Compendium of Cancer Genome Aberrations

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HAEM5:Hepatosplenic T-cell lymphoma (view source)

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{{DISPLAYTITLE:Hepatosplenic T-cell lymphoma}}
 
{{DISPLAYTITLE:Hepatosplenic T-cell lymphoma}}
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[[HAEM5:Table_of_Contents|Haematolymphoid Tumours (5th ed.)]]
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{{Under Construction}}
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<blockquote class="blockedit">{{Box-round|title=HAEM5 Conversion Notes|This page was converted to the new template on 2023-12-07. The original page can be found at [[HAEM4:Hepatosplenic T-cell Lymphoma]].
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}}</blockquote>
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<span style="color:#0070C0">(General Instructions – The main focus of these pages is the clinically significant genetic alterations in each disease type. Use [https://www.genenames.org/ <u>HUGO-approved gene names and symbols</u>] (italicized when appropriate), [https://varnomen.hgvs.org/ HGVS-based nomenclature for variants], as well as generic names of drugs and testing platforms or assays if applicable. Please complete tables whenever possible and do not delete them (add N/A if not applicable in the table and delete the examples). Please do not delete or alter the section headings. The use of bullet points alongside short blocks of text rather than only large paragraphs is encouraged. Additional instructions below in italicized blue text should not be included in the final page content. Please also see </span><u>[[Author_Instructions]]</u><span style="color:#0070C0"> and [[Frequently Asked Questions (FAQs)|<u>FAQs</u>]] as well as contact your [[Leadership|<u>Associate Editor</u>]] or [mailto:CCGA@cancergenomics.org <u>Technical Support</u>])</span>
      
==Primary Author(s)*==
 
==Primary Author(s)*==
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*Forough Sargolzaeiaval, MD
 
*Forough Sargolzaeiaval, MD
 
*Michelle Don, MD, MS
 
*Michelle Don, MD, MS
−
__TOC__
     −
==Cancer Category / Type==
+
==WHO Classification of Disease==
   −
*HAEM5: Mature T-cell and NK-cell Neoplasms
  −
  −
==Cancer Sub-Classification / Subtype==
  −
  −
*[[HAEM5: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, and uncommonly lymph nodes 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">{{Cite journal|title=BlueBooksOnline|url=https://tumourclassification.iarc.who.int/chaptercontent/63/229}}</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" />.
  −
  −
==Synonyms / Terminology==
  −
  −
*Hepatosplenic T-cell lymphoma (HSTL)
  −
  −
==Epidemiology / Prevalence==
  −
  −
* 1.4-2% of peripheral T-cell lymphomas<ref name=":1" />
  −
* ~75% are Classic γδ type<ref name=":1" />
  −
* Male predominance in gamma-delta 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>
  −
  −
==Clinical Features==
   
{| class="wikitable"
 
{| class="wikitable"
−
|'''Signs and Symptoms'''
+
!Structure
−
|Splenomegaly (most common symptom)<ref name=":2" />
+
!Disease
−
B-symptoms (night sweats, fever, weight loss and fatigue)<ref name=":0" />
+
|-
−
 
+
|Book
−
Hepatomegaly<ref name=":1" /><ref name=":2" />
+
|Haematolymphoid Tumours (5th ed.)
−
 
+
|-
−
Lymphadenopathy (uncommon)<ref name=":0" /><ref name=":2" />
+
|Category
 +
|T-cell and NK-cell lymphoid proliferations and lymphomas
 +
|-
 +
|Family
 +
|Mature T-cell and NK-cell neoplasms
 +
|-
 +
|Type
 +
|N/A
 +
|-
 +
|Subtype(s)
 +
|Hepatosplenic T-cell lymphoma
 +
|}
 +
==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"
 +
|+
 +
|Acceptable
 +
|
 
|-
 
|-
−
|'''Laboratory Findings'''
+
|Not Recommended
−
|Cytopenias (most commonly thrombocytopenia)<ref name=":0" /><ref name=":2" />
+
|
−
Elevated serum levels of B2M<ref name=":1" />
  −
 
