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 (WHO Classification, 5th ed.)]]


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


<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 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>
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*FNU Monika, MBBS
*FNU Monika, MBBS
*Andrew Siref, MD
*Andrew Siref, MD
__TOC__


==WHO Classification of Disease==
==WHO Classification of Disease==
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|}
|}


==Definition / Description of Disease==
==Related Terminology==
 
*'''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==
 
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"
|'''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'''<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 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" />
 
<br />
==Immunophenotype==
 
* '''The most common immunophenotypic profile in EATL is given below:'''
 
{| class="wikitable sortable"
|-
!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. <u>33579790</u>'''


{| 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">{{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).
**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
==WHO Essential and Desirable Genetic Diagnostic Criteria==
<span style="color:#0070C0">(''Instructions: The table will have the diagnostic criteria from the WHO book <u>autocompleted</u>; remove any <u>non</u>-genetics related criteria. If applicable, add text about other classification'' ''systems that define this entity and specify how the genetics-related criteria differ.'')</span>
{| class="wikitable"
|+
|WHO Essential Criteria (Genetics)*
|
|-
|WHO Desirable Criteria (Genetics)*
|
|-
|Other Classification
|
|}
<nowiki>*</nowiki>Note: These are only the genetic/genomic criteria. Additional diagnostic criteria can be found in the [https://tumourclassification.iarc.who.int/home <u>WHO Classification of Tumours</u>].
==Related Terminology==
<span style="color:#0070C0">(''Instructions: The table will have the related terminology from the WHO <u>autocompleted</u>.)''</span>
{| class="wikitable"
{| class="wikitable"
|+
|+
|Acceptable
|Acceptable
|
|N/A
|-
|-
|Not Recommended
|Not Recommended
|
|Type I enteropathy-associated T-cell lymphoma
|}
|}


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|
|}
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<blockquote class='blockedit'>{{Box-round|title=v4:Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications).|Please incorporate this section into the relevant tables found in:
<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
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*'''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'''
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{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
!Chr #!!'''Gain, Loss, Amp, LOH'''!!'''Minimal Region Cytoband and/or Genomic Coordinates [Genome Build; Size]'''!!'''Relevant Gene(s)'''
!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'''
!Diagnostic, Prognostic, and Therapeutic Significance - D, P, T
!'''Established Clinical Significance Per Guidelines - Yes or No (Source)'''
!Established Clinical Significance Per Guidelines - Yes or No (Source)
!'''Clinical Relevance Details/Other Notes'''
!Clinical Relevance Details/Other Notes
|-
|-
|<span class="blue-text">EXAMPLE:</span>
|<span class="blue-text">EXAMPLE:</span>
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|}
|}


<blockquote class='blockedit'>{{Box-round|title=v4:Genomic Gain/Loss/LOH|The content below was from the old template. Please incorporate above.}}</blockquote>
<blockquote class="blockedit">{{Box-round|title=v4:Genomic Gain/Loss/LOH|The content below was from the old template. Please incorporate above.}}</blockquote>


{| class="wikitable"
{| class="wikitable"
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!Chromosomal Pattern
!Chromosomal Pattern
!Molecular Pathogenesis
!Molecular Pathogenesis
!'''Prevalence -'''
!Prevalence -  
'''Common >20%, Recurrent 5-20% or Rare <5% (Disease)'''
Common >20%, Recurrent 5-20% or Rare <5% (Disease)
!'''Diagnostic, Prognostic, and Therapeutic Significance - D, P, T'''
!Diagnostic, Prognostic, and Therapeutic Significance - D, P, T
!'''Established Clinical Significance Per Guidelines - Yes or No (Source)'''
!Established Clinical Significance Per Guidelines - Yes or No (Source)
!'''Clinical Relevance Details/Other Notes'''
!Clinical Relevance Details/Other Notes
|-
|-
|<span class="blue-text">EXAMPLE:</span>
|<span class="blue-text">EXAMPLE:</span>
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|}
|}


<blockquote class='blockedit'>{{Box-round|title=v4:Characteristic Chromosomal Aberrations / Patterns|The content below was from the old template. Please incorporate above.}}</blockquote>
<blockquote class="blockedit">{{Box-round|title=v4:Characteristic Chromosomal Aberrations / Patterns|The content below was from the old template. Please incorporate above.}}</blockquote>


*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>
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{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
!Gene!!'''Genetic Alteration'''!!'''Tumor Suppressor Gene, Oncogene, Other'''!!'''Prevalence -'''
!Gene!!Genetic Alteration!!Tumor Suppressor Gene, Oncogene, Other!!Prevalence -
'''Common >20%, Recurrent 5-20% or Rare <5% (Disease)'''
Common >20%, Recurrent 5-20% or Rare <5% (Disease)
!'''Diagnostic, Prognostic, and Therapeutic Significance - D, P, T  '''
!Diagnostic, Prognostic, and Therapeutic Significance - D, P, T  
!'''Established Clinical Significance Per Guidelines - Yes or No (Source)'''
!Established Clinical Significance Per Guidelines - Yes or No (Source)
!'''Clinical Relevance Details/Other Notes'''
!Clinical Relevance Details/Other Notes
|-
|-
|<span class="blue-text">EXAMPLE:</span>''EGFR''
|<span class="blue-text">EXAMPLE:</span>''EGFR''
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{| 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)
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|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%
|
|
|
|
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|}
|}


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*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>
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==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" />
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)


*N/A
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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==Notes==
==Notes==
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