|Type I enteropathy-associated T-cell lymphoma
|}
|}


==Gene Rearrangements==
Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: Details on clinical significance such as prognosis and other important information can be provided in the notes section. Please include references throughout the table. Do not delete the table.'')</span>
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
!Finding
!Driver Gene!!Fusion(s) and Common Partner Genes!!Molecular Pathogenesis!!Typical Chromosomal Alteration(s)
!Type 1 RCD!!Type 2 RCD
!Prevalence -Common >20%, Recurrent 5-20% or Rare <5% (Disease)
!Diagnostic, Prognostic, and Therapeutic Significance - D, P, T
!Established Clinical Significance Per Guidelines - Yes or No (Source)
!Clinical Relevance Details/Other Notes
|-
|-
|Positive (universal)
|<span class="blue-text">EXAMPLE:</span> ''ABL1''||<span class="blue-text">EXAMPLE:</span> ''BCR::ABL1''||<span class="blue-text">EXAMPLE:</span> The pathogenic derivative is the der(22) resulting in fusion of 5’ BCR and 3’ABL1.||<span class="blue-text">EXAMPLE:</span> t(9;22)(q34;q11.2)
| ||CD3, CD7
|<span class="blue-text">EXAMPLE:</span> Common (CML)
|<span class="blue-text">EXAMPLE:</span> D, P, T
|<span class="blue-text">EXAMPLE:</span> Yes (WHO, NCCN)
|<span class="blue-text">EXAMPLE:</span>
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). BCR::ABL1 is generally favorable in CML (add reference).
|-
|-
|Positive (frequent)
|<span class="blue-text">EXAMPLE:</span> ''CIC''
| ||CD30 (harbinger of transformation to EATL from RCD2), NKP46 (not seen in IEL of CD or RCD1), CD103,
|<span class="blue-text">EXAMPLE:</span> ''CIC::DUX4''
cytotoxic granule-associated markers (TIA1, granzyme B, perforin)
|<span class="blue-text">EXAMPLE:</span> Typically, the last exon of ''CIC'' is fused to ''DUX4''. The fusion breakpoint in ''CIC'' is usually intra-exonic and removes an inhibitory sequence, upregulating ''PEA3'' genes downstream of ''CIC'' including ''ETV1'', ''ETV4'', and ''ETV5''.
|-
|<span class="blue-text">EXAMPLE:</span> t(4;19)(q25;q13)
|Negative (frequent)
|<span class="blue-text">EXAMPLE:</span> Common (CIC-rearranged sarcoma)
| ||CD4, CD8, CD5, CD56, TCR, EBER
|<span class="blue-text">EXAMPLE:</span> D
|
|<span class="blue-text">EXAMPLE:</span>
 
''DUX4'' has many homologous genes; an alternate translocation in a minority of cases is t(10;19), but this is usually indistinguishable from t(4;19) by short-read sequencing (add references).
|-
|-
|Ki-67
|<span class="blue-text">EXAMPLE:</span> ''ALK''
| ||high
|<span class="blue-text">EXAMPLE:</span> ''ELM4::ALK''
|}


Immunophenotype of intraepithelial lymphocytes (IEL):<ref name=":7">{{Cite journal|last=P|first=Domizio|last2=Ra|first2=Owen|last3=Na|first3=Shepherd|last4=Ic|first4=Talbot|last5=Aj|first5=Norton|date=1993|title=Primary lymphoma of the small intestine. A clinicopathological study of 119 cases|url=https://pubmed.ncbi.nlm.nih.gov/8470758/|language=en|pmid=8470758}}</ref><ref name=":0">{{Cite journal|last=Deleeuw|first=Ronald J.|last2=Zettl|first2=Andreas|last3=Klinker|first3=Erdwine|last4=Haralambieva|first4=Eugenia|last5=Trottier|first5=Magan|last6=Chari|first6=Raj|last7=Ge|first7=Yong|last8=Gascoyne|first8=Randy D.|last9=Chott|first9=Andreas|date=2007-05|title=Whole-genome analysis and HLA genotyping of enteropathy-type T-cell lymphoma reveals 2 distinct lymphoma subtypes|url=https://pubmed.ncbi.nlm.nih.gov/17484883|journal=Gastroenterology|volume=132|issue=5|pages=1902–1911|doi=10.1053/j.gastro.2007.03.036|issn=0016-5085|pmid=17484883}}</ref>


*Varies depending on background type 1 or type 2 refractory celiac disease (RCD).
Other fusion partners include ''KIF5B, NPM1, STRN, TFG, TPM3, CLTC, KLC1''
**Type 1 (RCD1):
|<span class="blue-text">EXAMPLE:</span> Fusions result in constitutive activation of the ''ALK'' tyrosine kinase. The most common ''ALK'' fusion is ''EML4::ALK'', with breakpoints in intron 19 of ''ALK''. At the transcript level, a variable (5’) partner gene is fused to 3’ ''ALK'' at exon 20. Rarely, ''ALK'' fusions contain exon 19 due to breakpoints in intron 18.
***Milder symptoms with high 5-year survival with low risk of EATL development
|<span class="blue-text">EXAMPLE:</span> N/A
***Flow cytometry: sCD3+, CD8+, CD5+
|<span class="blue-text">EXAMPLE:</span> Rare (Lung adenocarcinoma)
**Type 2 (RCD2):
|<span class="blue-text">EXAMPLE:</span> T
***Severe symptoms with protein-losing enteropathy leads to malnourishment (BMI < 18); low 5-year survival with increased risk of EATL
|
***Flow cytometry: sCD3<sup>_</sup>, CD8-, CD5-
|<span class="blue-text">EXAMPLE:</span>
***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 [[HAEM5:Monomorphic epitheliotropic intestinal T-cell lymphoma|MEITL]]; not seen in [[HAEM5:Indolent T-cell lymphoma of the gastrointestinal tract|indolent T-cell LPD of GI tract]]
****CD30+ indicates progression to EATL
**'''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. <u>33579790</u>'''