  −
Elevated serum levels of LDH<ref name=":1" />
   
|}
 
|}
   −
==Sites of Involvement==
+
==Gene Rearrangements==
   −
*Spleen
+
*No known chromosomal rearrangements at this time
−
*Liver
  −
*Bone marrow
  −
*Lymph node (uncommon)
  −
*Skin (rarely, in relapse cases)
  −
*With or without leukemic involvement
     −
<br />
+
{| class="wikitable sortable"
−
==Morphologic Features==
+
|-
−
 
+
!Driver Gene!!Fusion(s) and Common Partner Genes!!Molecular Pathogenesis!!Typical Chromosomal Alteration(s)
−
*Typically shows a sinusoidal pattern
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!Prevalence -Common >20%, Recurrent 5-20% or Rare <5% (Disease)
−
 
+
!Diagnostic, Prognostic, and Therapeutic Significance - D, P, T
−
==Immunophenotype==
+
!Established Clinical Significance Per Guidelines - Yes or No (Source)
 +
!Clinical Relevance Details/Other Notes
 +
|-
 +
|N/A
 +
|
 +
|
 +
|
 +
|
 +
|
 +
|
 +
|
 +
|}
    +
==Individual Region Genomic Gain/Loss/LOH==
 
{| class="wikitable sortable"
 
{| class="wikitable sortable"
 
|-
 
|-
−
!Finding!!Marker
+
!Chr #!!'''Gain, Loss, Amp, LOH'''!!'''Minimal Region Cytoband and/or Genomic Coordinates [Genome Build; Size]'''!!'''Relevant Gene(s)'''
 +
!'''Diagnostic, Prognostic, and Therapeutic Significance - D, P, T'''
 +
!'''Established Clinical Significance Per Guidelines - Yes or No (Source)'''
 +
!'''Clinical Relevance Details/Other Notes'''
 +
|-
 +
|<span class="blue-text">EXAMPLE:</span>
 +
7
 +
|<span class="blue-text">EXAMPLE:</span> Loss
 +
|<span class="blue-text">EXAMPLE:</span>
 +
chr7
 +
|<span class="blue-text">EXAMPLE:</span>
 +
Unknown
 +
|<span class="blue-text">EXAMPLE:</span> D, P
 +
|<span class="blue-text">EXAMPLE:</span> No
 +
|<span class="blue-text">EXAMPLE:</span>
 +
Presence of monosomy 7 (or 7q deletion) is sufficient for a diagnosis of AML with MDS-related changes when there is ≥20% blasts and no prior therapy (add reference).  Monosomy 7/7q deletion is associated with a poor prognosis in AML (add references).
 +
|-
 +
|<span class="blue-text">EXAMPLE:</span>
 +
8
 +
|<span class="blue-text">EXAMPLE:</span> Gain
 +
|<span class="blue-text">EXAMPLE:</span>
 +
chr8
 +
|<span class="blue-text">EXAMPLE:</span>
 +
Unknown
 +
|<span class="blue-text">EXAMPLE:</span> D, P
 +
|
 +
|<span class="blue-text">EXAMPLE:</span>
 +
Common recurrent secondary finding for t(8;21) (add references).
 
|-
 
|-
−
|Positive (typically)||CD2, CD3, γδ T-cell receptor, TIA1, Granzyme M<ref name=":1" />
+
|<span class="blue-text">EXAMPLE:</span>
 +
17
 +
|<span class="blue-text">EXAMPLE:</span> Amp
 +
|<span class="blue-text">EXAMPLE:</span>
 +
17q12; chr17:39,700,064-39,728,658 [hg38; 28.6 kb]
 +
|<span class="blue-text">EXAMPLE:</span>
 +
''ERBB2''
 +
|<span class="blue-text">EXAMPLE:</span> D, P, T
 +
|
 +
|<span class="blue-text">EXAMPLE:</span>
 +
Amplification of ''ERBB2'' is associated with HER2 overexpression in HER2 positive breast cancer (add references). Add criteria for how amplification is defined.
 
