View source for HAEM4:Hepatosplenic T-cell Lymphoma

{{DISPLAYTITLE:Hepatosplenic T-cell Lymphoma}}


<blockquote class='blockedit'>{{Box-round|title=PREVIOUS EDITION|This page from the 4th edition of Haematolymphoid Tumours is being updated. See 5th edition [[HAEM5:Table_of_Contents|Table of Contents]].
}}</blockquote>
==Primary Author(s)*==

*Michelle Don, MD, MS
__TOC__

==Cancer Category/Type==

*[[Mature T- and NK-cell Neoplasms]]

==Cancer Sub-Classification / Subtype==

*[[Hepatosplenic T-cell Lymphoma|'''Hepatosplenic T-cell Lymphoma''']] (HSTL)

==Definition / Description of Disease==

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

==Synonyms / Terminology==

*Hepatosplenic T-cell lymphoma (HSTL)

==Epidemiology / Prevalence==

*1-2% of T-natural killer cell lymphomas<ref name=":1" />
*~80% are Classic γδ type<ref name=":1" />
*M:F ~ 3:1<ref name=":1" />
*Median age ~ 35 years old<ref name=":1" />

==Clinical Features==

*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" />

==Sites of Involvement<ref name=":1" />==

*Spleen
*Liver
*Bone marrow
*Lymph node (uncommon)
*With or without leukemic involvement

==Morphologic Features==

*Typically shows a sinusoidal pattern

==Immunophenotype==

{| class="wikitable sortable"
|-
!Finding!!Marker
|-
|Positive (typically)||CD3, γδ T-cell receptor, TIA1, Granzyme M<ref name=":1" />
|-
|Negative||CD4, CD8<ref name=":1" />
|}
==Chromosomal Rearrangements (Gene Fusions)==

*No known chromosomal rearrangements at this time.

==Characteristic Chromosomal Aberrations / Patterns==

*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" />

==Genomic Gain/Loss/LOH==

{| 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
|Loss
|Seen in 19% of cases<ref name=":4" />
|-
|1q
|Gain
|Seen in 13% of cases<ref name=":4" />
|}
<br />

==Gene Mutations (SNV/INDEL)==

 {| class="wikitable sortable"
|-
!Gene!!Mutation!!Role/function!!Presumed Mechanism (LOF/GOF/Other; Driver/Passenger)!!Prevalence<ref name=":4" />
!Notes
|-
|STAT3||Src homology 2 (SH2) domain
|Signaling pathway||Oncogenic driver mutation||9%
|
*Also seen in 40% of T-large granular lymphocyte leukemia<ref name=":2" />
|-
|STAT5b
|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
|
|Signaling pathway
|Activate signaling pathways important to cell survival<ref name=":4" />
|9%
|
|-
|SETD2
|SET2–RPB1 interacting domain (SRI) domain ( 31 ) at the COOH-terminus of the SETD2 protein product
(other mutations interspersed among different domains have also been seen)<ref name=":4" />
|Tumor suppressor gene, chromatin modifier*<ref name=":4" />
|Biallelic loss of function<ref name=":4" />
|71% (cases showing at least one loss of function mutation)
|
*Most frequently silenced gene and most frequent mutated chromatin modifier in HSTL<ref name=":4" />

*More than 44% of patients had more than 1 mutation in SETD2.<ref name=":2" />
|-
|INO80
|
|Chromatin modifier*
|
|21%
|
|-
|TET3
|
|Chromatin modifier*
|
|15%
|
|-
|SMARCA2
|
|Chromatin modifier*
|
|10%
|
|}
'''*'''Chromatin modifiers make up the most commonly mutated genes in HSTL<ref name=":4" />

Specific mutations in the above genes can be found elsewhere ([https://cancer.sanger.ac.uk/cosmic COSMIC], [https://www.cbioportal.org/ cBioPortal])

