Difference between revisions of "HAEM5:Hepatosplenic T-cell lymphoma"

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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.)]]
 
  
−
{{Under Construction}}
 
−
 
−
<blockquote class='blockedit'>{{Box-round|title=HAEM5 Conversion Notes|This page was converted to the new template on 2023-11-03. 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__
 
__TOC__
  
−
==Cancer Category/Type==
+
==WHO Classification of Disease==
  
−
*[[Mature T- and NK-cell Neoplasms]]
+
{| class="wikitable"
−
 
+
!Structure
−
==Cancer Sub-Classification / Subtype==
+
!Disease
−
 
+
|-
−
*[[Hepatosplenic T-cell Lymphoma|'''Hepatosplenic T-cell Lymphoma''']] (HSTL)
+
|Book
 +
|Haematolymphoid Tumours (5th ed.)
 +
|-
 +
|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
 +
|}
  
 
==Definition / Description of Disease==
 
==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" />.  
+
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=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><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==
 
==Synonyms / Terminology==
Line 29: Line 39:
 
==Epidemiology / Prevalence==
 
==Epidemiology / Prevalence==
  
−
*1-2% of T-natural killer cell lymphomas<ref name=":1" />
+
*1.4-2% of peripheral T-cell lymphomas<ref name=":1" />
−
*~80% are Classic γδ type<ref name=":1" />
+
*~75% are Classic γδ type<ref name=":1" />
−
*M:F ~ 3:1<ref name=":1" />
+
*Male predominance in gamma-delta subtype<ref name=":1" />
−
*Median age ~ 35 years old<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==
 
==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'''
 
|'''Signs and Symptoms'''
−
|EXAMPLE Asymptomatic (incidental finding on complete blood counts)
+
|Splenomegaly (most common symptom)<ref name=":2" />
−
 
+
B-symptoms (night sweats, fever, weight loss and fatigue)<ref name=":0" />
−
EXAMPLE B-symptoms (weight loss, fever, night sweats)
 
  
−
EXAMPLE Fatigue
+
Hepatomegaly<ref name=":1" /><ref name=":2" />
  
−
EXAMPLE Lymphadenopathy (uncommon)
+
Lymphadenopathy (uncommon)<ref name=":0" /><ref name=":2" />
 
|-
 
|-
 
|'''Laboratory Findings'''
 
|'''Laboratory Findings'''
−
|EXAMPLE Cytopenias
+
|Cytopenias (most commonly thrombocytopenia)<ref name=":0" /><ref name=":2" />
 +
Elevated serum levels of B2M<ref name=":1" />
  
−
EXAMPLE Lymphocytosis (low level)
+
Elevated serum levels of LDH<ref name=":1" />
 
|}
 
|}
  
−
 
−
<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==
 
==Sites of Involvement==
−
 
  
 
*Spleen
 
*Spleen
Line 71: Line 67:
 
*Bone marrow
 
*Bone marrow
 
*Lymph node (uncommon)
 
*Lymph node (uncommon)
 +
*Skin (rarely, in relapse cases)
 
*With or without leukemic involvement
 
*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==
 
==Morphologic Features==
  
Line 85: Line 80:
 
!Finding!!Marker
 
!Finding!!Marker
 
|-
 
|-
−
|Positive (typically)||CD3, γδ T-cell receptor, TIA1, Granzyme M<ref name=":1" />
+
|Positive (typically)||CD2, CD3, γδ T-cell receptor, TIA1, Granzyme M<ref name=":1" />
 
|-
 
|-
−
|Negative||CD4, CD8<ref name=":1" />
+
|Negative||CD5, CD4, CD8<ref name=":1" />
 
|}
 
|}
 
==Chromosomal Rearrangements (Gene Fusions)==
 
==Chromosomal Rearrangements (Gene Fusions)==
  
−
Put your text here and fill in the table
+
*No known chromosomal rearrangements at this time
 +
 
 +
==Individual Region Genomic Gain / Loss / LOH==
  
 
{| class="wikitable sortable"
 