|-
 
|-
−
|Negative||CD5, CD4, CD8<ref name=":1" />
+
|
 +
|
 +
|
 +
|
 +
|
 +
|
 +
|
 
|}
 
|}
−
==Chromosomal Rearrangements (Gene Fusions)==
  −
  −
* No known chromosomal rearrangements at this time
  −
  −
==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 Genomic Coordinates [Genome Build]!!Minimal Region Cytoband
−
!Diagnostic Significance (Yes, No or Unknown)<ref name=":2" /><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>
+
!Diagnostic Significance (Yes, No or Unknown)<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><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>
 
!Prognostic Significance (Yes, No or Unknown)<ref name=":2" /><ref name=":4" />
 
!Prognostic Significance (Yes, No or Unknown)<ref name=":2" /><ref name=":4" />
 
!Therapeutic Significance (Yes, No or Unknown)
 
!Therapeutic Significance (Yes, No or Unknown)
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|Gain
 
|Gain
 
|
 
|
−
|Chr7
+
|Constant loss of 7p22.1p14.1
 +
Gain of 7q22.11q31.1
 
|Yes
 
|Yes
 
|Yes
 
|Yes
 
|No
 
|No
−
|Considered a primary aberration<ref name=":2" />
+
|Considered a primary aberration<ref name=":2" />, seen in 40-70% of cases<ref name=":1">{{Cite journal|title=Hepatosplenic T-cell lymphoma. In: WHO Classification of Tumours Editorial Board. Haematolymphoid tumours [Internet]|url=https://tumourclassification.iarc.who.int/chaptercontent/63/229|displayauthors=1|last=Medeiros|first=Jeffrey|date=2024|journal=WHO classification of tumours series, 5th ed.|volume=vol. 11|pages=|via=Lyon (France): International Agency for Research on Cancer}}</ref>
 
|-
 
|-
 
|8
 
|8
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|Yes
 
|Yes
 
|No
 
|No
−
|Considered a secondary aberration<ref name=":2" />
+
|Considered a secondary aberration<ref name=":2" />, seen in 10-50% of cases<ref name=":1" />
 
|-
 
|-
 
|Y
 
|Y
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|Seen in 10-15% of cases<ref name=":1" />
 
|Seen in 10-15% of cases<ref name=":1" />
 
|}<br />
 
|}<br />
−
==Characteristic Chromosomal Patterns==
     −
* 7q aberrations and trisomy 8 are considered specific for HSTL, but not sensitive<ref name=":2" />
+
==Characteristic Chromosomal or Other Global Mutational Patterns==
 +
{| class="wikitable sortable"
 +
|-
 +
!Chromosomal Pattern
 +
!Molecular Pathogenesis
 +
!'''Prevalence -'''
 +
'''Common >20%, Recurrent 5-20% or Rare <5% (Disease)'''
 +
!'''Diagnostic, Prognostic, and Therapeutic Significance - D, P, T'''
 +
!'''Established Clinical Significance Per Guidelines - Yes or No (Source)'''
 +
!'''Clinical Relevance Details/Other Notes'''
 +
|-
 +
|<span class="blue-text">EXAMPLE:</span>
 +
Co-deletion of 1p and 18q
 +
|<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).
 +
|<span class="blue-text">EXAMPLE:</span> Common (Oligodendroglioma)
 +
|<span class="blue-text">EXAMPLE:</span> D, P
 +
|
 +
|
 +
|-
 +
|<span class="blue-text">EXAMPLE:</span>
 +
Microsatellite instability - hypermutated
 +
|
 +
|<span class="blue-text">EXAMPLE:</span> Common (Endometrial carcinoma)
 +
|<span class="blue-text">EXAMPLE:</span> P, T
 +
|
 +
|
 +
|-
 +
|
 +
|
 +
|
 +
|
 +
|
 +
|
 +
|}
 +
 
 +
*7q aberrations and trisomy 8 are considered specific for HSTL, but not sensitive<ref name=":2" />
    
{| class="wikitable sortable"
 
{| class="wikitable sortable"
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!Notes
 
!Notes
 
|-
 
|-
−
|Isochromsome 7q<ref>{{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.
+
|Isochromosome 7q<ref>{{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.
 
