Compendium of Cancer Genome Aberrations

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{{DISPLAYTITLE:Hepatosplenic T-cell lymphoma}}
[[HAEM5:Table_of_Contents|Haematolymphoid Tumours (5th ed.)]]
{{Under Construction}}
<blockquote class='blockedit'>{{Box-round|title=HAEM5 Conversion Notes|This page was converted to the new template on 2023-11-30. The original page can be found at [[HAEM4:Hepatosplenic T-cell Lymphoma]].
}}</blockquote>
==Primary Author(s)*==
==Primary Author(s)*==
Forough Sargolzaeiaval, MD


*Michelle Don, MD, MS
Michelle Don, MD, MS
__TOC__
 
==Cancer Category / Type==
 
*[[Mature T- and NK-cell Neoplasms]]
 
==Cancer Sub-Classification / Subtype==
 
*[[Hepatosplenic T-cell Lymphoma|'''Hepatosplenic T-cell Lymphoma''']] (HSTL)
 
==Definition / Description of Disease==
 
Aggressive subtype of peripheral T-cell lymphoma. HSTL is an extranodal T-cell lymphoma that is known to have a poor response to therapy and an overall poor prognosis. This lymphoma is characterized by sinusoidal infiltration of the liver spleen and often bone marrow by cytotoxic T-cells that most commonly express the γδ T-cell receptor. Less commonly, some patients may have a variant of this lymphoma that is associated with αβ expressing cytotoxic T-cells<ref name=":0">Medeiros LJ, O'Malley DP, Caraway NP, Vega F, Elenitoba-Johnson KS, Lim MS: AFIP Atlas of Tumor Pathology. Washington, DC: American Registry of Pathology, 2017.</ref><ref name=":1">Gaulard P, et al., (2017). Hepatosplenic T-cell lymphoma, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Arber DA, Hasserjian RP, Le Beau MM, Orazi A, and Siebert R, Editors. IARC Press: Lyon, France, p 381-382</ref><ref name=":2">Yabe M, Miranda RN, Medeiros LJ. Hepatosplenic T-cell Lymphoma: a review of clinicopathologic features, pathogenesis, and prognostic factors. ''Hum Pathol''. 2018;74:5‐16. doi:10.1016/j.humpath.2018.01.005</ref>. Most cases occur de novo, with a subset of approximately 20-30% occurring in the setting of iatrogenic immunosuppression<ref name=":2" />. Thus, this entity is also included in the list of the World Health Organization's post-transplant lymphoproliferative disorders<ref name=":1" />.
 
==Synonyms / Terminology==
 
*Hepatosplenic T-cell lymphoma (HSTL)


==Epidemiology / Prevalence==
==WHO Classification of Disease==


*1-2% of T-natural killer cell lymphomas<ref name=":1" />
*~80% are Classic γδ type<ref name=":1" />
*M:F ~ 3:1<ref name=":1" />
*Median age ~ 35 years old<ref name=":1" />
==Clinical Features==
Put your text here and fill in the table <span style="color:#0070C0">(''Instruction: Can include references in the table'') </span>
{| class="wikitable"
{| class="wikitable"
|'''Signs and Symptoms'''
!Structure
|EXAMPLE Asymptomatic (incidental finding on complete blood counts)
!Disease
 
|-
EXAMPLE B-symptoms (weight loss, fever, night sweats)
|Book
 
|Haematolymphoid Tumours (5th ed.)
EXAMPLE Fatigue
 
EXAMPLE Lymphadenopathy (uncommon)
|-
|-
|'''Laboratory Findings'''
|Category
|EXAMPLE Cytopenias
|T-cell and NK-cell lymphoid proliferations and lymphomas
 
EXAMPLE Lymphocytosis (low level)
|}
 
 
<blockquote class='blockedit'>{{Box-round|title=v4:Clinical Features|The content below was from the old template. Please incorporate above.}}
 
*Splenomegaly (most common symptom)<ref name=":2" />
*Diagnosed late in the course of the disease
*B-symptoms (night sweats, fever, weight loss and fatigue)<ref name=":0" />
*Hepatosplenomegaly<ref name=":2" />
*Cytopenias (most commonly thrombocytopenia)<ref name=":0" /><ref name=":2" />
*Lymphadenopathy (uncommon)<ref name=":2" /><ref name=":0" />
 
</blockquote>
==Sites of Involvement==
 
 
*Spleen
*Liver
*Bone marrow
*Lymph node (uncommon)
*With or without leukemic involvement
 
 
<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=":1" /></blockquote>
==Morphologic Features==
 