==Chromosomal Rearrangements (Gene Fusions)==
Both balanced and unbalanced forms are observed by FISH (add references).
 
|-
No recurrent gene fusions have been reported.<blockquote class="blockedit">{{Box-round|title=v4:Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications).|Please incorporate this section into the relevant tables found in:
|<span class="blue-text">EXAMPLE:</span> ''ABL1''
|<span class="blue-text">EXAMPLE:</span> N/A
|<span class="blue-text">EXAMPLE:</span> Intragenic deletion of exons 2–7 in ''EGFR'' removes the ligand-binding domain, resulting in a constitutively active tyrosine kinase with downstream activation of multiple oncogenic pathways.
|<span class="blue-text">EXAMPLE:</span> N/A
|<span class="blue-text">EXAMPLE:</span> Recurrent (IDH-wildtype Glioblastoma)
|<span class="blue-text">EXAMPLE:</span> D, P, T
|
|
|-
|
|
|
|
|
|
|
|
|}
<blockquote class="blockedit">{{Box-round|title=v4:Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications).|Please incorporate this section into the relevant tables found in:
* Chromosomal Rearrangements (Gene Fusions)
* Chromosomal Rearrangements (Gene Fusions)
* Individual Region Genomic Gain/Loss/LOH
* Individual Region Genomic Gain/Loss/LOH
* Characteristic Chromosomal Patterns
* Characteristic Chromosomal Patterns
* Gene Mutations (SNV/INDEL)}}
* Gene Mutations (SNV/INDEL)}}</blockquote>


*'''Diagnosis'''  
*'''Diagnosis'''  
**No specific recurrent genetic abnormality that is diagnostic for EATL
**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<ref name=":0" /><ref name=":3" />
***Gain of 1q and 5q more frequent in EATL, whereas 8q24 (MYC) gain is more frequent in MEITL<ref name=":0">{{Cite journal|last=Deleeuw|first=Ronald J.|last2=Zettl|first2=Andreas|last3=Klinker|first3=Erdwine|last4=Haralambieva|first4=Eugenia|last5=Trottier|first5=Magan|last6=Chari|first6=Raj|last7=Ge|first7=Yong|last8=Gascoyne|first8=Randy D.|last9=Chott|first9=Andreas|date=2007-05|title=Whole-genome analysis and HLA genotyping of enteropathy-type T-cell lymphoma reveals 2 distinct lymphoma subtypes|url=https://pubmed.ncbi.nlm.nih.gov/17484883|journal=Gastroenterology|volume=132|issue=5|pages=1902–1911|doi=10.1053/j.gastro.2007.03.036|issn=0016-5085|pmid=17484883}}</ref><ref name=":3" />
***SETD2 mutations are common in both EATL (32%)<ref name=":4" /> and MEITL (91%)<ref>{{Cite journal|last=Roberti|first=Annalisa|last2=Dobay|first2=Maria Pamela|last3=Bisig|first3=Bettina|last4=Vallois|first4=David|last5=Boéchat|first5=Cloé|last6=Lanitis|first6=Evripidis|last7=Bouchindhomme|first7=Brigitte|last8=Parrens|first8=Marie-Cécile|last9=Bossard|first9=Céline|date=09 07, 2016|title=Type II enteropathy-associated T-cell lymphoma features a unique genomic profile with highly recurrent SETD2 alterations|url=https://pubmed.ncbi.nlm.nih.gov/27600764|journal=Nature Communications|volume=7|pages=12602|doi=10.1038/ncomms12602|issn=2041-1723|pmc=5023950|pmid=27600764}}</ref>
***SETD2 mutations are common in both EATL (32%)<ref name=":4" /> and MEITL (91%)<ref>{{Cite journal|last=Roberti|first=Annalisa|last2=Dobay|first2=Maria Pamela|last3=Bisig|first3=Bettina|last4=Vallois|first4=David|last5=Boéchat|first5=Cloé|last6=Lanitis|first6=Evripidis|last7=Bouchindhomme|first7=Brigitte|last8=Parrens|first8=Marie-Cécile|last9=Bossard|first9=Céline|date=09 07, 2016|title=Type II enteropathy-associated T-cell lymphoma features a unique genomic profile with highly recurrent SETD2 alterations|url=https://pubmed.ncbi.nlm.nih.gov/27600764|journal=Nature Communications|volume=7|pages=12602|doi=10.1038/ncomms12602|issn=2041-1723|pmc=5023950|pmid=27600764}}</ref>
*'''Prognosis'''
*'''Prognosis'''
Line 162: Line 126:
**No FDA-approved targeted therapies currently available<ref>{{Cite journal|displayauthors=1|last=National Comprehensive Cancer Network|first=|date=January 2021|title=NCCN Clinical Practice Guidelines in Oncology: Peripheral T-cell Lymphomas|url=https://www.nccn.org/professionals/physician_gls/pdf/t-cell.pdf|journal=|volume=|pages=|via=}}</ref>
**No FDA-approved targeted therapies currently available<ref>{{Cite journal|displayauthors=1|last=National Comprehensive Cancer Network|first=|date=January 2021|title=NCCN Clinical Practice Guidelines in Oncology: Peripheral T-cell Lymphomas|url=https://www.nccn.org/professionals/physician_gls/pdf/t-cell.pdf|journal=|volume=|pages=|via=}}</ref>