{| class="wikitable sortable"
 
|-
 
|-
−
!Chromosomal Rearrangement!!Genes in Fusion (5’ or 3’ Segments)!!Pathogenic Derivative!!Prevalence
+
!Chr #!!Gain / Loss / Amp / LOH!!Minimal Region Genomic Coordinates [Genome Build]!!Minimal Region Cytoband
−
!Diagnostic Significance (Yes, No or Unknown)
+
!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>
−
!Prognostic Significance (Yes, No or Unknown)
+
!Prognostic Significance (Yes, No or Unknown)<ref name=":2" /><ref name=":4" />
 
!Therapeutic Significance (Yes, No or Unknown)
 
!Therapeutic Significance (Yes, No or Unknown)
 
!Notes
 
!Notes
 
|-
 
|-
−
|EXAMPLE t(9;22)(q34;q11.2)||EXAMPLE 3'ABL1 / 5'BCR||EXAMPLE der(22)||EXAMPLE 20% (COSMIC)
+
|7q
−
EXAMPLE 30% (add reference)
+
|Gain
 +
|
 +
|Constant loss of 7p22.1p14.1
 +
Gain of 7q22.11q31.1
 +
|Yes
 
|Yes
 
|Yes
 
|No
 
|No
−
|Yes
+
|Considered a primary aberration<ref name=":2" />, seen in 40-70% of cases<ref name=":1" />
−
|EXAMPLE
 
−
 
 
−
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.}}
 
−
 
 
−
*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>
 
−
 
 
−
{| class="wikitable sortable"
 
 
|-
 
|-
−
!Chr #!!Gain / Loss / Amp / LOH!!Minimal Region Genomic Coordinates [Genome Build]!!Minimal Region Cytoband
+
|8
−
!Diagnostic Significance (Yes, No or Unknown)
+
|Gain (trisomy)
−
!Prognostic Significance (Yes, No or Unknown)
+
|
−
!Therapeutic Significance (Yes, No or Unknown)
+
|Chr8
−
!Notes
 
−
|-
 
−
|EXAMPLE
 
−
 
 
−
7
 
−
|EXAMPLE Loss
 
−
|EXAMPLE
 
−
 
 
−
chr7:1- 159,335,973 [hg38]
 
−
|EXAMPLE
 
−
 
 
−
chr7
 
 
|Yes
 
|Yes
 
|Yes
 
|Yes
 
|No
 
|No
−
|EXAMPLE
+
|Considered a secondary aberration<ref name=":2" />, seen in 10-50% of cases<ref name=":1" />
−
 
 
−
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
+
|Y
−
 
+
|Loss
−
8
+
|
−
|EXAMPLE Gain
+
|ChrY
−
|EXAMPLE
 
−
 
 
−
chr8:1-145,138,636 [hg38]
 
−
|EXAMPLE
 
−
 
 
−
chr8
 
 
|No
 
|No
 
|No
 
|No
 
|No
 
|No
−
|EXAMPLE
+
|Seen in 20-25% of cases<ref name=":1" />
−
 
 
−
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" />
 
 
|-
 
|-
 
|10q
 
|10q
 
|Loss
 
|Loss
−
|Seen in 19% of cases<ref name=":4" />
+
|
 +
|Chr10
 +
|No
 +
|No
 +
|No
 +
|Seen in 10-20% of cases<ref name=":1" />
 
|-
 
|-
 
|1q
 
|1q
 
|Gain
 
|Gain
−
|Seen in 13% of cases<ref name=":4" />
+
|
−
|}
+
|Chr1
−
<br />
+
|No
−
 
+
|No
−
</blockquote>
+
|No
 +
|Seen in 10-15% of cases<ref name=":1" />
 +
|}<br />
 
==Characteristic Chromosomal Patterns==
 
==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>
+
*7q aberrations and trisomy 8 are considered specific for HSTL, but not sensitive<ref name=":2" />
  
 
{| class="wikitable sortable"
 