*Typically shows a sinusoidal pattern
 
==Immunophenotype==
 
{| class="wikitable sortable"
|-
|-
!Finding!!Marker
|Family
|Mature T-cell and NK-cell neoplasms
|-
|-
|Positive (typically)||CD3, γδ T-cell receptor, TIA1, Granzyme M<ref name=":1" />
|Type
|N/A
|-
|-
|Negative||CD4, CD8<ref name=":1" />
|Subtype(s)
|Hepatosplenic T-cell lymphoma
|}
|}
==Chromosomal Rearrangements (Gene Fusions)==
==Related Terminology==


Put your text here and fill in the table
{| class="wikitable"
|Acceptable
|N/A
|-
|Not Recommended
|Erythrophagocytic Tγ lymphoma
|}


==Gene Rearrangements==
No known chromosomal rearrangements at this time.
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
!Chromosomal Rearrangement!!Genes in Fusion (5’ or 3’ Segments)!!Pathogenic Derivative!!Prevalence
!Driver Gene!!Fusion(s) and Common Partner Genes!!Molecular Pathogenesis!!Typical Chromosomal Alteration(s)
!Diagnostic Significance (Yes, No or Unknown)
!Prevalence -Common >20%, Recurrent 5-20% or Rare <5% (Disease)
!Prognostic Significance (Yes, No or Unknown)
!Diagnostic, Prognostic, and Therapeutic Significance - D, P, T
!Therapeutic Significance (Yes, No or Unknown)
!Established Clinical Significance Per Guidelines - Yes or No (Source)
!Notes
!Clinical Relevance Details/Other Notes
|-
|-
|EXAMPLE t(9;22)(q34;q11.2)||EXAMPLE 3'ABL1 / 5'BCR||EXAMPLE der(22)||EXAMPLE 20% (COSMIC)
|N/A
EXAMPLE 30% (add reference)
|N/A
|Yes
|N/A
|No
|N/A
|Yes
|N/A
|EXAMPLE
|N/A
 
|N/A
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).
|N/A
|}
|}
 
<blockquote class='blockedit'>{{Box-round|title=v4:Chromosomal Rearrangements (Gene Fusions)|The content below was from the old template. Please incorporate above.}}
 
*No known chromosomal rearrangements at this time.
 
</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)}}
 
*7q aberrations and trisomy 8 are considered specific for HSTL, but not sensitive<ref name=":2" />
*''SETD2, INO80, TET3'', and ''STAT5B -'' seen almost exclusively in hepatosplenic T-cell lymphoma, compared to other B and T-cell lymphoma, which can support a diagnosis of HSTL in difficult cases<ref name=":4" />
**''RHOA'', has not been seen in HSTL cases, and is more commonly seen in peripheral T-cell lymphoma, NOS and angioimmunoblastic T- cell lymphoma<ref name=":4" />
*''PI3KCD, JAK1/2,'' and ''STAT5B'' mutations suggest potential therapeutic targets<ref name=":2" />
*''SyK'' expression was seen one study, which is not typical for normal T-cells<ref name=":5" />
**''Syk'' is a protein tyrosine kinase usually involved in B-cell receptor signaling<ref name=":5" />
**''Syk'' inhibitors may be a potential targeted therapeutic option<ref name=":5" />
*A single study has shown use of IFNα2c therapy-induced changes in CpG methylation<ref name=":7">{{Cite journal|last=Bhat|first=Jaydeep|last2=Bergmann|first2=Anke K.|last3=Waschina|first3=Silvio|last4=Nerl|first4=Christoph|last5=Kaleta|first5=Christoph|last6=Siebert|first6=Reiner|last7=Ammerpohl|first7=Ole|last8=Kabelitz|first8=Dieter|date=2020-08-20|title=DNA methylation profile of a hepatosplenic gamma/delta T-cell lymphoma patient associated with response to interferon-α therapy|url=https://pubmed.ncbi.nlm.nih.gov/32820235|journal=Cellular & Molecular Immunology|doi=10.1038/s41423-020-0518-4|issn=2042-0226|pmid=32820235}}</ref>
**CpG methylation changes have the potential to serve as biomarkers of drug responses and/or disease progression<ref name=":7" />
*The likely methylation of ''AIM1'' seen in HSTL  may provide rationale for demethylating agents as therapeutic options<ref name=":5" />
 