===Important to note:===
{| class="wikitable sortable"
|-
!Type!!Gene/Region/Other
|-
|Mutually Exclusive||STAT3 and STAT5b

*Only 1 reported case with both mutations present<ref name=":4">McKinney, M., Moffitt, A.B., Gaulard, P., Travert, M., De Leval, L., Nicolae, A., Raffeld, M., Jaffe, E.S., Pittaluga, S., Xi, L. and Heavican, T., 2017. The genetic basis of hepatosplenic T-cell lymphoma. ''Cancer discovery'', ''7''(4), pp.369-379.</ref>
|}

==Epigenomics (Methylation)==

*''AIM1'' is dramatically reduced in HSTL likely due to promoter methylation<ref name=":5" />
**Suggest ''AIM1'' may play a role as a tumor suppressor gene in HSTL oncogenesis<ref name=":5">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.</ref>

*Eight consistently hypermethylated genes (''BCL11B'', ''CD5'', ''CXCR6'', ''GIMAP7'', ''LTA'', SEPT9, ''UBAC2'', ''UXS1'') and four consistently hypomethylated genes (''ADARB1'', ''NFIC'', ''NR1H3'', ''ST3GAL3'') in HSTL<ref name=":6">{{Cite journal|last=Bergmann|first=Anke K.|last2=Fataccioli|first2=Virginie|last3=Castellano|first3=Giancarlo|last4=Martin-Garcia|first4=Nadine|last5=Pelletier|first5=Laura|last6=Ammerpohl|first6=Ole|last7=Bergmann|first7=Juri|last8=Bhat|first8=Jaydeep|last9=Pau|first9=Enrique Carrillo-de Santa|date=03 2019|title=DNA methylation profiling of hepatosplenic T-cell lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/30337361|journal=Haematologica|volume=104|issue=3|pages=e104–e107|doi=10.3324/haematol.2018.196196|issn=1592-8721|pmc=6395348|pmid=30337361}}</ref>.
**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<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" />

==Genes and Main Pathways Involved==

*HSTL (both γδ and αβ phenotypes) show a similar molecular blueprint<ref name=":5" />
**Clustering of expression profiles of HSTL samples show separate clustering compared to the other T-cell lymphomas irrespective of their αβ or γδ lineage<ref name=":5" />
**Overexpression of genes encoding NK-cell–associated molecules (''KIRs'', ''KLR'', ''CD244'', and ''NCAM1)'', oncogenes (''FOS'', ''VAV3'', ''MAF'', and ''BRAF''), cell adhesion (eg, ''VCAM1'', ''CD11d'', and ''ICAM1''), tsignal transduction (eg, ''SPRY2'', ''RHOB'', ''MAP4K3'', and ''SPRY1''), the sonic hedgehog pathway (eg, ''GLI3'', ''PRKAR2B'', ''PRKACB'', and ''PRKAR1A''), the WNT pathway (eg, ''FRZB'', ''TCF7L2'', ''BAMBI'', ''TLE1'', ''CTNNB1'', ''APC'', and ''FZD5''), and ''S1PR5'', and the tyrosine kinase ''SYK''<ref name=":5" />
**''AIM1'' (absent in melanoma 1) was among the most down-expressed genes<ref name=":5" />
***Genes showing significant under expression in HSTL includes those associated with cytotoxicity (eg, ''Granulysin'', ''Granzyme H'', ''Granzyme K'', and ''Granzyme B''), cytokines (eg, ''LTA'', ''TNF'', and ''IFNG''), and ''CD5''<ref name=":5" />

==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''<ref name=":4" /> 
**Presence of RHOA mutation, can potentially exclude HSTL from the differential diagnosis<ref name=":4" />

==Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)==

*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" />

==Familial Forms==

*N/A

==Other Information==

*N/A

==Links==

*[[T-cell Large Granular Lymphocytic Leukemia]]

==References==
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<references /><br />
==Notes==
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[[Category:HAEM4]] [[Category:DISEASE]]