View source for HAEM5:Monomorphic epitheliotropic intestinal T-cell lymphoma

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

{{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:Monomorphic Epitheliotropic Intestinal T-cell Lymphoma]].
}}</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); to add (or move) a row or column to a table, click within the table and select the > symbol that appears to be given options. Please do not delete or alter the section headings. The use of bullet points alongside short blocks of text rather than only large paragraphs is encouraged. Additional instructions below in italicized blue text should not be included in the final page content. Please also see </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)*==

Derick Okwan-Duodu MD, PhD; Sumire Kitahara, MD

__TOC__

==WHO Classification of Disease==

{| class="wikitable"
!Structure
!Disease
|-
|Book
|Haematolymphoid Tumours (5th ed.)
|-
|Category
|T-cell and NK-cell lymphoid proliferations and lymphomas
|-
|Family
|Mature T-cell and NK-cell neoplasms
|-
|Type
|Intestinal T-cell and NK-cell lymphoid proliferations and lymphomas
|-
|Subtype(s)
|Monomorphic epitheliotropic intestinal T-cell lymphoma
|}

==Definition / Description of Disease==

*Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) is a primary intestinal T-cell lymphoma derived from intraepithelial lymphocytes that, unlike enteropathy-associated T-cell lymphoma, is not clearly associated with celiac disease

==Synonyms / Terminology==

*Formerly and no longer referred to as type II enteropathy-associated T-cell lymphoma (EATL)

==Epidemiology / Prevalence==

*More prevalent in Asian and Hispanic/indigenous population
*< 1 per 1,000,000

==Clinical Features==

Put your text here and fill in the table <span style="color:#0070C0">(''Instruction: Can include references in the table. Do not delete table.'') </span>
{| class="wikitable"
|'''Signs and Symptoms'''
|<span class="blue-text">EXAMPLE:</span> Asymptomatic (incidental finding on complete blood counts)

<span class="blue-text">EXAMPLE:</span> B-symptoms (weight loss, fever, night sweats)

<span class="blue-text">EXAMPLE:</span> Fatigue

<span class="blue-text">EXAMPLE:</span> Lymphadenopathy (uncommon)
|-
|'''Laboratory Findings'''
|<span class="blue-text">EXAMPLE:</span> Cytopenias

<span class="blue-text">EXAMPLE:</span> Lymphocytosis (low level)
|}


<blockquote class='blockedit'>{{Box-round|title=v4:Clinical Features|The content below was from the old template. Please incorporate above.}}

*Abdominal pain
*Weight loss
*Diarrhea
*Long-standing history of malabsorption is atypical

</blockquote>
==Sites of Involvement==

*Small Intestine (jejunum > ileum) > large intestine > stomach

==Morphologic Features==

*Monomorphic small- to medium-sized neoplastic cells
*Uniformly round and regular nuclei
*Finely dispersed chromatin
*Inconspicuous nucleoli
*Abundant rim of pale cytoplasm

==Immunophenotype==

Put your text here and fill in the table <span style="color:#0070C0">(''Instruction: Can include references in the table. Do not delete table.'') </span>

{| class="wikitable sortable"
|-
!Finding!!Marker
|-
|Positive (universal)||<span class="blue-text">EXAMPLE:</span> CD1
|-
|Positive (subset)||<span class="blue-text">EXAMPLE:</span> CD2
|-
|Negative (universal)||<span class="blue-text">EXAMPLE:</span> CD3
|-
|Negative (subset)||<span class="blue-text">EXAMPLE:</span> CD4
|}


<blockquote class='blockedit'>{{Box-round|title=v4:Immunophenotype|The content below was from the old template. Please incorporate above.}}
'''Postive''': '''CD3, CD8, CD56''', TCR gamma > TCR beta, '''TIA1''', CD20 in 20% of cases, '''MATK''' in >80% of neoplastic cells helps distinguish from EATL, '''SYK''' <ref name=":1" /> (distinguishes from EATL), NKP46