{| class="wikitable sortable"
Line 215: Line 152:
 
!Chromosomal Pattern
 
!Chromosomal Pattern
 
!Diagnostic Significance (Yes, No or Unknown)
 
!Diagnostic Significance (Yes, No or Unknown)
−
!Prognostic Significance (Yes, No or Unknown)
+
!Prognostic Significance (Yes, No or Unknown)<ref name=":2" /><ref name=":4" />
 
!Therapeutic Significance (Yes, No or Unknown)
 
!Therapeutic Significance (Yes, No or Unknown)
 
!Notes
 
!Notes
 
|-
 
|-
−
|EXAMPLE
+
|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:
  
−
Co-deletion of 1p and 18q
+
*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
 +
|Yes
 
|Yes
 
|Yes
 
|No
 
|No
−
|No
+
|See table under "Genomic Gain/Loss/LOH"
−
|EXAMPLE:
 
  
−
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.}}
+
Co-occurrence of Isochromosome 7q and trisomy 8 can be seen in 8-53% of cases<ref name=":2" />
  
−
*Most common genetic abnormalities include Isochromosome 7q and trisomy 8 (see table below "Genomic Gain/Loss/LOH")<ref name=":4" />
 
−
*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>
+
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" />
−
==Gene Mutations (SNV/INDEL)==
+
|-
−
 
+
|Loss of chromosome 10q
−
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>
+
Gain of chromosome 1q
 +
|No
 +
|Yes
 +
|No
 +
|occur in a significant minority of HSTL cases<ref name=":4" />
 +
|}<br />
 +
==Gene Mutations (SNV / INDEL)==
  
 
{| 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!!'''Presumed Mechanism (Tumor Suppressor Gene [TSG] / Oncogene / Other)'''!!'''Prevalence (COSMIC /  TCGA / Other)'''!!'''Concomitant Mutations'''!!'''Mutually Exclusive Mutations'''
−
!'''Diagnostic Significance (Yes, No or Unknown)'''
+
!'''Diagnostic Significance (Yes, No or Unknown)'''<ref name=":4" />
−
!Prognostic Significance (Yes, No or Unknown)
+
!Prognostic Significance (Yes, No or Unknown)<ref name=":2" /><ref name=":4" />
−
!Therapeutic Significance (Yes, No or Unknown)
+
!Therapeutic Significance (Yes, No or Unknown)<ref name=":2" /><ref>{{Cite journal|last=Pro|first=Barbara|last2=Allen|first2=Pamela|last3=Behdad|first3=Amir|date=2020-10-29|title=Hepatosplenic T-cell lymphoma: a rare but challenging entity|url=https://pubmed.ncbi.nlm.nih.gov/32756940|journal=Blood|volume=136|issue=18|pages=2018–2026|doi=10.1182/blood.2019004118|issn=1528-0020|pmc=7596851|pmid=32756940}}</ref>
 
!Notes
 
!Notes
 
|-
 
|-
−
|EXAMPLE: TP53; Variable LOF mutations
+
|''STAT3''; missense mutation
 +
|Oncogenic driver mutation
 +
|9%
 +
|
 +
|''STAT5b''; Only 1 reported case with both mutations present<ref name=":4" />
 +
|No
 +
|No
 +
|Yes
 +
|Also seen in 40% of T-large granular lymphocyte leukemia<ref name=":2" />
 +
|-
 +
|''STAT5b''; missense mutation
 +
|Oncogenic driver mutation
 +
|31%
 +
|
 +
|''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>
 +
|No
 +
|Yes
 +
|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>{{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''
 +
|Activate signaling
 +
pathways important to cell survival<ref name=":4" />
 +
|9%
 
|
 
|
 
|
 
|
 +
|No
 +
|No
 +
|Yes
 
|
 
|
−
|EXAMPLE:  Excludes hairy cell leukemia (HCL) (add reference).
+
|-
−
<br />
+
|''SETD2''; biallelic LOF
−
|}
+
|Tumor suppressor gene, chromatin modifier*<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 content.
+
|25%
 +
|
 +
|
 +
|Yes
 +
|No
 +
|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" />
  