Cases with chromosome 7 abnormalities show:
 
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>
+
*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>
   −
* Gain of 7q22.11q31.1 (38.77 Mb; 86259620–124892276 bp)<ref name=":3" /> Can be seen in conjunction with trisomy 8
+
*Gain of 7q22.11q31.1 (38.77 Mb; 86259620–124892276 bp)<ref name=":3" />
    
Can be seen in conjunction with trisomy 8
 
Can be seen in conjunction with trisomy 8
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|Yes
 
|Yes
 
|No
 
|No
−
|
+
|See table under "Genomic Gain/Loss/LOH"
−
* See table under "Genomic Gain/Loss/LOH"
+
 
 +
 
 +
Co-occurrence of Isochromosome 7q and trisomy 8 can be seen in 8-53% of cases<ref name=":2" />
   −
<br />
     −
* 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" />
+
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
+
|Loss of chromosome 10q  
 +
Gain of chromosome 1q
 
|No
 
|No
 
|Yes
 
|Yes
 
|No
 
|No
 +
|occur in a significant minority of HSTL cases<ref name=":4" />
 +
|}<br />
 +
 +
==Gene Mutations (SNV/INDEL)==
 +
Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: This table is not meant to be an exhaustive list; please include only genes/alterations that are recurrent or common as well either disease defining and/or clinically significant. If a gene has multiple mechanisms depending on the type or site of the alteration, add multiple entries in the table. For clinical significance, denote associations with FDA-approved therapy (not an extensive list of applicable drugs) and NCCN or other national guidelines if applicable; Can also refer to CGC workgroup tables as linked on the homepage if applicable as well as any high impact papers or reviews of gene mutations in this entity. Details on clinical significance such as prognosis and other important information such as concomitant and mutually exclusive mutations can be provided in the notes section. Please include references throughout the table. Do not delete the table.'') </span>
 +
{| class="wikitable sortable"
 +
|-
 +
!Gene!!'''Genetic Alteration'''!!'''Tumor Suppressor Gene, Oncogene, Other'''!!'''Prevalence -'''
 +
'''Common >20%, Recurrent 5-20% or Rare <5% (Disease)'''
 +
!'''Diagnostic, Prognostic, and Therapeutic Significance - D, P, T  '''
 +
!'''Established Clinical Significance Per Guidelines - Yes or No (Source)'''
 +
!'''Clinical Relevance Details/Other Notes'''
 +
|-
 +
|<span class="blue-text">EXAMPLE:</span>''EGFR''
 +
 +
<br />
 +
|<span class="blue-text">EXAMPLE:</span> Exon 18-21 activating mutations
 +
|<span class="blue-text">EXAMPLE:</span> Oncogene
 +
|<span class="blue-text">EXAMPLE:</span> Common (lung cancer)
 +
|<span class="blue-text">EXAMPLE:</span> T
 +
|<span class="blue-text">EXAMPLE:</span> Yes (NCCN)
 +
|<span class="blue-text">EXAMPLE:</span> Exons 18, 19, and 21 mutations are targetable for therapy. Exon 20 T790M variants cause resistance to first generation TKI therapy and are targetable by second and third generation TKIs (add references).
 +
|-
 +
|<span class="blue-text">EXAMPLE:</span> ''TP53''; Variable LOF mutations
 +
<br />
 +
|<span class="blue-text">EXAMPLE:</span> Variable LOF mutations
 +
|<span class="blue-text">EXAMPLE:</span> Tumor Supressor Gene
 +
|<span class="blue-text">EXAMPLE:</span> Common (breast cancer)
 +
|<span class="blue-text">EXAMPLE:</span> P
 +
|
 +
|<span class="blue-text">EXAMPLE:</span> >90% are somatic; rare germline alterations associated with Li-Fraumeni syndrome (add reference). Denotes a poor prognosis in breast cancer.
 +
|-
 +
|<span class="blue-text">EXAMPLE:</span> ''BRAF''; Activating mutations
 +
|<span class="blue-text">EXAMPLE:</span> Activating mutations
 +
|<span class="blue-text">EXAMPLE:</span> Oncogene
 +
|<span class="blue-text">EXAMPLE:</span> Common (melanoma)
 +
|<span class="blue-text">EXAMPLE:</span> T
 +
|
 +
|
 +
|-
 
|
 
|
−
* occur in a significant minority of HSTL cases<ref name=":4" />
+
|
−
|}<br />
+
|
−
==Gene Mutations (SNV / INDEL)==
+
|
 +
|
 +
|
 +
|
 +
|}Note: A more extensive list of mutations can be found in [https://www.cbioportal.org/ <u>cBioportal</u>], [https://cancer.sanger.ac.uk/cosmic <u>COSMIC</u>], and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.
    