<blockquote class="blockedit">
<center><span style="color:Maroon">'''End of V4 Section'''</span>
----
</blockquote>
</blockquote>
==Individual Region Genomic Gain / Loss / LOH==


Put your text here and fill in the table <span style="color:#0070C0">(''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.'') </span>
==Individual Region Genomic Gain/Loss/LOH==
Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: Includes aberrations not involving gene rearrangements. Details on clinical significance such as prognosis and other important information can be provided in the notes section. Can refer to CGC workgroup tables as linked on the homepage if applicable. Please include references throughout the table. Do not delete the table.'') </span>
{| class="wikitable sortable"
|-
!Chr #!!Gain, Loss, Amp, LOH!!Minimal Region Cytoband and/or Genomic Coordinates [Genome Build; Size]!!Relevant Gene(s)
!Diagnostic, Prognostic, and Therapeutic Significance - D, P, T
!Established Clinical Significance Per Guidelines - Yes or No (Source)
!Clinical Relevance Details/Other Notes
|-
|<span class="blue-text">EXAMPLE:</span>
7
|<span class="blue-text">EXAMPLE:</span> Loss
|<span class="blue-text">EXAMPLE:</span>
chr7
|<span class="blue-text">EXAMPLE:</span>
Unknown
|<span class="blue-text">EXAMPLE:</span> D, P
|<span class="blue-text">EXAMPLE:</span> No
|<span class="blue-text">EXAMPLE:</span>
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 references).
|-
|<span class="blue-text">EXAMPLE:</span>
8
|<span class="blue-text">EXAMPLE:</span> Gain
|<span class="blue-text">EXAMPLE:</span>
chr8
|<span class="blue-text">EXAMPLE:</span>
Unknown
|<span class="blue-text">EXAMPLE:</span> D, P
|
|<span class="blue-text">EXAMPLE:</span>
Common recurrent secondary finding for t(8;21) (add references).
|-
|<span class="blue-text">EXAMPLE:</span>
17
|<span class="blue-text">EXAMPLE:</span> Amp
|<span class="blue-text">EXAMPLE:</span>
17q12; chr17:39,700,064-39,728,658 [hg38; 28.6 kb]
|<span class="blue-text">EXAMPLE:</span>
''ERBB2''
|<span class="blue-text">EXAMPLE:</span> D, P, T
|
|<span class="blue-text">EXAMPLE:</span>
Amplification of ''ERBB2'' is associated with HER2 overexpression in HER2 positive breast cancer (add references). Add criteria for how amplification is defined.
|-
|
|
|
|
|
|
|
|}
 
 
Put your text here and fill in the table <span style="color:#0070C0">(''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.'') </span>


{| class="wikitable sortable"
{| class="wikitable sortable"
Line 182: Line 203:
|
|
|
|
|EXAMPLE
|<span class="blue-text">EXAMPLE:</span>


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).
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).
Line 193: Line 214:
|
|
|
|
|EXAMPLE
|<span class="blue-text">EXAMPLE:</span>


Common recurrent secondary finding for t(8;21) (add reference).
Common recurrent secondary finding for t(8;21) (add reference).
Line 270: Line 291:
|}
|}


<blockquote class="blockedit">{{Box-round|title=v4:Genomic Gain/Loss/LOH|The content below was from the old template. Please incorporate above.}}
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{| class="wikitable"
{| class="wikitable"
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<br />
<br />
<blockquote class="blockedit">
<center><span style="color:Maroon">'''End of V4 Section'''</span>
----
</blockquote>
</blockquote>
==Characteristic Chromosomal Patterns==
Put your text here <span style="color:#0070C0">(''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'')</span>


==Characteristic Chromosomal or Other Global Mutational Patterns==
Put your text here and fill in the table <span style="color:#0070C0">(I''nstructions: Included in this category are alterations such as 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; microsatellite instability; homologous recombination deficiency; mutational signature pattern; etc. Details on clinical significance such as prognosis and other important information can be provided in the notes section. Please include references throughout the table. Do not delete the table.'')</span>
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
!Chromosomal Pattern
!Chromosomal Pattern
!Diagnostic Significance (Yes, No or Unknown)
!Molecular Pathogenesis
!Prognostic Significance (Yes, No or Unknown)
!Prevalence -
!Therapeutic Significance (Yes, No or Unknown)
Common >20%, Recurrent 5-20% or Rare <5% (Disease)
!Notes
!Diagnostic, Prognostic, and Therapeutic Significance - D, P, T
!Established Clinical Significance Per Guidelines - Yes or No (Source)
!Clinical Relevance Details/Other Notes
|-
|-
|EXAMPLE
|<span class="blue-text">EXAMPLE:</span>
 
Co-deletion of 1p and 18q
Co-deletion of 1p and 18q
|Yes
|<span class="blue-text">EXAMPLE:</span> See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference).
|No
|<span class="blue-text">EXAMPLE:</span> Common (Oligodendroglioma)
|No
|<span class="blue-text">EXAMPLE:</span> D, P
|EXAMPLE:
|
 
|
See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference).
|-
|<span class="blue-text">EXAMPLE:</span>
Microsatellite instability - hypermutated
|
|<span class="blue-text">EXAMPLE:</span> Common (Endometrial carcinoma)
|<span class="blue-text">EXAMPLE:</span> P, T
|
|
|-
|
|
|
|
|
|
|}
|}


