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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 2023-12-07. The original page can be found at [[HAEM4:Hepatosplenic T-cell Lymphoma]].
−}}</blockquote>
__TOC__
−==Cancer Category / Type==
−*[[HAEM4:Mature T- 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 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==
−Put your text here and fill in the table <span style="color:#0070C0">(''Instruction: Can include references in the table'') </span>
+EXAMPLE B-symptoms (weight loss, fever, night sweats)+ +EXAMPLE Fatigue+ +EXAMPLE Lymphadenopathy (uncommon)+
−EXAMPLE Lymphocytosis (low level)
+ +<blockquote class='blockedit'>{{Box-round|title=v4:Clinical Features|The content below was from the old template. Please incorporate above.}}+ +*Splenomegaly (most common symptom)<ref name=":2" />+*Diagnosed late in the course of the disease+*B-symptoms (night sweats, fever, weight loss and fatigue)<ref name=":0" />
−*Hepatosplenomegaly<ref name=":2" />
−*Cytopenias (most commonly thrombocytopenia)<ref name=":0" /><ref name=":2" />
−*Lymphadenopathy (uncommon)<ref name=":2" /><ref name=":0" />
−
−==Sites of Involvement==
−
−
−*Spleen
−*Liver
−*Bone marrow
−*Lymph node (uncommon)
−*With or without leukemic involvement
−
−
−<blockquote class='blockedit'>{{Box-round|title=Unassigned References|The following referenees were placed in the header. Please place them into the appropriate locations in the text.}}<ref name=":1" /></blockquote>
−==Morphologic Features==
−
−*Typically shows a sinusoidal pattern
−
−==Immunophenotype==
−
−!Finding!!Marker+==Chromosomal Rearrangements (Gene Fusions)==
−Put your text here and fill in the table+
+EXAMPLE 30% (add reference)+ +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>
+!Prognostic Significance (Yes, No or Unknown)+
−chr7:1- 159,335,973 [hg38]
−|EXAMPLE
−
+
−chr8:1-145,138,636 [hg38]
−|EXAMPLE
−
+<blockquote class='blockedit'>{{Box-round|title=v4:Genomic Gain/Loss/LOH|The content below was from the old template. Please incorporate above.}}
+<br />
−==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>
Co-deletion of 1p and 18q+
+
+|EXAMPLE:
−See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference).
−|}
−*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" />
−==Gene Mutations (SNV / INDEL)==+ +Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: This table is not meant to be an exhaustive list; please include only genes/alterations that are recurrent and common as well either disease defining and/or clinically significant. Can include references in the table. For clinical significance, denote associations with FDA-approved therapy (not an extensive list of applicable drugs) and NCCN or other national guidelines if applicable; Can also refer to CGC workgroup tables as linked on the homepage if applicable as well as any high impact papers or reviews of gene mutations in this entity.'') </span>+!Therapeutic Significance (Yes, No or Unknown)+!Notes+ +EGFR; Exon 20 mutations+ + +|EXAMPLE: Excludes hairy cell leukemia (HCL) (add reference).+<br />
− +<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"
|Signaling pathway||Oncogenic driver mutation||9%+*Also seen in 40% of T-large granular lymphocyte leukemia<ref name=":2" />+|Src homology 2 (SH2) domain
−|Signaling pathway
*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" />+
+
+
+
+|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" />
*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" />+|Chromatin modifier*
|Chromatin modifier*
'''*'''Chromatin modifiers make up the most commonly mutated genes in HSTL<ref name=":4" />+Specific mutations in the above genes can be found elsewhere ([https://cancer.sanger.ac.uk/cosmic COSMIC], [https://www.cbioportal.org/ cBioPortal])+===Important to note:===
−{| class="wikitable sortable"
−|-
−!Type!!Gene/Region/Other
−|-
−|Mutually Exclusive||STAT3 and STAT5b