{| class="wikitable sortable"
 
{| class="wikitable sortable"
Line 186: Line 308:  
!Notes
 
!Notes
 
|-
 
|-
−
|STAT3; Src homology 2 (SH2) domain
+
|''STAT3''; missense mutation
 
|Oncogenic driver mutation
 
|Oncogenic driver mutation
 
|9%
 
|9%
 
|
 
|
−
|STAT5b; Only 1 reported case with both mutations present<ref name=":4" />
+
|''STAT5b''; Only 1 reported case with both mutations present<ref name=":4" />
 
|No
 
|No
 
|No
 
|No
Line 196: Line 318:  
|Also seen in 40% of T-large granular lymphocyte leukemia<ref name=":2" />
 
|Also seen in 40% of T-large granular lymphocyte leukemia<ref name=":2" />
 
|-
 
|-
−
|STAT5b; Src homology 2 (SH2) domain
+
|''STAT5b''; missense mutation
 
|Oncogenic driver mutation
 
|Oncogenic driver mutation
 
|31%
 
|31%
 
|
 
|
−
|STAT3; Only 1 reported case with both mutations present<ref name=":4" />
+
|''STAT3''; Only 1 reported case with both mutations present<ref name=":4" />
 
|Yes<ref name=":4" /><ref>{{Cite journal|last=Desmares|first=Anne|last2=Bouzy|first2=Simon|last3=Thonier|first3=Florian|last4=Goustille|first4=Julien|last5=Llamas-Gutierrez|first5=Francisco|last6=Genevieve|first6=Franck|last7=Cottin|first7=Laurane|last8=Baseggio|first8=Lucile|last9=Lemaire|first9=Pierre|date=2024-01-25|title=Hepatosplenic T-cell lymphoma displays an original oyster-shell cytological pattern and a distinct genomic profile from that of gamma-delta T-cell large granular lymphocytic leukemia|url=https://pubmed.ncbi.nlm.nih.gov/38268478|journal=Haematologica|doi=10.3324/haematol.2023.283856|issn=1592-8721|pmid=38268478}}</ref>
 
|Yes<ref name=":4" /><ref>{{Cite journal|last=Desmares|first=Anne|last2=Bouzy|first2=Simon|last3=Thonier|first3=Florian|last4=Goustille|first4=Julien|last5=Llamas-Gutierrez|first5=Francisco|last6=Genevieve|first6=Franck|last7=Cottin|first7=Laurane|last8=Baseggio|first8=Lucile|last9=Lemaire|first9=Pierre|date=2024-01-25|title=Hepatosplenic T-cell lymphoma displays an original oyster-shell cytological pattern and a distinct genomic profile from that of gamma-delta T-cell large granular lymphocytic leukemia|url=https://pubmed.ncbi.nlm.nih.gov/38268478|journal=Haematologica|doi=10.3324/haematol.2023.283856|issn=1592-8721|pmid=38268478}}</ref>
 
|No
 
|No
 
|Yes
 
|Yes
−
|
+
|Highest functional potency: ''STAT5B'' N642H and V712E mutations<ref name=":2" />
−
* Highest functional potency: ''STAT5B'' N642H and V712E mutations<ref name=":2" />
+
 