</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==
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
!Chr #!!Gain / Loss / Amp / LOH!!Minimal Region Genomic Coordinates [Genome Build]!!Minimal Region Cytoband
!Chr #!!Gain, Loss, Amp, LOH!!Minimal Region Cytoband and/or Genomic Coordinates [Genome Build; Size]!!Relevant Gene(s)
!Diagnostic Significance (Yes, No or Unknown)
!Diagnostic, Prognostic, and Therapeutic Significance - D, P, T
!Prognostic Significance (Yes, No or Unknown)
!Established Clinical Significance Per Guidelines - Yes or No (Source)
!Therapeutic Significance (Yes, No or Unknown)
!Clinical Relevance Details/Other Notes
!Notes
|-
|-
|EXAMPLE
|7
 
|Gain
7
|7q, chr7
|EXAMPLE Loss
|Unknown
|EXAMPLE
|D, P
 
chr7:1- 159,335,973 [hg38]
|EXAMPLE
 
chr7
|Yes
|Yes
|No
|No
|EXAMPLE
|Considered a primary aberration<ref name=":2">Yabe M, Miranda RN, Medeiros LJ. Hepatosplenic T-cell Lymphoma: a review of clinicopathologic features, pathogenesis, and prognostic factors. ''Hum Pathol''. 2018;74:5‐16. doi:10.1016/j.humpath.2018.01.005</ref>, seen in 40-70% of cases<ref name=":1">{{Cite journal|displayauthors=1|last=Medeiros|first=Jeffrey|date=2024|title=Hepatosplenic T-cell lymphoma. In: WHO Classification of Tumours Editorial Board. Haematolymphoid tumours [Internet]|url=https://tumourclassification.iarc.who.int/chaptercontent/63/229|journal=WHO classification of tumours series, 5th ed.|volume=vol. 11|pages=|via=Lyon (France): International Agency for Research on Cancer}}</ref>
 
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).
|-
|-
|EXAMPLE
|8
 
|Gain (trisomy)
8
|Chr8
|EXAMPLE Gain
|Unknown
|EXAMPLE
|D, P
 
chr8:1-145,138,636 [hg38]
|EXAMPLE
 
chr8
|No
|No
|Considered a secondary aberration<ref name=":2" />, seen in 10-50% of cases<ref name=":1" />
|-
|Y
|Loss
|ChrY
|Unknown
|Unknown
|No
|No
|No
|Seen in 20-25% of cases<ref name=":1" />
|EXAMPLE
 
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.}}
 
{| class="wikitable sortable"
|-
!Chromosome Number!!Gain/Loss/Amp/LOH!!Notes
|-
|7q
|Gain
|Considered a primary aberration<ref name=":2" />
|-
|-
|8||Gain (trisomy)||Considered a secondary aberration<ref name=":2" />
|10
|-
|10q
|Loss
|Loss
|Seen in 19% of cases<ref name=":4" />
|10q, chr10
|Unknown
|P
|No
|Seen in 10-20% of cases<ref name=":1" />
|-
|-
|1q
|1
|Gain
|Gain
|Seen in 13% of cases<ref name=":4" />
|1q, chr1
|Unknown
|P
|No
|Seen in 10-15% of cases<ref name=":1" />
|}
|}
<br />
==Characteristic Chromosomal or Other Global Mutational Patterns==
 
7q aberrations and trisomy 8 are considered specific for HSTL, but not sensitive<ref name=":2" />
</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>
 
{| 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
|Isochromosome 7q<ref name=":8">{{Cite journal|last=Wlodarska|first=Iwona|last2=Martin-Garcia|first2=Nadine|last3=Achten|first3=Ruth|last4=De Wolf-Peeters|first4=Chris|last5=Pauwels|first5=Patrick|last6=Tulliez|first6=Micheline|last7=de Mascarel|first7=Antoine|last8=Brière|first8=Josette|last9=Patey|first9=Martine|date=2002-03|title=Fluorescence in situ hybridization study of chromosome 7 aberrations in hepatosplenic T-cell lymphoma: isochromosome 7q as a common abnormality accumulating in forms with features of cytologic progression|url=https://pubmed.ncbi.nlm.nih.gov/11807981|journal=Genes, Chromosomes & Cancer|volume=33|issue=3|pages=243–251|doi=10.1002/gcc.10021|issn=1045-2257|pmid=11807981}}</ref> and chromosome 7 imbalances including ring chromosome 7.
Can be seen in conjunction with trisomy 8
|Cases with chromosome 7 abnormalities show:
*Constant loss of 7p22.1p14.1 (34.88 Mb; 3506316-38406226 bp)<ref name=":3">{{Cite journal|last=Finalet Ferreiro|first=Julio|last2=Rouhigharabaei|first2=Leila|last3=Urbankova|first3=Helena|last4=van der Krogt|first4=Jo-Anne|last5=Michaux|first5=Lucienne|last6=Shetty|first6=Shashirekha|last7=Krenacs|first7=Laszlo|last8=Tousseyn|first8=Thomas|last9=De Paepe|first9=Pascale|date=2014|title=Integrative genomic and transcriptomic analysis identified candidate genes implicated in the pathogenesis of hepatosplenic T-cell lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/25057852|journal=PloS One|volume=9|issue=7|pages=e102977|doi=10.1371/journal.pone.0102977|issn=1932-6203|pmc=4109958|pmid=25057852}}</ref>