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*HLA-DQ2 (HLA-DQA1*0501 and DQB1*02) homozygosity - increased (at least 5-fold) risk for RCD and EATL<ref>{{Cite journal|last=A|first=Al-Toma|last2=Ms|first2=Goerres|last3=Jw|first3=Meijer|last4=As|first4=Peña|last5=Jb|first5=Crusius|last6=Cj|first6=Mulder|date=2006|title=Human leukocyte antigen-DQ2 homozygosity and the development of refractory celiac disease and enteropathy-associated T-cell lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/16527694/|language=en|pmid=16527694}}</ref>
*HLA-DQ2 (HLA-DQA1*0501 and DQB1*02) homozygosity - increased (at least 5-fold) risk for RCD and EATL<ref>{{Cite journal|last=A|first=Al-Toma|last2=Ms|first2=Goerres|last3=Jw|first3=Meijer|last4=As|first4=Peña|last5=Jb|first5=Crusius|last6=Cj|first6=Mulder|date=2006|title=Human leukocyte antigen-DQ2 homozygosity and the development of refractory celiac disease and enteropathy-associated T-cell lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/16527694/|language=en|pmid=16527694}}</ref>
*HLA-DQB1*02 genotype correlated with 5q gain <ref name=":0" />
*HLA-DQB1*02 genotype correlated with 5q gain <ref name=":0" />


<blockquote class="blockedit">
<center><span style="color:Maroon">'''End of V4 Section'''</span>
----
</blockquote>
</blockquote>
==Gene Mutations (SNV / INDEL)==


Put your text here and fill in the table <span style="color:#0070C0">(''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.'') </span>
==Gene Mutations (SNV/INDEL)==
Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: This table is not meant to be an exhaustive list; please include only genes/alterations that are recurrent or common as well either disease defining and/or clinically significant. If a gene has multiple mechanisms depending on the type or site of the alteration, add multiple entries 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. Details on clinical significance such as prognosis and other important information such as concomitant and mutually exclusive mutations can be provided in the notes section. Please include references throughout the table. Do not delete the table.'') </span>
{| class="wikitable sortable"
|-
!Gene!!Genetic Alteration!!Tumor Suppressor Gene, Oncogene, Other!!Prevalence -
Common >20%, Recurrent 5-20% or Rare <5% (Disease)
!Diagnostic, Prognostic, and Therapeutic Significance - D, P, T  
!Established Clinical Significance Per Guidelines - Yes or No (Source)
!Clinical Relevance Details/Other Notes
|-
|<span class="blue-text">EXAMPLE:</span>''EGFR''
 
<br />
|<span class="blue-text">EXAMPLE:</span> Exon 18-21 activating mutations
|<span class="blue-text">EXAMPLE:</span> Oncogene
|<span class="blue-text">EXAMPLE:</span> Common (lung cancer)
|<span class="blue-text">EXAMPLE:</span> T
|<span class="blue-text">EXAMPLE:</span> Yes (NCCN)
|<span class="blue-text">EXAMPLE:</span> Exons 18, 19, and 21 mutations are targetable for therapy. Exon 20 T790M variants cause resistance to first generation TKI therapy and are targetable by second and third generation TKIs (add references).
|-
|<span class="blue-text">EXAMPLE:</span> ''TP53''; Variable LOF mutations
<br />
|<span class="blue-text">EXAMPLE:</span> Variable LOF mutations
|<span class="blue-text">EXAMPLE:</span> Tumor Supressor Gene
|<span class="blue-text">EXAMPLE:</span> Common (breast cancer)
|<span class="blue-text">EXAMPLE:</span> P
|
|<span class="blue-text">EXAMPLE:</span> >90% are somatic; rare germline alterations associated with Li-Fraumeni syndrome (add reference). Denotes a poor prognosis in breast cancer.
|-
|<span class="blue-text">EXAMPLE:</span> ''BRAF''; Activating mutations
|<span class="blue-text">EXAMPLE:</span> Activating mutations
|<span class="blue-text">EXAMPLE:</span> Oncogene
|<span class="blue-text">EXAMPLE:</span> Common (melanoma)
|<span class="blue-text">EXAMPLE:</span> T
|
|
|-
|
|
|
|
|
|
|
|}Note: A more extensive list of mutations can be found in [https://www.cbioportal.org/ <u>cBioportal</u>], [https://cancer.sanger.ac.uk/cosmic <u>COSMIC</u>], and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.
 


{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
!Gene; Genetic Alteration<ref name=":4" /><ref>{{Cite journal|last=Sh|first=Swerdlow|last2=Jr|first2=Cook|date=2020|title=As the world turns, evolving lymphoma classifications-past, present and future|url=https://pubmed.ncbi.nlm.nih.gov/31493426/|language=en|pmid=31493426}}</ref>!!'''Presumed Mechanism (Tumor Suppressor Gene [TSG] / Oncogene / Other)'''!!'''Prevalence (COSMIC /  TCGA / Other)'''<ref name=":4" />!!'''Concomitant Mutations'''!!'''Mutually Exclusive Mutations'''
!Gene; Genetic Alteration<ref name=":4" /><ref>{{Cite journal|last=Sh|first=Swerdlow|last2=Jr|first2=Cook|date=2020|title=As the world turns, evolving lymphoma classifications-past, present and future|url=https://pubmed.ncbi.nlm.nih.gov/31493426/|language=en|pmid=31493426}}</ref>!!Presumed Mechanism (Tumor Suppressor Gene [TSG] / Oncogene / Other)!!Prevalence (COSMIC /  TCGA / Other)<ref name=":4" />!!Concomitant Mutations!!Mutually Exclusive Mutations
!'''Diagnostic Significance (Yes, No or Unknown)'''
!Diagnostic Significance (Yes, No or Unknown)
!Prognostic Significance (Yes, No or Unknown)
!Prognostic Significance (Yes, No or Unknown)
!Therapeutic Significance (Yes, No or Unknown)
!Therapeutic Significance (Yes, No or Unknown)
Line 422: Line 507:
|JAK1
|JAK1
|Oncogene
|Oncogene
|23% '''48%'''
|23% 48%
|
|
|
|
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|STAT3
|STAT3
|oncogene
|oncogene
|16%, '''38%'''
|16%, 38%
|
|
|
|
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|
|
|-
|-
|'''SOCS3'''
|SOCS3
|'''TSG'''
|TSG
|'''8%'''
|8%
|
|
|
|
Line 574: Line 659:
==Genes and Main Pathways Involved==
==Genes and Main Pathways Involved==


Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: Can include references in the table.'')</span>
Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: Can include references in the table. Do not delete table.'')</span>
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
Line 581: Line 666:
|SETD2, TET2, YLPM1; loss of function mutations
|SETD2, TET2, YLPM1; loss of function mutations
|Gene regulation
|Gene regulation
|EXAMPLE: Increased cell growth and proliferation
|<span class="blue-text">EXAMPLE:</span> Increased cell growth and proliferation
|-
|-
|JAK1, JAK3, STAT3, STAT5B, SOCS1
|JAK1, JAK3, STAT3, STAT5B, SOCS1
|JAK-STAT pathway
|JAK-STAT pathway
|EXAMPLE: Unregulated cell division
|<span class="blue-text">EXAMPLE:</span> Unregulated cell division
|-
|-
|EXAMPLE:  KMT2C and ARID1A; Inactivating mutations
|<span class="blue-text">EXAMPLE:</span>  KMT2C and ARID1A; Inactivating mutations
|EXAMPLE:  Histone modification, chromatin remodeling
|<span class="blue-text">EXAMPLE:</span>  Histone modification, chromatin remodeling
|EXAMPLE:  Abnormal gene expression program
|<span class="blue-text">EXAMPLE:</span>  Abnormal gene expression program
|}
|}


<blockquote class="blockedit">{{Box-round|title=v4:Genes and Main Pathways Involved|The content below was from the old template. Please incorporate above.}}
<blockquote class="blockedit">{{Box-round|title=v4:Genes and Main Pathways Involved|The content below was from the old template. Please incorporate above.}}</blockquote>


*Chromatin modifying genes: SETD2, TET2, YLPM1; loss of function mutations<ref name=":4" /><ref name=":10">{{Cite journal|last=A|first=Nicolae|last2=L|first2=Xi|last3=Th|first3=Pham|last4=Ta|first4=Pham|last5=W|first5=Navarro|last6=Hg|first6=Meeker|last7=S|first7=Pittaluga|last8=Es|first8=Jaffe|last9=M|first9=Raffeld|date=2016|title=Mutations in the JAK/STAT and RAS signaling pathways are common in intestinal T-cell lymphomas|url=https://pubmed.ncbi.nlm.nih.gov/27389054/|language=en|doi=10.1038/leu.2016.178|pmc=PMC5093023|pmid=27389054}}</ref><ref name=":11">{{Cite journal|last=G|first=Malamut|last2=R|first2=El Machhour|last3=N|first3=Montcuquet|last4=S|first4=Martin-Lannerée|last5=I|first5=Dusanter-Fourt|last6=V|first6=Verkarre|last7=Jj|first7=Mention|last8=G|first8=Rahmi|last9=H|first9=Kiyono|date=2010|title=IL-15 triggers an antiapoptotic pathway in human intraepithelial lymphocytes that is a potential new target in celiac disease-associated inflammation and lymphomagenesis|url=https://pubmed.ncbi.nlm.nih.gov/20440074/|language=en|doi=10.1172/JCI41344|pmc=PMC2877946|pmid=20440074}}</ref><ref name=":12">{{Cite journal|last=Mention|first=Jean-Jacques|last2=Ben Ahmed|first2=Mélika|last3=Bègue|first3=Bernadette|last4=Barbe|first4=Ullah|last5=Verkarre|first5=Virginie|last6=Asnafi|first6=Vahid|last7=Colombel|first7=Jean-Frédéric|last8=Cugnenc|first8=Paul-Henri|last9=Ruemmele|first9=Frank M.|date=2003-09|title=Interleukin 15: a key to disrupted intraepithelial lymphocyte homeostasis and lymphomagenesis in celiac disease|url=https://pubmed.ncbi.nlm.nih.gov/12949719|journal=Gastroenterology|volume=125|issue=3|pages=730–745|doi=10.1016/s0016-5085(03)01047-3|issn=0016-5085|pmid=12949719}}</ref>
*Chromatin modifying genes: SETD2, TET2, YLPM1; loss of function mutations<ref name=":4" /><ref name=":10">{{Cite journal|last=A|first=Nicolae|last2=L|first2=Xi|last3=Th|first3=Pham|last4=Ta|first4=Pham|last5=W|first5=Navarro|last6=Hg|first6=Meeker|last7=S|first7=Pittaluga|last8=Es|first8=Jaffe|last9=M|first9=Raffeld|date=2016|title=Mutations in the JAK/STAT and RAS signaling pathways are common in intestinal T-cell lymphomas|url=https://pubmed.ncbi.nlm.nih.gov/27389054/|language=en|doi=10.1038/leu.2016.178|pmc=PMC5093023|pmid=27389054}}</ref><ref name=":11">{{Cite journal|last=G|first=Malamut|last2=R|first2=El Machhour|last3=N|first3=Montcuquet|last4=S|first4=Martin-Lannerée|last5=I|first5=Dusanter-Fourt|last6=V|first6=Verkarre|last7=Jj|first7=Mention|last8=G|first8=Rahmi|last9=H|first9=Kiyono|date=2010|title=IL-15 triggers an antiapoptotic pathway in human intraepithelial lymphocytes that is a potential new target in celiac disease-associated inflammation and lymphomagenesis|url=https://pubmed.ncbi.nlm.nih.gov/20440074/|language=en|doi=10.1172/JCI41344|pmc=PMC2877946|pmid=20440074}}</ref><ref name=":12">{{Cite journal|last=Mention|first=Jean-Jacques|last2=Ben Ahmed|first2=Mélika|last3=Bègue|first3=Bernadette|last4=Barbe|first4=Ullah|last5=Verkarre|first5=Virginie|last6=Asnafi|first6=Vahid|last7=Colombel|first7=Jean-Frédéric|last8=Cugnenc|first8=Paul-Henri|last9=Ruemmele|first9=Frank M.|date=2003-09|title=Interleukin 15: a key to disrupted intraepithelial lymphocyte homeostasis and lymphomagenesis in celiac disease|url=https://pubmed.ncbi.nlm.nih.gov/12949719|journal=Gastroenterology|volume=125|issue=3|pages=730–745|doi=10.1016/s0016-5085(03)01047-3|issn=0016-5085|pmid=12949719}}</ref>
Line 600: Line 685:
*Overexpression of genes involved in Interferon-γ signaling<ref name=":4" />
*Overexpression of genes involved in Interferon-γ signaling<ref name=":4" />