Variably positive between cases: granzyme B, perforin

Negative: CD5, EBV/EBER

'''INCORPORATE INTO TABLE'''

</blockquote>
==Chromosomal Rearrangements (Gene Fusions)==

Put your text here and fill in the table

{| class="wikitable sortable"
|-
!Chromosomal Rearrangement!!Genes in Fusion (5’ or 3’ Segments)!!Pathogenic Derivative!!Prevalence
!Diagnostic Significance (Yes, No or Unknown)
!Prognostic Significance (Yes, No or Unknown)
!Therapeutic Significance (Yes, No or Unknown)
!Notes
|-
|<span class="blue-text">EXAMPLE:</span> t(9;22)(q34;q11.2)||<span class="blue-text">EXAMPLE:</span> 3'ABL1 / 5'BCR||<span class="blue-text">EXAMPLE:</span> der(22)||<span class="blue-text">EXAMPLE:</span> 20% (COSMIC)
<span class="blue-text">EXAMPLE:</span> 30% (add reference)
|Yes
|No
|Yes
|<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).
|}		
			

<blockquote class='blockedit'>{{Box-round|title=v4:Chromosomal Rearrangements (Gene Fusions)|The content below was from the old template. Please incorporate above.}}

*N/A
*'''No consistent gene fusion reported'''

</blockquote>


<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)
* Individual Region Genomic Gain/Loss/LOH
* Characteristic Chromosomal Patterns
* Gene Mutations (SNV/INDEL)}}

*'''Diagnosis'''
**Because of non-specific findings, careful clinical history, along with immunophenotype and morphology, is necessary to arrive at diagnosis

{| class="wikitable sortable mw-collapsible mw-collapsed"
|+
!IHC
!Significance
!Note
|-
|SYK
|Possible role in diagnosis (inclusion)
|Strongly diagnostic<ref name=":1">{{Cite journal|last=G|first=Mutzbauer|last2=K|first2=Maurus|last3=C|first3=Buszello|last4=J|first4=Pischimarov|last5=S|first5=Roth|last6=A|first6=Rosenwald|last7=A|first7=Chott|last8=E|first8=Geissinger|date=2018|title=SYK expression in monomorphic epitheliotropic intestinal T-cell lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/29052597/|language=en|pmid=29052597}}</ref>
|-
|CD56
|Possible role in diagnosis (inclusion)
|Contrasts with majority of EATL
|-
|EBV
|Possible role in diagnosis (exclusion)
|Strongly associated with extranodal NK/T- cell lymphoma, but negative in MEITL
|-
|MATK
|Possible role in diagnosis (inclusion)
|If present in >80% of tumor cells, helps distinguish from EATL
|-
|Gamma delta TCR
|Possible role in diagnosis (inclusion)
|Much more frequent in MEITL compared to EATL (silent or alpha beta TCR)
|}

*'''Prognosis'''
**Poor (median survival of 7 months)
**Resection, chemotherapy combined with autologous stem cell transplantation improves survival <ref>{{Cite journal|last=P|first=Nijeboer|last2=Lr|first2=de Baaij|last3=O|first3=Visser|last4=Bi|first4=Witte|last5=Sa|first5=Cillessen|last6=Cj|first6=Mulder|last7=G|first7=Bouma|date=2015|title=Treatment response in enteropathy associated T-cell lymphoma; survival in a large multicenter cohort|url=https://pubmed.ncbi.nlm.nih.gov/25716069/|language=en|pmid=25716069}}</ref>
*'''Therapeutic Implications'''
**Alemtuzumab and single use of brentuximab and romidepsin in adjuvant setting<ref>{{Cite journal|date=2020-02-07|title=Enteropathy-Associated T-Cell Lymphoma|url=http://dx.doi.org/10.32388/jjq2o0|journal=Definitions|publisher=Qeios}}</ref>
**PEG-asparaginase has been considered as option<ref>{{Cite journal|last=C|first=Gentille|last2=Q|first2=Qin|last3=A|first3=Barbieri|last4=Ps|first4=Ravi|last5=S|first5=Iyer|date=2017|title=Use of PEG-asparaginase in monomorphic epitheliotropic intestinal T-cell lymphoma, a disease with diagnostic and therapeutic challenges|url=https://pubmed.ncbi.nlm.nih.gov/29062389/|language=en|doi=10.3332/ecancer.2017.771|pmc=PMC5636209|pmid=29062389}}</ref>