Co-deletion of 1p and 18q
*Gain of 7q22.11q31.1 (38.77 Mb; 86259620–124892276 bp)<ref name=":3" />
|Yes
|Common
|No
|D, P
|No
|No
|EXAMPLE:
|See table under "Genomic Gain/Loss/LOH"
 
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.}}


*Most common genetic abnormalities include Isochromosome 7q and trisomy 8 (see table below "Genomic Gain/Loss/LOH")<ref name=":4" />
Co-occurrence of Isochromosome 7q and trisomy 8 can be seen in 8-53% of cases<ref name=":2" />
*Isochromsome 7q<ref>Wlodarska, Iwona, et al. "Fluorescence in situ hybridization study of chromosome 7 aberrations in hepatosplenic T‐cell lymphoma: isochromosome 7q as a common abnormality accumulating in forms with features of cytologic progression." ''Genes, Chromosomes and Cancer'' 33.3 (2002): 243-251.</ref> and chromosome 7 imbalances including ring chromosome 7
**Variable frequency in the literature (25-58%)<ref name=":2" />
**Considered to be a primary chromosomal aberration<ref name=":2" />
**Cases with chromosome 7 abnormalities show:
***Constant loss of 7p22.1p14.1 (34.88 Mb; 3506316-38406226 bp)<ref name=":3">Ferreiro, Julio Finalet, et al. "Integrative genomic and transcriptomic analysis identified candidate genes implicated in the pathogenesis of hepatosplenic T-cell lymphoma." ''PloS one'' 9.7 (2014): e102977.</ref>
***Gain of 7q22.11q31.1 (38.77 Mb; 86259620–124892276 bp)<ref name=":3" />
**Can be seen in conjunction with trisomy 8 (please see below)
***Cases without diagnostic detection of i(7q) or trisomy 8, often have detection of these abnormalities at the time of relapse or disease progression<ref name=":2" />
*Loss of chromosome 10q and gain of chromosome 1q occur in a significant minority of HSTL cases<ref name=":4" />


</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>
Cases without diagnostic detection of i(7q) or trisomy 8, often have detection of these abnormalities at the time of relapse or disease progression<ref name=":2" />
|-
|Loss of chromosome 10q
Gain of chromosome 1q
|
|Recurrent
|P
|No
|occur in a significant minority of HSTL cases<ref name=":4">McKinney, M., Moffitt, A.B., Gaulard, P., Travert, M., De Leval, L., Nicolae, A., Raffeld, M., Jaffe, E.S., Pittaluga, S., Xi, L. and Heavican, T., 2017. The genetic basis of hepatosplenic T-cell lymphoma. ''Cancer discovery'', ''7''(4), pp.369-379.</ref>
|}


==Gene Mutations (SNV/INDEL)==
Chromatin modifiers make up the most commonly mutated genes in HSTL, detected in 62% of cases. <ref name=":4" />
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
!Gene; Genetic Alteration!!'''Presumed Mechanism (Tumor Suppressor Gene [TSG] / Oncogene / Other)'''!!'''Prevalence (COSMIC /  TCGA / Other)'''!!'''Concomitant Mutations'''!!'''Mutually Exclusive Mutations'''
!Gene!!Genetic Alteration!!Tumor Suppressor Gene, Oncogene, Other!!Prevalence -
!'''Diagnostic Significance (Yes, No or Unknown)'''
Common >20%, Recurrent 5-20% or Rare <5% (Disease)
!Prognostic Significance (Yes, No or Unknown)
!Diagnostic, Prognostic, and Therapeutic Significance - D, P, T  
!Therapeutic Significance (Yes, No or Unknown)
!Established Clinical Significance Per Guidelines - Yes or No (Source)
!Notes
!Clinical Relevance Details/Other Notes
|-
|-
|EXAMPLE: TP53; Variable LOF mutations
|''STAT3''; missense mutation
|missense mutation
|Oncogenic driver mutation
|Recurrent
|T
|No
|Also seen in 40% of T-large granular lymphocyte leukemia<ref name=":2" />
|-
|''STAT5b''; missense mutation
|missense mutation
|Oncogenic driver mutation
|Common
|D, T
|No
|Highest functional potency: ''STAT5B'' N642H and V712E mutations<ref name=":2" />