−
<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
+
|Chromatin modifier*
−
|-
+
|21%
−
|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" />
+
|Yes
−
|-
+
|Yes<ref name=":2" />
−
|STAT5b
+
|Yes
−
|Src homology 2 (SH2) domain
 
−
|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
+
|''ARID1B''
 +
|Chromatin modifier*
 +
|19%
 
|
 
|
−
|Signaling pathway
 
−
|Activate signaling pathways important to cell survival<ref name=":4" />
 
−
|9%
 
 
|
 
|
−
|-
+
|No
−
|SETD2
+
|No
−
|SET2–RPB1 interacting domain (SRI) domain ( 31 ) at the COOH-terminus of the SETD2 protein product
+
|No
−
(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
+
|''TET3''
 +
|Chromatin modifier*
 +
|15%
 
|
 
|
−
|Chromatin modifier*
 
 
|
 
|
−
|21%
+
|Yes
 +
|No
 +
|Yes
 
|
 
|
 
|-
 
|-
−
|TET3
+
|''SMARCA2''
−
|
 
 
|Chromatin modifier*
 
|Chromatin modifier*
 +
|10%
 
|
 
|
−
|15%
 
 
|
 
|
−
|-
+
|No
−
|SMARCA2
+
|No
−
|
+
|No
−
|Chromatin modifier*
 
−
|
 
−
|10%
 
 
|
 
|
 
|}
 
|}
−
'''*'''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" />
  
−
Specific mutations in the above genes can be found elsewhere ([https://cancer.sanger.ac.uk/cosmic COSMIC], [https://www.cbioportal.org/ cBioPortal])
+
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
−
 
 
−
===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==
  
Line 363: Line 297:
 
***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" />
 
|-
 
|-
−
|EXAMPLE: BRAF and MAP2K1; Activating mutations
+
|''STAT, PIK3CD''
−
|EXAMPLE: MAPK signaling
+
|Signaling pathways
−
|EXAMPLE: Increased cell growth and proliferation
+
|PI-3 kinase and JAK-STAT signaling pathways maintain proliferation and survival within HSTL cells
 
|-
 
|-
−
|EXAMPLE: CDKN2A; Inactivating mutations
+
|''SETD2''
−
|EXAMPLE: Cell cycle regulation
+
|Tumor suppressor, chromatin modifier
−
|EXAMPLE: Unregulated cell division
+
|Reduced SETD2 protein expression and increased proliferation of HSTL cells
 
|-
 
|-
−
|EXAMPLE:  KMT2C and ARID1A; Inactivating mutations
+
|''INO80, ARID1B, TET3, SMARCA2''
−
|EXAMPLE:  Histone modification, chromatin remodeling
+
|Chromatin modifier
−
|EXAMPLE:  Abnormal gene expression program
+
|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
 +
|-
 +
|''GLI3, PRKAR2B, PRKACB, and PRKAR1A'' overexpression
 +
|Sonic hedgehog pathway
 +
|Abnormal tissue patterning and growth
 +
|-
 +
|''FRZB, TCF7L2, BAMBI, TLE1, CTNNB1, APC, and FZD5'' overexpression
 +
|WNT pathway
 +
|Disruption of normal WNT signaling balance, potentially leading to abnormal cell proliferation, differentiation, and migration
 +
|-
 +
|''ABCB1, GSTP1'' overexpression
 +
|Multidrug resistance signaling
 +
|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" />
  
−
*HSTL (both γδ and αβ phenotypes) show a similar molecular blueprint<ref name=":5" />
+
*''Syk'' is a protein tyrosine kinase usually involved in B-cell receptor signaling<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==
  
Line 399: Line 378:
 
*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==
Line 412: Line 391:
 
==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 />
 
(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 />
  
−
'''
+
<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 CCGA coordinators (contact information provided on the homepage).  Additional global feedback or concerns are also welcome.
 