 +
 
 +
One study showed increased CD56 expression with ''STAT5b''<ref>{{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>
   −
* One study showed increased CD56 expression with STAT5b<ref>{{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>
     −
* Also seen in ~2% of T-large granular lymphocyte leukemia<ref name=":2" />
+
Also seen in ~2% of T-large granular lymphocyte leukemia<ref name=":2" />
 
|-
 
|-
−
|PIK3CD
+
|''PIK3CD''
 
|Activate signaling
 
|Activate signaling
−
pathways important to 9% cell survival<ref name=":4" />
+
pathways important to cell survival<ref name=":4" />
 
|9%
 
|9%
 
|
 
|
Line 222: Line 345:  
|
 
|
 
|-
 
|-
−
|SETD2; biallelic LOF
+
|''SETD2''; biallelic LOF
−
 
  −
 
  −
SET2–RPB1 interacting domain (SRI) domain ( 31 ) at the COOH-terminus of the SETD2 protein product
   
|Tumor suppressor gene, chromatin modifier*<ref name=":4" />
 
|Tumor suppressor gene, chromatin modifier*<ref name=":4" />
−
|25% (71% of cases showing at least one LOF mutation)
+
|25%
 
|
 
|
 
|
 
|
Line 233: Line 353:  
|No
 
|No
 
|Yes
 
|Yes
−
|
+
|''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" />
+
 
 +
 
 +
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" />
+
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" />
 
|-
 
|-
−
|INO80
+
|''INO80''
 
|Chromatin modifier*
 
|Chromatin modifier*
 
|21%
 
|21%
Line 248: Line 371:  
|
 
|
 
|-
 
|-
−
|ARID1B
+
|''ARID1B''
 
|Chromatin modifier*
 
|Chromatin modifier*
 
|19%
 
|19%
Line 258: Line 381:  
|
 
|
 
|-
 
|-
−
|TET3
+
|''TET3''
 
|Chromatin modifier*
 
|Chromatin modifier*
 
|15%
 
|15%
Line 268: Line 391:  
|
 
|
 
|-
 
|-
−
|SMARCA2
+
|''SMARCA2''
 
|Chromatin modifier*
 
|Chromatin modifier*
 
|10%
 
|10%
Line 278: Line 401:  
|
 
|
 
|}
 
|}
−
<nowiki>*</nowiki>Chromatin modifiers make up the most commonly mutated genes in HSTL <ref name=":4" />
+
<nowiki>*</nowiki>Chromatin modifiers make up the most commonly mutated genes in HSTL, detected in 62% of cases. <ref name=":4" />
    
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 conten
 
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 conten
 +
 
==Epigenomic Alterations==
 
==Epigenomic Alterations==
   Line 291: Line 415:  
****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>
+
*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" />
+
**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==
 
{| class="wikitable sortable"
 
{| class="wikitable sortable"
 
|-
 
|-
−
!Gene; Genetic Alteration<ref name=":5" />!!Pathway<ref name=":5" />!!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
 
|''KIRs'', ''KLR'', ''CD244'', and ''NCAM1'' overexpression
Line 311: Line 447:  
|Increased inflammatory response due to enhanced leukocyte endothelial transmigration
 
|Increased inflammatory response due to enhanced leukocyte endothelial transmigration
 
|-
 
|-
−
|''SPRY2'', ''RHOB'', ''MAP4K3'', and ''SPRY1'' overexpression
+
|''SPRY2'', ''RHOB*'', ''MAP4K3'', and ''SPRY1'' overexpression
 
|Signal transduction
 
|Signal transduction
 
|Altered cellular growth, differentiation, and migration. Overactive signaling pathways could contribute to oncogenesis
 
|Altered cellular growth, differentiation, and migration. Overactive signaling pathways could contribute to oncogenesis
Line 331: Line 467:  
|Distribution and accumulation of neoplastic γδ cells in the spleen and bone marrow
 
|Distribution and accumulation of neoplastic γδ cells in the spleen and bone marrow
 
|-
 
|-
−
|''SYK*'' overexpression
+
|''SYK**'' overexpression
 
|Tyrosine kinase
 
|Tyrosine kinase
 
|Cell growth and survival of neoplastic HSTL cells
 
|Cell growth and survival of neoplastic HSTL cells
Line 347: Line 483:  
|Reduced inflammatory and immune responses
 
|Reduced inflammatory and immune responses
 
|}
 
|}
−
''*SyK'' expression was seen one study, which is not typical for normal T-cells<ref name=":5" />
+
<nowiki>*</nowiki>''RHOA'' mutations predominantly favor Peripheral T-cell lymphomas, not otherwise specified (PTCL-NOS) and angioimmunoblastic T-cell lymphoma (AITL)<ref name=":4" />  
   −
* ''Syk'' is a protein tyrosine kinase usually involved in B-cell receptor signaling<ref name=":5" />
+
''**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" />
    
