HAEM5:Enteropathy-associated T-cell lymphoma: Difference between revisions
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<blockquote class= | <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]]. | ||
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|Enteropathy-associated T-cell lymphoma | |Enteropathy-associated T-cell lymphoma | ||
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==WHO Essential and Desirable Genetic Diagnostic Criteria== | ==WHO Essential and Desirable Genetic Diagnostic Criteria== | ||
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<blockquote class= | <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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<blockquote class= | <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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<blockquote class= | <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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<blockquote class= | <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> | ||
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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. <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" /> | |||
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) { 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" /> | |||
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) { 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 | |||
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 { 8583077 ; 23313469 ; 21566094 }. | |||
*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 [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> | |||
* 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== | ||