<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:DISEASE]][[Category:Diseases H]]
+
[[Category:HAEM5]]
 +
[[Category:DISEASE]]
 +
[[Category:Diseases H]]

Latest revision as of 18:26, 18 October 2024


Primary Author(s)*

  • Forough Sargolzaeiaval, MD
  • Michelle Don, MD, MS

WHO Classification of Disease

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 N/A
Subtype(s) Hepatosplenic T-cell lymphoma

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 [1][2][3]. Most cases occur de novo, with a subset of approximately 20-30% occurring in the setting of iatrogenic immunosuppression [3].

Synonyms / Terminology

  • Hepatosplenic T-cell lymphoma (HSTL)

Epidemiology / Prevalence

  • 1.4-2% of peripheral T-cell lymphomas[2]
  • ~75% are Classic γδ type[2]
  • Male predominance in gamma-delta subtype[2]
  • Median age ~ 35 years old[3], 51% with age >60 years old[4]

Clinical Features

Signs and Symptoms Splenomegaly (most common symptom)[3]

B-symptoms (night sweats, fever, weight loss and fatigue)[1]

Hepatomegaly[2][3]

Lymphadenopathy (uncommon)[1][3]

Laboratory Findings Cytopenias (most commonly thrombocytopenia)[1][3]

Elevated serum levels of B2M[2]

Elevated serum levels of LDH[2]

Sites of Involvement

  • Spleen
  • Liver
  • Bone marrow
  • Lymph node (uncommon)
  • Skin (rarely, in relapse cases)
  • With or without leukemic involvement

Morphologic Features

  • Typically shows a sinusoidal pattern

Immunophenotype

Finding Marker
Positive (typically) CD2, CD3, γδ T-cell receptor, TIA1, Granzyme M[2]
Negative CD5, CD4, CD8[2]

Chromosomal Rearrangements (Gene Fusions)

  • No known chromosomal rearrangements at this time

Individual Region Genomic Gain / Loss / LOH

Chr # Gain / Loss / Amp / LOH Minimal Region Genomic Coordinates [Genome Build] Minimal Region Cytoband Diagnostic Significance (Yes, No or Unknown)[3][5] Prognostic Significance (Yes, No or Unknown)[3][5] Therapeutic Significance (Yes, No or Unknown) Notes
7q Gain Constant loss of 7p22.1p14.1

Gain of 7q22.11q31.1

Yes Yes No Considered a primary aberration[3], seen in 40-70% of cases[2]
8 Gain (trisomy) Chr8 Yes Yes No Considered a secondary aberration[3], seen in 10-50% of cases[2]
Y Loss ChrY No No No Seen in 20-25% of cases[2]
10q Loss Chr10 No No No Seen in 10-20% of cases[2]
1q Gain Chr1 No No No Seen in 10-15% of cases[2]


Characteristic Chromosomal Patterns

  • 7q aberrations and trisomy 8 are considered specific for HSTL, but not sensitive[3]
Chromosomal Pattern Diagnostic Significance (Yes, No or Unknown) Prognostic Significance (Yes, No or Unknown)[3][5] Therapeutic Significance (Yes, No or Unknown) Notes
Isochromosome 7q[6] and chromosome 7 imbalances including ring chromosome 7.

Cases with chromosome 7 abnormalities show:

  • Constant loss of 7p22.1p14.1 (34.88 Mb; 3506316-38406226 bp)[7]
  • Gain of 7q22.11q31.1 (38.77 Mb; 86259620–124892276 bp)[7]

Can be seen in conjunction with trisomy 8

Yes Yes No See table under "Genomic Gain/Loss/LOH"


Co-occurrence of Isochromosome 7q and trisomy 8 can be seen in 8-53% of cases[3]


Cases without diagnostic detection of i(7q) or trisomy 8, often have detection of these abnormalities at the time of relapse or disease progression[3]

Loss of chromosome 10q

Gain of chromosome 1q

No Yes No occur in a significant minority of HSTL cases[5]