−*Only 1 reported case with both mutations present<ref name=":4">McKinney, M., Moffitt, A.B., Gaulard, P., Travert, M., De Leval, L., Nicolae, A., Raffeld, M., Jaffe, E.S., Pittaluga, S., Xi, L. and Heavican, T., 2017. The genetic basis of hepatosplenic T-cell lymphoma. ''Cancer discovery'', ''7''(4), pp.369-379.</ref>
−|}
−</blockquote>
Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: Can include references in the table.'')</span>
<blockquote class='blockedit'>{{Box-round|title=v4:Genes and Main Pathways Involved|The content below was from the old template. Please incorporate above.}}+**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>
+
+
+
+
+
+'''+
+
+
{{DISPLAYTITLE:Hepatosplenic T-cell lymphoma}}
{{DISPLAYTITLE:Hepatosplenic T-cell lymphoma}}
−==Primary Author(s)*==
==Primary Author(s)*==
+*Forough Sargolzaeiaval, MD
*Michelle Don, MD, MS
*Michelle Don, MD, MS
−==WHO Classification of Disease==
−{| class="wikitable"
{| class="wikitable"
−|'''Signs and Symptoms'''
+!Structure
−|EXAMPLE Asymptomatic (incidental finding on complete blood counts)
+!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
|-
|-
−|'''Laboratory Findings'''
+|Subtype(s)
−|EXAMPLE Cytopenias
+|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)*
−|
−</blockquote>
−{| class="wikitable sortable"
|-
|-
−|WHO Desirable Criteria (Genetics)*
+|
|-
|-
−|Positive (typically)||CD3, γδ T-cell receptor, TIA1, Granzyme M<ref name=":1" />
+|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
+|
|-
|-
−|Negative||CD4, CD8<ref name=":1" />
+|Not Recommended
+|
|}
|}
−==Gene Rearrangements==
+*No known chromosomal rearrangements at this time
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
−!Chromosomal Rearrangement!!Genes in Fusion (5’ or 3’ Segments)!!Pathogenic Derivative!!Prevalence
+!Driver Gene!!Fusion(s) and Common Partner Genes!!Molecular Pathogenesis!!Typical Chromosomal Alteration(s)
−!Diagnostic Significance (Yes, No or Unknown)
+!Prevalence -Common >20%, Recurrent 5-20% or Rare <5% (Disease)
−!Prognostic Significance (Yes, No or Unknown)
+!Diagnostic, Prognostic, and Therapeutic Significance - D, P, T
−!Therapeutic Significance (Yes, No or Unknown)
+!Established Clinical Significance Per Guidelines - Yes or No (Source)
−!Notes
+!Clinical Relevance Details/Other Notes
|-
|-
−|EXAMPLE t(9;22)(q34;q11.2)||EXAMPLE 3'ABL1 / 5'BCR||EXAMPLE der(22)||EXAMPLE 20% (COSMIC)
+|N/A
−|
−|Yes
+|
−|No
+|
−|Yes
+|
−|EXAMPLE
+|
−|
−|
−|}
+|}
−==Individual Region Genomic Gain/Loss/LOH==
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
−!Chr #!!Gain / Loss / Amp / LOH!!Minimal Region Genomic Coordinates [Genome Build]!!Minimal Region Cytoband
+!Chr #!!'''Gain, Loss, Amp, LOH'''!!'''Minimal Region Cytoband and/or Genomic Coordinates [Genome Build; Size]'''!!'''Relevant Gene(s)'''
−!Diagnostic Significance (Yes, No or Unknown)
+!'''Diagnostic, Prognostic, and Therapeutic Significance - D, P, T'''
−!'''Established Clinical Significance Per Guidelines - Yes or No (Source)'''
−!Therapeutic Significance (Yes, No or Unknown)
+!'''Clinical Relevance Details/Other Notes'''
−!Notes
|-
|-
−|EXAMPLE
+|<span class="blue-text">EXAMPLE:</span>
−7
7
−|EXAMPLE Loss
+|<span class="blue-text">EXAMPLE:</span> Loss
−|EXAMPLE
+|<span class="blue-text">EXAMPLE:</span>
−chr7
chr7
−|Yes
+|<span class="blue-text">EXAMPLE:</span>
−|Yes
+Unknown
−|No
+|<span class="blue-text">EXAMPLE:</span> D, P
−|EXAMPLE
+|<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 reference).
+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).
|-
|-
−|EXAMPLE
+|<span class="blue-text">EXAMPLE:</span>
−8
8
−|EXAMPLE Gain
+|<span class="blue-text">EXAMPLE:</span> Gain
−|EXAMPLE
+|<span class="blue-text">EXAMPLE:</span>
−chr8
chr8
−|No
+|<span class="blue-text">EXAMPLE:</span>
−|No
+Unknown
−|No
+|<span class="blue-text">EXAMPLE:</span> D, P
−|EXAMPLE
+|
−|<span class="blue-text">EXAMPLE:</span>
−Common recurrent secondary finding for t(8;21) (add reference).
+Common recurrent secondary finding for t(8;21) (add references).
+|-
+|<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.