</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. Do not delete table.'') </span>

{| class="wikitable sortable"
|-
!Chr #!!Gain / Loss / Amp / LOH!!Minimal Region Genomic Coordinates [Genome Build]!!Minimal Region Cytoband
!Diagnostic Significance (Yes, No or Unknown)
!Prognostic Significance (Yes, No or Unknown)
!Therapeutic Significance (Yes, No or Unknown)
!Notes
|-
|<span class="blue-text">EXAMPLE:</span>

7
|<span class="blue-text">EXAMPLE:</span> Loss
|<span class="blue-text">EXAMPLE:</span>

chr7:1- 159,335,973 [hg38]
|<span class="blue-text">EXAMPLE:</span>

chr7
|Yes
|Yes
|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 reference).
|-
|<span class="blue-text">EXAMPLE:</span>

8
|<span class="blue-text">EXAMPLE:</span> Gain
|<span class="blue-text">EXAMPLE:</span>

chr8:1-145,138,636 [hg38]
|<span class="blue-text">EXAMPLE:</span>

chr8
|No
|No
|No
|<span class="blue-text">EXAMPLE:</span>

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

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


In contrast to EATL, gains at 1q32.2-41 and 5q34-35.5 are reported less commonly. However, one study from Japan<ref name=":3" /> described a series a non-celiac associated intestinal T-cell lymphoma with MEITL immunophenotype that demonstrated these gains at a frequency comparable to Western EATL, suggesting more overlap between Western EATL and Asian MEITL than previously thought, requiring additional investigation to further study these observations.

{| class="wikitable sortable"
|-
!Chromosome Number!!Gain/Loss/Amp/LOH!!Region
!Genes
!Prevalence
|-
|8q||gain||q24
|MYC
|25-38%
|-
|9q||gain||q22.31;q33.2; q34.3-13
|PPP6C, ASS1,CARD9
|75%
|-
|1q
|gain
|q32.2-44
|CKS1B
|50%
|-
|5q
|gain
|q34
|
|38%
|-
|8p
|gain
|p11.23
|
|63%
|-
|4p
|gain
|p15.1
|
|63%
|-
|7q
|gain
|q34
|
|63%
|-
|12p
|gain
|p13.31
|ETV6
|
|-
|7p
|loss
|p14.1
|MAFK
|75%
|-
|8p
|loss
|p23.3-p11.21
|
|38%
|-
|16q
|loss
|
|
|50%
|}	
		

<blockquote class='blockedit'>{{Box-round|title=Unassigned References|The following referenees were placed in the header. Please place them into the appropriate locations in the text.}}<ref>{{Cite journal|last=Rj|first=Deleeuw|last2=A|first2=Zettl|last3=E|first3=Klinker|last4=E|first4=Haralambieva|last5=M|first5=Trottier|last6=R|first6=Chari|last7=Y|first7=Ge|last8=Rd|first8=Gascoyne|last9=A|first9=Chott|date=2007|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/|language=en|pmid=17484883}}</ref><ref name=":3">{{Cite journal|last=S|first=Tomita|last2=Yy|first2=Kikuti|last3=J|first3=Carreras|last4=M|first4=Kojima|last5=K|first5=Ando|last6=H|first6=Takasaki|last7=R|first7=Sakai|last8=K|first8=Takata|last9=T|first9=Yoshino|date=2015|title=Genomic and immunohistochemical profiles of enteropathy-associated T-cell lymphoma in Japan|url=https://pubmed.ncbi.nlm.nih.gov/26226842/|language=en|pmid=26226842}}</ref></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. Do not delete table.'')</span>