Gene Mutations (SNV / INDEL)

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)[5] Prognostic Significance (Yes, No or Unknown)[3][5] Therapeutic Significance (Yes, No or Unknown)[3][8] Notes
STAT3; missense mutation Oncogenic driver mutation 9% STAT5b; Only 1 reported case with both mutations present[5] No No Yes Also seen in 40% of T-large granular lymphocyte leukemia[3]
STAT5b; missense mutation Oncogenic driver mutation 31% STAT3; Only 1 reported case with both mutations present[5] Yes[5][9] No Yes Highest functional potency: STAT5B N642H and V712E mutations[3]


One study showed increased CD56 expression with STAT5b[10]


Also seen in ~2% of T-large granular lymphocyte leukemia[3]

PIK3CD Activate signaling

pathways important to cell survival[5]

9% No No Yes
SETD2; biallelic LOF Tumor suppressor gene, chromatin modifier*[5] 25% Yes No 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[5]


71% of cases showing at least one LOF mutation[5], and more than 44% of patients with SETD2 mutations had more than 1 mutation detected[3]

INO80 Chromatin modifier* 21% Yes Yes[3] Yes
ARID1B Chromatin modifier* 19% No No No
TET3 Chromatin modifier* 15% Yes No Yes
SMARCA2 Chromatin modifier* 10% No No No

*Chromatin modifiers make up the most commonly mutated genes in HSTL, detected in 62% of cases. [5]

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

  • AIM1 is dramatically reduced in HSTL likely due to promoter methylation[11]
    • Suggest AIM1 may play a role as a tumor suppressor gene in HSTL oncogenesis[11]
  • Eight consistently hypermethylated genes (BCL11B, CD5, CXCR6, GIMAP7, LTA, SEPT9, UBAC2, UXS1) and four consistently hypomethylated genes (ADARB1, NFIC, NR1H3, ST3GAL3) in HSTL[12].
    • Hypermethylated genes (LTA, CD5, CXCR6, GIMAP7, BCL11B and SEPT9) are relevant to the pathobiology of T-cell leukemias/lymphomas, and are hypermethylated at active promoter sites mainly around transcription start sites[12].
      • 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[12].
        • Note: This finding is not specific to HSTL and can be seen in other T-cell lymphomas[12]
  • A single study has shown use of IFNα2c therapy-induced changes in CpG methylation[13]
    • CpG methylation changes have the potential to serve as biomarkers of drug responses and/or disease progression[13]

Genes and Main Pathways Involved

Gene; Genetic Alteration[5][11] Pathway[5][11] Pathophysiologic Outcome[5][11]
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
GLI3, PRKAR2B, PRKACB, and PRKAR1A overexpression Sonic hedgehog pathway Abnormal tissue patterning and growth
FRZB, TCF7L2, BAMBI, TLE1, CTNNB1, APC, and FZD5 overexpression WNT pathway Disruption of normal WNT signaling balance, potentially leading to abnormal cell proliferation, differentiation, and migration
ABCB1, GSTP1 overexpression Multidrug resistance signaling 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

*RHOA mutations predominantly favor Peripheral T-cell lymphomas, not otherwise specified (PTCL-NOS) and angioimmunoblastic T-cell lymphoma (AITL)[5]

**SyK expression was seen one study, which is not typical for normal T-cells[11]

  • Syk is a protein tyrosine kinase usually involved in B-cell receptor signaling[11]

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

  • Karyotype may show trisomy 8, if present
  • 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[11]
    • Presence of RHOA mutation, can potentially exclude HSTL from the differential diagnosis[11]

Familial Forms

  • N/A

Additional Information

  • N/A

Links

References

(use the "Cite" icon at the top of the page) (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. 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.)