<blockquote class="blockedit">
<center><span style="color:Maroon">'''End of V4 Section'''</span>
----
</blockquote>
</blockquote>
==Genetic Diagnostic Testing Methods==
==Genetic Diagnostic Testing Methods==
Line 618: Line 706:


==Additional Information==
==Additional Information==
This disease is <u>defined/characterized</u> as detailed below:
*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.<ref name=":13">{{Cite journal|last=Cording|first=Sascha|last2=Lhermitte|first2=Ludovic|last3=Malamut|first3=Georgia|last4=Berrabah|first4=Sofia|last5=Trinquand|first5=Amélie|last6=Guegan|first6=Nicolas|last7=Villarese|first7=Patrick|last8=Kaltenbach|first8=Sophie|last9=Meresse|first9=Bertrand|date=2022-03|title=Oncogenetic landscape of lymphomagenesis in coeliac disease|url=https://pubmed.ncbi.nlm.nih.gov/33579790|journal=Gut|volume=71|issue=3|pages=497–508|doi=10.1136/gutjnl-2020-322935|issn=1468-3288|pmc=8862029|pmid=33579790}}</ref>
*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 <ref name=":5">Govind Bhagat, et al. Enteropathy-associated T-cell lymphoma. In:  WHO Classification of Tumours Editorial Board. Haematolymphoid tumours [Internet]. Lyon (France): International Agency for Research on Cancer; 2024 [cited 2024 July 2]. (WHO classification of tumors series, 5th ed.; vol. 11). Available from: <nowiki>https://tumourclassification.iarc.who.int/chaptercontent/63/224</nowiki> </ref><ref>{{Cite journal|last=Soderquist|first=Craig R.|last2=Bhagat|first2=Govind|date=2021|title=Cellular and molecular bases of refractory celiac disease|url=https://pubmed.ncbi.nlm.nih.gov/33707055|journal=International Review of Cell and Molecular Biology|volume=358|pages=207–240|doi=10.1016/bs.ircmb.2020.12.001|issn=1937-6448|pmid=33707055}}</ref>.
*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<ref name=":5" />
*Risk factors include homozygosity for HLA-DQ2 and advanced age<ref name=":5" />
The <u>epidemiology/prevalence</u> of this disease is detailed below:
*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)<ref name=":6">{{Cite journal|last=Wh|first=Verbeek|last2=Jm|first2=Van De Water|last3=A|first3=Al-Toma|last4=Jj|first4=Oudejans|last5=Cj|first5=Mulder|last6=Vm|first6=Coupé|date=2008|title=Incidence of enteropathy--associated T-cell lymphoma: a nation-wide study of a population-based registry in The Netherlands|url=https://pubmed.ncbi.nlm.nih.gov/18618372/|language=en|pmid=18618372}}</ref><ref name=":1">{{Cite journal|last=Aj|first=Ferreri|last2=Pl|first2=Zinzani|last3=S|first3=Govi|last4=Sa|first4=Pileri|date=2011|title=Enteropathy-associated T-cell lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/20655757/|language=en|pmid=20655757}}</ref><ref name=":2">{{Cite journal|last=J|first=Delabie|last2=H|first2=Holte|last3=Jm|first3=Vose|last4=F|first4=Ullrich|last5=Es|first5=Jaffe|last6=Kj|first6=Savage|last7=Jm|first7=Connors|last8=L|first8=Rimsza|last9=Nl|first9=Harris|date=2011|title=Enteropathy-associated T-cell lymphoma: clinical and histological findings from the international peripheral T-cell lymphoma project|url=https://pubmed.ncbi.nlm.nih.gov/21566094/|language=en|pmid=21566094}}</ref><ref>{{Cite journal|last=A|first=Rubio-Tapia|last2=Ja|first2=Murray|date=2010|title=Classification and management of refractory coeliac disease|url=https://pubmed.ncbi.nlm.nih.gov/20332526/|language=en|doi=10.1136/gut.2009.195131|pmc=PMC2861306|pmid=20332526}}</ref><ref>{{Cite journal|last=G|first=Malamut|last2=P|first2=Afchain|last3=V|first3=Verkarre|last4=T|first4=Lecomte|last5=A|first5=Amiot|last6=D|first6=Damotte|last7=Y|first7=Bouhnik|last8=Jf|first8=Colombel|last9=Jc|first9=Delchier|date=2009|title=Presentation and long-term follow-up of refractory celiac disease: comparison of type I with type II|url=https://pubmed.ncbi.nlm.nih.gov/19014942/|language=en|pmid=19014942}}</ref>
*EATL accounts for 3% of peripheral T-cell lymphomas and represents 66% of all primary intestinal T-cell lymphomas<ref name=":5" />
*More common in regions with a high prevalence of CD, particularly Europe (0.05–0.14 cases per 100 000 population)<ref>{{Cite journal|last=Catassi|first=Carlo|last2=Bearzi|first2=Italo|last3=Holmes|first3=Geoffrey K. T.|date=2005-04|title=Association of celiac disease and intestinal lymphomas and other cancers|url=https://pubmed.ncbi.nlm.nih.gov/15825131|journal=Gastroenterology|volume=128|issue=4 Suppl 1|pages=S79–86|doi=10.1053/j.gastro.2005.02.027|issn=0016-5085|pmid=15825131}}</ref><ref>{{Cite journal|last=Sieniawski|first=Michal|last2=Angamuthu|first2=Nithia|last3=Boyd|first3=Kathryn|last4=Chasty|first4=Richard|last5=Davies|first5=John|last6=Forsyth|first6=Peter|last7=Jack|first7=Fergus|last8=Lyons|first8=Simon|last9=Mounter|first9=Philip|date=2010-05-06|title=Evaluation of enteropathy-associated T-cell lymphoma comparing standard therapies with a novel regimen including autologous stem cell transplantation|url=https://pubmed.ncbi.nlm.nih.gov/20197551|journal=Blood|volume=115|issue=18|pages=3664–3670|doi=10.1182/blood-2009-07-231324|issn=1528-0020|pmid=20197551}}</ref><ref name=":6" /> and the USA (0.016 cases per 100 000 population)
*Extremely rare in Asia due to low population frequency of celiac HLA risk alleles<ref name=":6" /><ref name=":1" /><ref name=":2" />
*> 60% of all cases in intestinal T- cell lymphomas<ref name=":6" /><ref name=":1" /><ref name=":2" />
*M:F 1.04:1 to 2.8:1<ref name=":6" /><ref name=":1" /><ref name=":2" />
*6th-7th decade of life<ref name=":6" /><ref name=":1" /><ref name=":2" />
*Mostly Caucasian (> 90%)<ref name=":6" /><ref name=":1" /><ref name=":2" />