EXAMPLE:


EGFR; Exon 20 mutations
One study showed increased CD56 expression with ''STAT5b''<ref name=":9">{{Cite journal|last=Nicolae|first=A.|last2=Xi|first2=L.|last3=Pittaluga|first3=S.|last4=Abdullaev|first4=Z.|last5=Pack|first5=S. D.|last6=Chen|first6=J.|last7=Waldmann|first7=T. A.|last8=Jaffe|first8=E. S.|last9=Raffeld|first9=M.|date=2014-11|title=Frequent STAT5B mutations in γδ hepatosplenic T-cell lymphomas|url=https://pubmed.ncbi.nlm.nih.gov/24947020|journal=Leukemia|volume=28|issue=11|pages=2244–2248|doi=10.1038/leu.2014.200|issn=1476-5551|pmc=7701980|pmid=24947020}}</ref>


EXAMPLE: BRAF; Activating mutations
|EXAMPLE: TSG
|EXAMPLE: 20% (COSMIC)


EXAMPLE: 30% (add Reference)
Also seen in ~2% of T-large granular lymphocyte leukemia<ref name=":2" />
|EXAMPLE: IDH1 R123H
|-
|EXAMPLE: EGFR amplification
|''PIK3CD''
|Activating mutations
|Activate signaling
pathways important to cell survival<ref name=":4" />
|Recurrent
|T
|No
|
|
|
|-
|
|''SETD2''; biallelic LOF
|EXAMPLE:  Excludes hairy cell leukemia (HCL) (add reference).
|biallelic LOF
<br />
|Tumor suppressor gene, chromatin modifier*<ref name=":4" />
|}
|Common
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.
|D, T
|No
|''SET2–RPB1'' interacting domain (SRI) domain ( 31 ) at the COOH-terminus of the SETD2 protein product
 


Most frequently silenced gene and most frequent mutated chromatin modifier in HSTL<ref name=":4" />


<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"
71% of cases showing at least one LOF mutation<ref name=":4" />, and more than 44% of patients with ''SETD2'' mutations had more than 1 mutation detected<ref name=":2" />
|-
|-
!Gene!!Mutation!!Role/function!!Presumed Mechanism (LOF/GOF/Other; Driver/Passenger)!!Prevalence<ref name=":4" />
|''INO80''
!Notes
|-
|STAT3||Src homology 2 (SH2) domain
|Signaling pathway||Oncogenic driver mutation||9%
|
|
*Also seen in 40% of T-large granular lymphocyte leukemia<ref name=":2" />
|Chromatin modifier*
|-
|Common
|STAT5b
|D, P, T
|Src homology 2 (SH2) domain
|No
|Signaling pathway
|Oncogenic driver mutation
|31%
|
*Highest functional potency: ''STAT5B'' N642H and V712E mutations<ref name=":2" />
*One study showed increased CD56 expression with STAT5b<ref>Nicolae A, Xi L, Pittaluga S, Abdullaev Z, Pack SD, Chen J, Waldmann TA, Jaffe ES, Raffeld M. Frequent STAT5B mutations in γδ hepatosplenic T-cell lymphomas. Leukemia. 2014 Nov;28(11):2244-8.</ref>
*Also seen in ~2% of T-large granular lymphocyte leukemia<ref name=":2" />
|-
|PIK3CD
|
|Signaling pathway
|Activate signaling pathways important to cell survival<ref name=":4" />
|9%
|
|
|-
|-
|SETD2
|''ARID1B''
|SET2–RPB1 interacting domain (SRI) domain ( 31 ) at the COOH-terminus of the SETD2 protein product
(other mutations interspersed among different domains have also been seen)<ref name=":4" />
|Tumor suppressor gene, chromatin modifier*<ref name=":4" />
|Biallelic loss of function<ref name=":4" />
|71% (cases showing at least one loss of function mutation)
|
*Most frequently silenced gene and most frequent mutated chromatin modifier in HSTL<ref name=":4" />
 
*More than 44% of patients had more than 1 mutation in SETD2.<ref name=":2" />
|-
|INO80
|
|
|Chromatin modifier*
|Chromatin modifier*
|
|Recurrent
|21%
|Unknown
|No
|
|
|-
|-
|TET3
|''TET3''
|
|
|Chromatin modifier*
|Chromatin modifier*
|
|Recurrent
|15%
|D, T
|No
|
|
|-
|-
|SMARCA2
|''SMARCA2''
|
|
|Chromatin modifier*
|Chromatin modifier*
|Recurrent
|Unknown
|No
|
|
|10%
|}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.
|
|}
'''*'''Chromatin modifiers make up the most commonly mutated genes in HSTL<ref name=":4" />
 