+|-
+|
+|
+|
+|
+|
+|
+|
|}
|}
−{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
−!Chromosome Number!!Gain/Loss/Amp/LOH!!Notes
+!Chr #!!Gain / Loss / Amp / LOH!!Minimal Region Genomic Coordinates [Genome Build]!!Minimal Region Cytoband
+!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" />
+!Therapeutic Significance (Yes, No or Unknown)
+!Notes
|-
|-
|7q
|7q
|Gain
|Gain
−|Considered a primary aberration<ref name=":2" />
+|
+|Constant loss of 7p22.1p14.1
+Gain of 7q22.11q31.1
+|Yes
+|Yes
+|No
+|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||Gain (trisomy)||Considered a secondary aberration<ref name=":2" />
+|8
+|Gain (trisomy)
+|
+|Chr8
+|Yes
+|Yes
+|No
+|Considered a secondary aberration<ref name=":2" />, seen in 10-50% of cases<ref name=":1" />
+|-
+|Y
+|Loss
+|
+|ChrY
+|No
+|No
+|No
+|Seen in 20-25% of cases<ref name=":1" />
|-
|-
|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
+|No
+|No
+|No
+|Seen in 10-15% of cases<ref name=":1" />
+|}<br />
+==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
+|
+|
+|-
+|
+|
+|
+|
+|
+|
|}
|}
−</blockquote>
+*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 223:
!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:
−*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"
−<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" />
−</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" />
−|-
−|Loss of chromosome 10q
−Gain of chromosome 1q
+|No
+|Yes
+|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"
{| class="wikitable sortable"
|-
|-
−!Gene; Genetic Alteration!!'''Presumed Mechanism (Tumor Suppressor Gene [TSG] / Oncogene / Other)'''!!'''Prevalence (COSMIC / TCGA / Other)'''!!'''Concomitant Mutations'''!!'''Mutually Exclusive Mutations'''
+!Gene!!'''Genetic Alteration'''!!'''Tumor Suppressor Gene, Oncogene, Other'''!!'''Prevalence -'''
−!'''Diagnostic Significance (Yes, No or Unknown)'''
+'''Common >20%, Recurrent 5-20% or Rare <5% (Disease)'''
−!Prognostic Significance (Yes, No or Unknown)
+!'''Diagnostic, Prognostic, and Therapeutic Significance - D, P, T '''
−!'''Established Clinical Significance Per Guidelines - Yes or No (Source)'''
−!'''Clinical Relevance Details/Other Notes'''
|-
|-
−|EXAMPLE: TP53; Variable LOF mutations
+|<span class="blue-text">EXAMPLE:</span>''EGFR''
−EXAMPLE:
+<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)
−EXAMPLE: BRAF; Activating mutations
+|<span class="blue-text">EXAMPLE:</span> T
−|EXAMPLE: TSG
+|<span class="blue-text">EXAMPLE:</span> Yes (NCCN)
−|EXAMPLE: 20% (COSMIC)
+|<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).
−|-
−EXAMPLE: 30% (add Reference)
+|<span class="blue-text">EXAMPLE:</span> ''TP53''; Variable LOF mutations
−|EXAMPLE: IDH1 R123H
+<br />
−|EXAMPLE: EGFR amplification
+|<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
+|
+|
+|-
+|
+|
+|
+|
|
|
|
|
|
|
−|}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.
−|}
−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.
−{| class="wikitable sortable"
−|-
|-
−!Gene!!Mutation!!Role/function!!Presumed Mechanism (LOF/GOF/Other; Driver/Passenger)!!Prevalence<ref name=":4" />
+!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)'''<ref name=":4" />
+!Prognostic Significance (Yes, No or Unknown)<ref name=":2" /><ref name=":4" />
+!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
|-
|-
−|STAT3||Src homology 2 (SH2) domain
+|''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
+|''STAT5b''; missense mutation
−|Oncogenic driver mutation
|Oncogenic driver mutation
|31%
|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" />
+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" />
|-
|-
−|PIK3CD
+|''PIK3CD''
+|Activate signaling
+pathways important to cell survival<ref name=":4" />
+|9%
|
|
−|Signaling pathway
+|
−|Activate signaling pathways important to cell survival<ref name=":4" />
+|No
−|9%
+|No
+|Yes
|
|
|-
|-
−|SETD2
+|''SETD2''; biallelic LOF
−|Tumor suppressor gene, chromatin modifier*<ref name=":4" />
|Tumor suppressor gene, chromatin modifier*<ref name=":4" />
−|Biallelic loss of function<ref name=":4" />
+|25%
−|71% (cases showing at least one loss of function mutation)
+|
|
|
−|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" />
+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*
+|21%
|
|
+|
+|Yes
+|Yes<ref name=":2" />
+|Yes
+|
+|-
+|''ARID1B''
|Chromatin modifier*
|Chromatin modifier*
+|19%
+|
|
|
−|21%
+|No
+|No
+|No
|
|
|-
|-
−|TET3
+|''TET3''
+|Chromatin modifier*
+|15%
|
|
−|
|
−|15%
+|Yes
+|No
+|Yes
|
|
|-
|-
−|SMARCA2
+|''SMARCA2''
+|Chromatin modifier*
+|10%
|
|
−|
|
−|10%
+|No
+|No
+|No
|
|
|}
|}
−<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
−==Epigenomic Alterations==
==Epigenomic Alterations==
Line 363:
Line 414:
***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==
−{| 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" />
−''**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" />
−==Genetic Diagnostic Testing Methods==
==Genetic Diagnostic Testing Methods==
Line 399:
Line 495:
*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 407:
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
−*N/A
+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
+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 415:
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 />
==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:DISEASE]][[Category:Diseases H]]
+[[Category:HAEM5]]
+[[Category:DISEASE]]
+[[Category:Diseases H]]