{| class="wikitable sortable"
|-
!Chromosomal Pattern
!Diagnostic Significance (Yes, No or Unknown)
!Prognostic Significance (Yes, No or Unknown)
!Therapeutic Significance (Yes, No or Unknown)
!Notes
|-
|<span class="blue-text">EXAMPLE:</span>

Co-deletion of 1p and 18q
|Yes
|No
|No
|<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).
|}

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

*No pathognomonic aberrations/patterns described, but multiple genomic gains and losses are frequent

</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 as either disease defining and/or clinically significant. Can include references in the table. For clinical significance, denote associations with FDA-approved therapy (not an extensive list of applicable drugs) and NCCN or other national guidelines if applicable. Can also refer to CGC workgroup tables as linked on the homepage if applicable as well as any high impact papers or reviews of gene mutations in this entity. Do not delete table.'') </span>

{| class="wikitable sortable"
|-
!Gene; Genetic Alteration!!'''Presumed Mechanism (Tumor Suppressor Gene [TSG] / Oncogene / Other)'''!!'''Prevalence (COSMIC /  TCGA / Other)'''!!'''Concomitant Mutations'''!!'''Mutually Exclusive Mutations'''
!'''Diagnostic Significance (Yes, No or Unknown)'''
!Prognostic Significance (Yes, No or Unknown)
!Therapeutic Significance (Yes, No or Unknown)
!Notes
|-
|<span class="blue-text">EXAMPLE:</span> TP53; Variable LOF mutations

<span class="blue-text">EXAMPLE:</span>

EGFR; Exon 20 mutations

<span class="blue-text">EXAMPLE:</span> BRAF; Activating mutations
|<span class="blue-text">EXAMPLE:</span> TSG
|<span class="blue-text">EXAMPLE:</span> 20% (COSMIC)

<span class="blue-text">EXAMPLE:</span> 30% (add Reference)
|<span class="blue-text">EXAMPLE:</span> IDH1 R123H
|<span class="blue-text">EXAMPLE:</span> EGFR amplification
|
|
|
|<span class="blue-text">EXAMPLE:</span>  Excludes hairy cell leukemia (HCL) (add reference).
<br />
|}
Note: A more extensive list of mutations can be found in cBioportal (https://www.cbioportal.org/), COSMIC (https://cancer.sanger.ac.uk/cosmic), ICGC (https://dcc.icgc.org/) and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.


<blockquote class='blockedit'>{{Box-round|title=v4:Gene Mutations (SNV/INDEL)|The content below was from the old template. Please incorporate above.}}


{| class="wikitable sortable"
|-
!Gene*!!Mutation!!Oncogene/Tumor Suppressor/Other!!Presumed Mechanism (LOF/GOF/Other; Driver/Passenger)!!Prevalence (COSMIC/TCGA/Other)
|-
|SETD2||mutation and/or deletion
|Tumor Suppressor||LOF frameshift indels or nonsense mutation||43% -93%
|-
|STAT5B
|
|'''Oncogene'''
|'''GOF'''
|up to 63%
|-
|JAK3
|
|'''Oncogene'''
|'''GOF'''
|46%
|}
'''*Specific mutations in these genes can be found elsewhere ([https://cancer.sanger.ac.uk/cosmic COSMIC], [https://www.cbioportal.org/ cBioPortal])'''