Specific mutations in the above genes can be found elsewhere ([https://cancer.sanger.ac.uk/cosmic COSMIC], [https://www.cbioportal.org/ cBioPortal])
 
===Important to note:===
{| class="wikitable sortable"
|-
!Type!!Gene/Region/Other
|-
|Mutually Exclusive||STAT3 and STAT5b
 
*Only 1 reported case with both mutations present<ref name=":4">McKinney, M., Moffitt, A.B., Gaulard, P., Travert, M., De Leval, L., Nicolae, A., Raffeld, M., Jaffe, E.S., Pittaluga, S., Xi, L. and Heavican, T., 2017. The genetic basis of hepatosplenic T-cell lymphoma. ''Cancer discovery'', ''7''(4), pp.369-379.</ref>
|}


</blockquote>
==Epigenomic Alterations==
==Epigenomic Alterations==


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***Hypermethylation of CpGs around transcription start sites shows a lack of protein expression of CD5 and CXCR6 by immunohistochemistry in HSTL, compared to normal lymphocytes<ref name=":6" />.
***Hypermethylation of CpGs around transcription start sites shows a lack of protein expression of CD5 and CXCR6 by immunohistochemistry in HSTL, compared to normal lymphocytes<ref name=":6" />.
****Note: This finding is not specific to HSTL and can be seen in other T-cell lymphomas<ref name=":6" />
****Note: This finding is not specific to HSTL and can be seen in other T-cell lymphomas<ref name=":6" />
*A single study has shown use of IFNα2c therapy-induced changes in CpG methylation<ref name=":7">{{Cite journal|last=Bhat|first=Jaydeep|last2=Bergmann|first2=Anke K.|last3=Waschina|first3=Silvio|last4=Nerl|first4=Christoph|last5=Kaleta|first5=Christoph|last6=Siebert|first6=Reiner|last7=Ammerpohl|first7=Ole|last8=Kabelitz|first8=Dieter|date=2021-05|title=DNA methylation profile of a hepatosplenic gamma/delta T-cell lymphoma patient associated with response to interferon-α therapy|url=https://pubmed.ncbi.nlm.nih.gov/32820235|journal=Cellular & Molecular Immunology|volume=18|issue=5|pages=1332–1335|doi=10.1038/s41423-020-0518-4|issn=2042-0226|pmc=8093208|pmid=32820235}}</ref>
**CpG methylation changes have the potential to serve as biomarkers of drug responses and/or disease progression<ref name=":7" />