==Genetic Diagnostic Testing Methods==
 
==Genetic Diagnostic Testing Methods==
Line 358: Line 496:  
*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=":5" />  
 
*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=":5" />
+
**Presence of ''RHOA'' mutation, can potentially exclude HSTL from the differential diagnosis<ref name=":5" />
    
==Familial Forms==
 
==Familial Forms==
Line 365: Line 503:     
==Additional Information==
 
==Additional Information==
 +
This disease is <u>defined/characterized</u> as detailed below:
 +
 +
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, and uncommonly lymph nodes 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" /><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" />.
 +
 +
The <u>epidemiology/prevalence</u> of this disease is detailed below:
 +
 +
*1.4-2% of peripheral T-cell lymphomas<ref name=":1" />
 +
*~75% are Classic γδ type<ref name=":1" />
 +
*Male predominance in gamma-delta 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>
 +
 +
The <u>clinical features</u> of this disease are detailed below:
 +
 +
Signs and symptoms - Splenomegaly (most common symptom); B-symptoms (night sweats, fever, weight loss and fatigue); Hepatomegaly; Lymphadenopathy (uncommon)
 +
 +
Laboratory findings - Cytopenias (most commonly thrombocytopenia); Elevated serum levels of B2M; Elevated serum levels of LDH
 +
 +
The <u>sites of involvement</u> of this disease are detailed below:
 +
 +
*Spleen
 +
*Liver
 +
*Bone marrow
 +
*Lymph node (uncommon)
 +
*Skin (rarely, in relapse cases)
 +
*With or without leukemic involvement
   −
*N/A
+
The <u>morphologic features</u> of this disease are detailed below:
 +
 
 +
*Typically shows a sinusoidal pattern
 +
 
 +
The <u>immunophenotype</u> of this disease is detailed below:
 +
 
 +
Positive (typically) - CD2, CD3, γδ T-cell receptor, TIA1, Granzyme M<ref name=":1" />
 +
 
 +
Negative (subset) – CD5, CD4, CD8<ref name=":1" />
    
==Links==
 
==Links==
Line 373: Line 544:     
==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 />
+
(use the "Cite" icon at the top of the page) <span style="color:#0070C0">(''Instructions: Add each reference into the text above by clicking where you want to insert the reference, selecting the “Cite” icon at the top of the wiki page, and using the “Automatic” tab option to search by PMID to select the reference to insert. 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. To insert the same reference again later in the page, select the “Cite” icon and “Re-use” to find the reference; DO NOT insert the same reference twice using the “Automatic” tab as it will be treated as two separate references. The reference list in this section will be automatically generated and sorted''</span><span style="color:#0070C0">''.''</span><span style="color:#0070C0">)</span> <references />
    
<br />
 
<br />
    
==Notes==
 
==Notes==
−
<nowiki>*</nowiki>Primary authors will typically be those that initially create and complete the content of a page.  If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the CCGA coordinators (contact information provided on the homepage).  Additional global feedback or concerns are also welcome.
+
<nowiki>*</nowiki>Primary authors will typically be those that initially create and complete the content of a page.  If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the [[Leadership|''<u>Associate Editor</u>'']] or other CCGA representative.  When pages have a major update, the new author will be acknowledged at the beginning of the page, and those who contributed previously will be acknowledged below as a prior author.
 +
 
 +
Prior Author(s): 
 +
 
 +
       
 
<nowiki>*</nowiki>''Citation of this Page'': “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>''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:HAEM5]]
 
[[Category:HAEM5]]
 
[[Category:DISEASE]]
 
[[Category:DISEASE]]
 
[[Category:Diseases H]]
 
[[Category:Diseases H]]
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