<blockquote class='blockedit'>{{Box-round|title=Unassigned References|The following referenees were placed in the header. Please place them into the appropriate locations in the text.}}<ref name=":0">{{Cite journal|last=Ab|first=Moffitt|last2=Sl|first2=Ondrejka|last3=M|first3=McKinney|last4=Re|first4=Rempel|last5=Jr|first5=Goodlad|last6=Ch|first6=Teh|last7=S|first7=Leppa|last8=S|first8=Mannisto|last9=Pe|first9=Kovanen|date=2017|title=Enteropathy-associated T cell lymphoma subtypes are characterized by loss of function of SETD2|url=https://pubmed.ncbi.nlm.nih.gov/28424246/|language=en|doi=10.1084/jem.20160894|pmc=PMC5413324|pmid=28424246}}</ref><ref name=":2">{{Cite journal|last=A|first=Roberti|last2=Mp|first2=Dobay|last3=B|first3=Bisig|last4=D|first4=Vallois|last5=C|first5=Boéchat|last6=E|first6=Lanitis|last7=B|first7=Bouchindhomme|last8=Mc|first8=Parrens|last9=C|first9=Bossard|date=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/|language=en|doi=10.1038/ncomms12602|pmc=PMC5023950|pmid=27600764}}</ref><ref>{{Cite journal|last=Ml|first=Nairismägi|last2=J|first2=Tan|last3=Jq|first3=Lim|last4=S|first4=Nagarajan|last5=Cc|first5=Ng|last6=V|first6=Rajasegaran|last7=D|first7=Huang|last8=Wk|first8=Lim|last9=Y|first9=Laurensia|date=2016|title=JAK-STAT and G-protein-coupled receptor signaling pathways are frequently altered in epitheliotropic intestinal T-cell lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/26854024/|language=en|doi=10.1038/leu.2016.13|pmc=PMC4895162|pmid=26854024}}</ref></blockquote>
</blockquote>
==Epigenomic Alterations==

*Defective H3K36 trimethylation<ref name=":2" />

==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. Do not delete table.'')</span>
{| class="wikitable sortable"
|-
!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
|-
|<span class="blue-text">EXAMPLE:</span> BRAF and MAP2K1; Activating mutations
|<span class="blue-text">EXAMPLE:</span> MAPK signaling
|<span class="blue-text">EXAMPLE:</span> Increased cell growth and proliferation
|-
|<span class="blue-text">EXAMPLE:</span> CDKN2A; Inactivating mutations
|<span class="blue-text">EXAMPLE:</span> Cell cycle regulation
|<span class="blue-text">EXAMPLE:</span> Unregulated cell division
|-
|<span class="blue-text">EXAMPLE:</span>  KMT2C and ARID1A; Inactivating mutations
|<span class="blue-text">EXAMPLE:</span>  Histone modification, chromatin remodeling
|<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.}}


*JAK-STAT (most common)
*RAS
*P53
*TERT
*BBX

'''Include these in the standard table.'''  


<blockquote class='blockedit'>{{Box-round|title=Unassigned References|The following referenees were placed in the header. Please place them into the appropriate locations in the text.}}<ref name=":0" /><ref>{{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></blockquote>
</blockquote>
==Genetic Diagnostic Testing Methods==

*Careful clinicopathologic correlation: lack of prior history of celiac disease or histologic features of celiac disease if no prior history known or documented
*Immunohistochemical evaluation (see Immunophenotype above and Clinical Significance below)
**Some immunostains not routinely available at commercial labs (e.g. SYK, MATK)
*

==Familial Forms==

*Not described

==Additional Information==

None

==Links==

[[HAEM4:Intestinal T-cell Lymphoma]]

==References==
(use the "Cite" icon at the top of the page) <span style="color:#0070C0">(''Instructions: Add each reference into the text above by clicking on where you want to insert the reference, selecting the “Cite” icon at the top of the page, and using the “Automatic” tab option to search such as by PMID to select the reference to insert. The reference list in this section will be automatically generated and sorted.''</span> <span style="color:#0070C0">''If a PMID is not available, such as for a book, please use the “Cite” icon, select “Manual” and then “Basic Form”, and include the entire reference''</span><span style="color:#0070C0">''.''</span><span style="color:#0070C0">) </span> <references />

'''

==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>''Citation of this Page'': “Monomorphic epitheliotropic intestinal T-cell lymphoma”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated {{REVISIONMONTH}}/{{REVISIONDAY}}/{{REVISIONYEAR}}, <nowiki>https://ccga.io/index.php/HAEM5:Monomorphic_epitheliotropic_intestinal_T-cell_lymphoma</nowiki>.
[[Category:HAEM5]][[Category:DISEASE]][[Category:Diseases M]]