==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>
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
!Gene; Genetic Alteration<ref name=":4" /><ref name=":5" />!!Pathway<ref name=":4" /><ref name=":5" />!!Pathophysiologic Outcome<ref name=":4" /><ref name=":5" />
|-
|''STAT, PIK3CD''
|Signaling pathways
|PI-3 kinase and JAK-STAT signaling pathways maintain proliferation and survival within HSTL cells
|-
|''SETD2''
|Tumor suppressor, chromatin modifier
|Reduced SETD2 protein expression and increased proliferation of HSTL cells
|-
|''INO80, ARID1B, TET3, SMARCA2''
|Chromatin modifier
|Disrupted regulation of cell differentiation and proliferation, resulting in development and progression of cancer
|-
|''KIRs'', ''KLR'', ''CD244'', and ''NCAM1'' overexpression
|NK-cell–associated molecules
|Dysregulation of NK cell-mediated cytotoxicity
|-
|''FOS'', ''VAV3'', ''MAF'', and ''BRAF'' overexpression
|Oncogene
|Enhanced oncogenic signaling promoting cellular transformation and tumorigenesis
|-
|''VCAM1'', ''CD11d'', and ''ICAM1'' overexpression
|Cell adhesion
|Increased inflammatory response due to enhanced leukocyte endothelial transmigration
|-
|''SPRY2'', ''RHOB*'', ''MAP4K3'', and ''SPRY1'' overexpression
|Signal transduction
|Altered cellular growth, differentiation, and migration. Overactive signaling pathways could contribute to oncogenesis
|-
|-
|EXAMPLE: BRAF and MAP2K1; Activating mutations
|''GLI3, PRKAR2B, PRKACB, and PRKAR1A'' overexpression
|EXAMPLE: MAPK signaling
|Sonic hedgehog pathway
|EXAMPLE: Increased cell growth and proliferation
|Abnormal tissue patterning and growth
|-
|-
|EXAMPLE: CDKN2A; Inactivating mutations
|''FRZB, TCF7L2, BAMBI, TLE1, CTNNB1, APC, and FZD5'' overexpression
|EXAMPLE: Cell cycle regulation
|WNT pathway
|EXAMPLE: Unregulated cell division
|Disruption of normal WNT signaling balance, potentially leading to abnormal cell proliferation, differentiation, and migration
|-
|-
|EXAMPLE:  KMT2C and ARID1A; Inactivating mutations
|''ABCB1, GSTP1'' overexpression
|EXAMPLE:  Histone modification, chromatin remodeling
|Multidrug resistance signaling
|EXAMPLE:  Abnormal gene expression program
|Enhanced efflux of chemotherapeutic agents from cancer cells, leading to reduced efficacy of treatment and the development of drug resistance
|-
|''S1PR5'' overexpression
|Homing of NK cells into the spleen
|Distribution and accumulation of neoplastic γδ cells in the spleen and bone marrow
|-
|''SYK**'' overexpression
|Tyrosine kinase
|Cell growth and survival of neoplastic HSTL cells
|-
|''AIM1'' down-expression
|Tumor suppressor
|Impaired cellular growth regulation leading to increased susceptibility to tumor formation
|-
|''Granulysin, Granzyme H, Granzyme K, and Granzyme B'' under-expression
|Cytotoxicity
|Compromised ability of NK cells and cytotoxic T lymphocytes to induce apoptosis
|-
|''LTA'', ''TNF'', and ''IFNG'' under-expression
|Cytokines
|Reduced inflammatory and immune responses
|}
|}
<nowiki>*</nowiki>''RHOA'' mutations predominantly favor Peripheral T-cell lymphomas, not otherwise specified (PTCL-NOS) and angioimmunoblastic T-cell lymphoma (AITL)<ref name=":4" />


<blockquote class='blockedit'>{{Box-round|title=v4:Genes and Main Pathways Involved|The content below was from the old template. Please incorporate above.}}
''**SyK'' expression was seen one study, which is not typical for normal T-cells<ref name=":5" /> ''Syk'' is a protein tyrosine kinase usually involved in B-cell receptor signaling<ref name=":5" />
 
*HSTL (both γδ and αβ phenotypes) show a similar molecular blueprint<ref name=":5" />
**Clustering of expression profiles of HSTL samples show separate clustering compared to the other T-cell lymphomas irrespective of their αβ or γδ lineage<ref name=":5" />
**Overexpression of genes encoding NK-cell–associated molecules (''KIRs'', ''KLR'', ''CD244'', and ''NCAM1)'', oncogenes (''FOS'', ''VAV3'', ''MAF'', and ''BRAF''), cell adhesion (eg, ''VCAM1'', ''CD11d'', and ''ICAM1''), tsignal transduction (eg, ''SPRY2'', ''RHOB'', ''MAP4K3'', and ''SPRY1''), the sonic hedgehog pathway (eg, ''GLI3'', ''PRKAR2B'', ''PRKACB'', and ''PRKAR1A''), the WNT pathway (eg, ''FRZB'', ''TCF7L2'', ''BAMBI'', ''TLE1'', ''CTNNB1'', ''APC'', and ''FZD5''), and ''S1PR5'', and the tyrosine kinase ''SYK''<ref name=":5" />
**''AIM1'' (absent in melanoma 1) was among the most down-expressed genes<ref name=":5" />
***Genes showing significant under expression in HSTL includes those associated with cytotoxicity (eg, ''Granulysin'', ''Granzyme H'', ''Granzyme K'', and ''Granzyme B''), cytokines (eg, ''LTA'', ''TNF'', and ''IFNG''), and ''CD5''<ref name=":5" />


</blockquote>
==Genetic Diagnostic Testing Methods==
==Genetic Diagnostic Testing Methods==


Clinical, morphologic, and immunophenotypic features are sufficient for diagnosis in most cases.  Cytogenetic testing could be used to support the diagnosis
Clinical, morphologic, and immunophenotypic features are sufficient for diagnosis in most cases.  Cytogenetic testing could be used to support the diagnosis.