*N/A
The <u>clinical features</u> of this disease are detailed below:
 
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.<ref name=":1" />
 
*CD can be diagnosed at the time of EATL diagnosis<ref name=":5" />
*Patients with RCD can sometimes present with small-intestinal ulceration (ulcerative jejunitis)<ref>{{Cite journal|last=Ashton-Key|first=M.|last2=Diss|first2=T. C.|last3=Pan|first3=L.|last4=Du|first4=M. Q.|last5=Isaacson|first5=P. G.|date=1997-08|title=Molecular analysis of T-cell clonality in ulcerative jejunitis and enteropathy-associated T-cell lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/9250161|journal=The American Journal of Pathology|volume=151|issue=2|pages=493–498|issn=0002-9440|pmc=1857986|pmid=9250161}}</ref><ref>{{Cite journal|last=Bagdi|first=E.|last2=Diss|first2=T. C.|last3=Munson|first3=P.|last4=Isaacson|first4=P. G.|date=1999-07-01|title=Mucosal intra-epithelial lymphocytes in enteropathy-associated T-cell lymphoma, ulcerative jejunitis, and refractory celiac disease constitute a neoplastic population|url=https://pubmed.ncbi.nlm.nih.gov/10381521|journal=Blood|volume=94|issue=1|pages=260–264|issn=0006-4971|pmid=10381521}}</ref>.
 
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
 
Signs and symptoms - Abdominal pain; Weight loss; Gluten-insensitive diarrhea/malabsorption; Bowel obstruction or perforation (50% cases)
 
Laboratory findings - Anemia; Hypoalbuminemia; Hemophagocytosis
 
The <u>sites of involvement</u> of this disease are detailed below:
 