  1. ↑ 1.0 1.1 1.2 1.3 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.
  2. ↑ 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 2.11 2.12 2.13 Medeiros, Jeffrey (2024). "Hepatosplenic T-cell lymphoma. In: WHO Classification of Tumours Editorial Board. Haematolymphoid tumours [Internet]". WHO classification of tumours series, 5th ed. vol. 11 – via Lyon (France): International Agency for Research on Cancer.CS1 maint: display-authors (link)
  3. ↑ 3.00 3.01 3.02 3.03 3.04 3.05 3.06 3.07 3.08 3.09 3.10 3.11 3.12 3.13 3.14 3.15 3.16 3.17 3.18 3.19 3.20 3.21 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
  4. ↑ Foss, Francine M.; et al. (2020-02). "Incidence and outcomes of rare T cell lymphomas from the T Cell Project: hepatosplenic, enteropathy associated and peripheral gamma delta T cell lymphomas". American Journal of Hematology. 95 (2): 151–155. doi:10.1002/ajh.25674. ISSN 1096-8652. PMC 8025136 Check |pmc= value (help). PMID 31709579. Check date values in: |date= (help)
  5. ↑ 5.00 5.01 5.02 5.03 5.04 5.05 5.06 5.07 5.08 5.09 5.10 5.11 5.12 5.13 5.14 5.15 5.16 5.17 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.
  6. ↑ Wlodarska, Iwona; et al. (2002-03). "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 & Cancer. 33 (3): 243–251. doi:10.1002/gcc.10021. ISSN 1045-2257. PMID 11807981. Check date values in: |date= (help)
  7. ↑ 7.0 7.1 Finalet Ferreiro, Julio; et al. (2014). "Integrative genomic and transcriptomic analysis identified candidate genes implicated in the pathogenesis of hepatosplenic T-cell lymphoma". PloS One. 9 (7): e102977. doi:10.1371/journal.pone.0102977. ISSN 1932-6203. PMC 4109958. PMID 25057852.
  8. ↑ Pro, Barbara; et al. (2020-10-29). "Hepatosplenic T-cell lymphoma: a rare but challenging entity". Blood. 136 (18): 2018–2026. doi:10.1182/blood.2019004118. ISSN 1528-0020. PMC 7596851 Check |pmc= value (help). PMID 32756940 Check |pmid= value (help).
  9. ↑ Desmares, Anne; et al. (2024-01-25). "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". Haematologica. doi:10.3324/haematol.2023.283856. ISSN 1592-8721. PMID 38268478 Check |pmid= value (help).
  10. ↑ Nicolae, A.; et al. (2014-11). "Frequent STAT5B mutations in γδ hepatosplenic T-cell lymphomas". Leukemia. 28 (11): 2244–2248. doi:10.1038/leu.2014.200. ISSN 1476-5551. PMC 7701980 Check |pmc= value (help). PMID 24947020. Check date values in: |date= (help)
  11. ↑ 11.0 11.1 11.2 11.3 11.4 11.5 11.6 11.7 11.8 Travert M, Huang Y, De Leval L, Martin-Garcia N, Delfau-Larue MH, Berger F, Bosq J, Brière J, Soulier J, Macintyre E, Marafioti T. Molecular features of hepatosplenic T-cell lymphoma unravels potential novel therapeutic targets. Blood, The Journal of the American Society of Hematology. 2012 Jun 14;119(24):5795-806.
  12. ↑ 12.0 12.1 12.2 12.3 Bergmann, Anke K.; et al. (03 2019). "DNA methylation profiling of hepatosplenic T-cell lymphoma". Haematologica. 104 (3): e104–e107. doi:10.3324/haematol.2018.196196. ISSN 1592-8721. PMC 6395348. PMID 30337361. Check date values in: |date= (help)
  13. ↑ 13.0 13.1 Bhat, Jaydeep; et al. (2021-05). "DNA methylation profile of a hepatosplenic gamma/delta T-cell lymphoma patient associated with response to interferon-α therapy". Cellular & Molecular Immunology. 18 (5): 1332–1335. doi:10.1038/s41423-020-0518-4. ISSN 2042-0226. PMC 8093208 Check |pmc= value (help). PMID 32820235 Check |pmid= value (help). Check date values in: |date= (help)


Notes

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