*Karyotype may show trisomy 8, if present
*Karyotype may show trisomy 8, if present
*FISH targeted isochromosome 7q and trisomy 8
*FISH targeted isochromosome 7q and trisomy 8
*Next generation sequencing to support mutations seen in HSTL including ''STAT3, STAT5B, PI3KCD,'' ''SETD2, INO80, TET3'', and ''STAT5B''<ref name=":4" />  
*Next generation sequencing to support mutations seen in HSTL including ''STAT3, STAT5B, PI3KCD,'' ''SETD2, INO80, TET3'', and ''STAT5B''<ref name=":5" />  
**Presence of RHOA mutation, can potentially exclude HSTL from the differential diagnosis<ref name=":4" />
**Presence of ''RHOA'' mutation, can potentially exclude HSTL from the differential diagnosis<ref name=":5" />


==Familial Forms==
==Familial Forms==
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==Additional Information==
==Additional Information==
HSTL is an aggressive subtype of extranodal, peripheral T-cell lymphoma with a poor response to therapy and an overall poor prognosis. This lymphoma is characterized by sinusoidal infiltration of the liver, spleen and often bone marrow, and uncommonly lymph nodes by cytotoxic T-cells that most commonly express the γδ T-cell receptor. Less commonly, this lymphoma can consist of a proliferation of αβ expressing cytotoxic T-cells <ref name=":0">Medeiros LJ, O'Malley DP, Caraway NP, Vega F, Elenitoba-Johnson KS, Lim MS: AFIP Atlas of Tumor Pathology. Washington, DC: American Registry of Pathology, 2017.</ref><ref name=":1" /><ref name=":2" />. Most cases occur de novo, with a subset of approximately 20-30% occurring in the setting of iatrogenic immunosuppression <ref name=":2" />.
<u>Epidemiology/prevalence</u>:
*1.4-2% of peripheral T-cell lymphomas<ref name=":1" />
*~75% are classic γδ type<ref name=":1" />
*Male predominance in γδ subtype<ref name=":1" />
*Median age ~35 years old<ref name=":2" />, 51% with age >60 years old<ref>{{Cite journal|last=Foss|first=Francine M.|last2=Horwitz|first2=Steven M.|last3=Civallero|first3=Monica|last4=Bellei|first4=Monica|last5=Marcheselli|first5=Luigi|last6=Kim|first6=Won Seog|last7=Cabrera|first7=Maria E.|last8=Dlouhy|first8=Ivan|last9=Nagler|first9=Arnon|date=2020-02|title=Incidence and outcomes of rare T cell lymphomas from the T Cell Project: hepatosplenic, enteropathy associated and peripheral gamma delta T cell lymphomas|url=https://pubmed.ncbi.nlm.nih.gov/31709579|journal=American Journal of Hematology|volume=95|issue=2|pages=151–155|doi=10.1002/ajh.25674|issn=1096-8652|pmc=8025136|pmid=31709579}}</ref>
<u>Clinical features:</u> Splenomegaly (most common symptom); B-symptoms (night sweats, fever, weight loss and fatigue); hepatomegaly; uncommonly lymphadenopathy; cytopenias (most commonly thrombocytopenia); elevated serum levels of B2M and LDH


*N/A
<u>Sites of involvement:</u> Spleen, liver, bone marrow, with or without leukemia involvement; uncommonly lymph nodes; rarely skin, usually in relapse cases
 
<u>Immunophenotype</u>:
 
Positive (typically) - CD2, CD3, γδ T-cell receptor, TIA1, Granzyme M<ref name=":1" />
 
Negative (subset) – CD5, CD4, CD8<ref name=":1" />


==Links==
==Links==


*[[T-cell Large Granular Lymphocytic Leukemia]]
*[[HAEM5:T-large granular lymphocytic leukaemia]]


==References==
==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 />
<references />


'''
==Notes==
<nowiki>*</nowiki>''Citation of this Page'': Sargolzaeiaval F, Don M. “Hepatosplenic T-cell lymphoma”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated {{REVISIONMONTH}}/{{REVISIONDAY}}/{{REVISIONYEAR}}, <nowiki>https://ccga.io/index.php/HAEM5:Hepatosplenic_T-cell_lymphoma</nowiki>.
 
 
<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.


==Notes==
Prior Author(s): N/A 
<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.
[[Category:HAEM5]]
<nowiki>*</nowiki>''Citation of this Page'': “Hepatosplenic T-cell lymphoma”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated {{REVISIONMONTH}}/{{REVISIONDAY}}/{{REVISIONYEAR}}, <nowiki>https://ccga.io/index.php/HAEM5:Hepatosplenic_T-cell_lymphoma</nowiki>.
[[Category:DISEASE]]
[[Category:HAEM5]][[Category:DISEASE]][[Category:Diseases H]]
[[Category:Diseases H]]
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