*Small intestine (predominantly jejunum and ileum > large intestine and stomach)<ref name=":1" />
*Dissemination to extra gastrointestinal sites: mesenteric and abdominal lymph nodes > bone marrow, lung, liver or skin<ref name=":2" /><ref>{{Cite journal|last=Egan|first=L. J.|last2=Walsh|first2=S. V.|last3=Stevens|first3=F. M.|last4=Connolly|first4=C. E.|last5=Egan|first5=E. L.|last6=McCarthy|first6=C. F.|date=1995-09|title=Celiac-associated lymphoma. A single institution experience of 30 cases in the combination chemotherapy era|url=https://pubmed.ncbi.nlm.nih.gov/8583077|journal=Journal of Clinical Gastroenterology|volume=21|issue=2|pages=123–129|issn=0192-0790|pmid=8583077}}</ref><ref name=":14">{{Cite journal|last=Malamut|first=Georgia|last2=Chandesris|first2=Olivia|last3=Verkarre|first3=Virginie|last4=Meresse|first4=Bertrand|last5=Callens|first5=Céline|last6=Macintyre|first6=Elizabeth|last7=Bouhnik|first7=Yoram|last8=Gornet|first8=Jean-Marc|last9=Allez|first9=Matthieu|date=2013-05|title=Enteropathy associated T cell lymphoma in celiac disease: a large retrospective study|url=https://pubmed.ncbi.nlm.nih.gov/23313469|journal=Digestive and Liver Disease: Official Journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver|volume=45|issue=5|pages=377–384|doi=10.1016/j.dld.2012.12.001|issn=1878-3562|pmc=7185558|pmid=23313469}}</ref>.
*Metastases involve intra-abdominal node > bone marrow > lung > liver > skin<ref name=":1" />
*CNS (rare)<ref name=":1" />
 
The <u>morphologic features</u> of this disease are detailed below:
 
*Pleomorphic medium to large sized neoplastic lymphoid cells with immunoblastic or anaplastic morphology.<ref name=":2" /><ref name=":5" />
*Angulated vesicular nuclei, prominent nucleoli, and a pale-staining cytoplasm [https://doi.org/10.3390/diagnostics13162629<nowiki>]</nowiki>
*Extensive inflammatory background of histiocytes, eosinophils, small lymphocytes, and plasma cells <ref name=":5" />
*Adjacent mucosa often displays the histological features of active CD, including increased IEL infiltration, crypt hyperplasia, and villous atrophy <ref name=":2" /><ref name=":5" /> [https://doi.org/10.3390/diagnostics13162629<nowiki>]</nowiki>
*Angioinvasion and angiodestruction are commonly seen <ref name=":5" />
*
*
*Neighborhood mucosa characterized by villous atrophy and crypt hyperplasia (non-malignant areas of celiac disease)<ref name=":2" />
*Round or angulated vesicular nuclei<ref name=":2" />
*Prominent nucleoli<ref name=":2" />
*Moderate-abundant pale cytoplasm<ref name=":2" />
*Extensive admixture of inflammatory cells (eosinophils, histiocytes)<ref name=":2" />
*Angiocentric and angioinvasive features with extensive necrosis<ref name=":2" />
 
The <u>immunophenotype</u> of this disease is detailed below:
 
*Approximately 25% of EATLs (primarily de novo EATL) are CD8+, and rare cases express TCRγδ<ref name=":14" /><ref>{{Cite journal|last=van Wanrooij|first=R. L. J.|last2=de Jong|first2=D.|last3=Langerak|first3=A. W.|last4=Ylstra|first4=B.|last5=van Essen|first5=H. F.|last6=Heideman|first6=D. a. M.|last7=Bontkes|first7=H. J.|last8=Mulder|first8=C. J. J.|last9=Bouma|first9=G.|date=2015|title=Novel variant of EATL evolving from mucosal γδ-T-cells in a patient with type I RCD|url=https://pubmed.ncbi.nlm.nih.gov/26462278|journal=BMJ open gastroenterology|volume=2|issue=1|pages=e000026|doi=10.1136/bmjgast-2014-000026|issn=2054-4774|pmc=4599158|pmid=26462278}}</ref>
*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.<ref name=":13" />
*The most common immunophenotypic profile in EATL is given below:
 
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
 
KI67 – high
{| class="wikitable"
!
!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):<ref name=":7">{{Cite journal|last=P|first=Domizio|last2=Ra|first2=Owen|last3=Na|first3=Shepherd|last4=Ic|first4=Talbot|last5=Aj|first5=Norton|date=1993|title=Primary lymphoma of the small intestine. A clinicopathological study of 119 cases|url=https://pubmed.ncbi.nlm.nih.gov/8470758/|language=en|pmid=8470758}}</ref><ref name=":0" />
 
*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<sup>_</sup>, 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 [[HAEM5:Monomorphic epitheliotropic intestinal T-cell lymphoma|MEITL]]; not seen in [[HAEM5:Indolent T-cell lymphoma of the gastrointestinal tract|indolent T-cell LPD of GI tract]]
****CD30+ indicates progression to EATL


==Links==
==Links==
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==References==
==References==
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==Notes==
==Notes==
<nowiki>*</nowiki>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.
<nowiki>*</nowiki>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 [[Leadership|''<u>Associate Editor</u>'']] or other CCGA representative.  When pages have a major update, the new author will be acknowledged at the beginning of the page, and those who contributed previously will be acknowledged below as a prior author.
 
Prior Author(s): 
 
       
<nowiki>*</nowiki>''Citation of this Page'': “Enteropathy-associated T-cell lymphoma”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated {{REVISIONMONTH}}/{{REVISIONDAY}}/{{REVISIONYEAR}}, <nowiki>https://ccga.io/index.php/HAEM5:Enteropathy-associated_T-cell_lymphoma</nowiki>.
<nowiki>*</nowiki>''Citation of this Page'': “Enteropathy-associated T-cell lymphoma”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated {{REVISIONMONTH}}/{{REVISIONDAY}}/{{REVISIONYEAR}}, <nowiki>https://ccga.io/index.php/HAEM5:Enteropathy-associated_T-cell_lymphoma</nowiki>.
[[Category:HAEM5]]
[[Category:HAEM5]]
[[Category:DISEASE]]
[[Category:DISEASE]]
[[Category:Diseases E]]
[[Category:Diseases E]]
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