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−==Definition / Description of Disease==
−Aggressive subtype of peripheral T-cell lymphoma. HSTL is an extranodal T-cell lymphoma that is known to have a poor response to therapy and an overall poor prognosis. This lymphoma is characterized by sinusoidal infiltration of the liver, spleen and often bone marrow, and uncommonly lymph nodes by cytotoxic T-cells that most commonly express the γδ T-cell receptor. Less commonly, some patients may have a variant of this lymphoma that is associated with αβ expressing cytotoxic T-cells <ref name=":0">Medeiros LJ, O'Malley DP, Caraway NP, Vega F, Elenitoba-Johnson KS, Lim MS: AFIP Atlas of Tumor Pathology. Washington, DC: American Registry of Pathology, 2017.</ref><ref name=":1">{{Cite journal|title=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==
−*Hepatosplenic T-cell lymphoma (HSTL)
−==Epidemiology / Prevalence==
−*1.4-2% of peripheral T-cell lymphomas<ref name=":1" />
−*~75% are Classic γδ type<ref name=":1" />
−*Male predominance in gamma-delta subtype<ref name=":1" />
−*Median age ~ 35 years old<ref name=":2" />, 51% with age >60 years old<ref>{{Cite journal|last=Foss|first=Francine M.|last2=Horwitz|first2=Steven M.|last3=Civallero|first3=Monica|last4=Bellei|first4=Monica|last5=Marcheselli|first5=Luigi|last6=Kim|first6=Won Seog|last7=Cabrera|first7=Maria E.|last8=Dlouhy|first8=Ivan|last9=Nagler|first9=Arnon|date=2020-02|title=Incidence and outcomes of rare T cell lymphomas from the T Cell Project: hepatosplenic, enteropathy associated and peripheral gamma delta T cell lymphomas|url=https://pubmed.ncbi.nlm.nih.gov/31709579|journal=American Journal of Hematology|volume=95|issue=2|pages=151–155|doi=10.1002/ajh.25674|issn=1096-8652|pmc=8025136|pmid=31709579}}</ref>
−==Clinical Features==
−{| class="wikitable"
−|'''Signs and Symptoms'''
−|Splenomegaly (most common symptom)<ref name=":2" />
−B-symptoms (night sweats, fever, weight loss and fatigue)<ref name=":0" />
−Hepatomegaly<ref name=":1" /><ref name=":2" />
−Lymphadenopathy (uncommon)<ref name=":0" /><ref name=":2" />
−|-
−|'''Laboratory Findings'''
−|Cytopenias (most commonly thrombocytopenia)<ref name=":0" /><ref name=":2" />
−Elevated serum levels of B2M<ref name=":1" />
−Elevated serum levels of LDH<ref name=":1" />
−|}
−==Sites of Involvement==
−*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==
−{| class="wikitable sortable"
−|-
−!Finding!!Marker
−|-
−|Positive (typically)||CD2, CD3, γδ T-cell receptor, TIA1, Granzyme M<ref name=":1" />
−|-
−|Negative||CD5, CD4, CD8<ref name=":1" />
+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). BCR::ABL1 is generally favorable in CML (add reference).+|<span class="blue-text">EXAMPLE:</span> Common (CIC-rearranged sarcoma)+ +''DUX4'' has many homologous genes; an alternate translocation in a minority of cases is t(10;19), but this is usually indistinguishable from t(4;19) by short-read sequencing (add references).
|<span class="blue-text">EXAMPLE:</span> ''ALK''
−|<span class="blue-text">EXAMPLE:</span> ''ELM4::ALK''
−Other fusion partners include ''KIF5B, NPM1, STRN, TFG, TPM3, CLTC, KLC1''
−|<span class="blue-text">EXAMPLE:</span> Fusions result in constitutive activation of the ''ALK'' tyrosine kinase. The most common ''ALK'' fusion is ''EML4::ALK'', with breakpoints in intron 19 of ''ALK''. At the transcript level, a variable (5’) partner gene is fused to 3’ ''ALK'' at exon 20. Rarely, ''ALK'' fusions contain exon 19 due to breakpoints in intron 18.
−|<span class="blue-text">EXAMPLE:</span> N/A
−|<span class="blue-text">EXAMPLE:</span> Rare (Lung adenocarcinoma)
−|<span class="blue-text">EXAMPLE:</span> T
−|
+Both balanced and unbalanced forms are observed by FISH (add references).+|-+|<span class="blue-text">EXAMPLE:</span> Intragenic deletion of exons 2–7 in ''EGFR'' removes the ligand-binding domain, resulting in a constitutively active tyrosine kinase with downstream activation of multiple oncogenic pathways.+|<span class="blue-text">EXAMPLE:</span> Recurrent (IDH-wildtype Glioblastoma)
|
==Individual Region Genomic Gain/Loss/LOH==
+
+
+
+
+
+
+
+
*Forough Sargolzaeiaval, MD
*Forough Sargolzaeiaval, MD
*Michelle Don, MD, MS
*Michelle Don, MD, MS
−==WHO Classification of Disease==
==WHO Classification of Disease==
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|Subtype(s)
|Subtype(s)
|Hepatosplenic T-cell lymphoma
|Hepatosplenic T-cell lymphoma
−|}
|}
==WHO Essential and Desirable Genetic Diagnostic Criteria==
==WHO Essential and Desirable Genetic Diagnostic Criteria==
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==Gene Rearrangements==
==Gene Rearrangements==
+
*No known chromosomal rearrangements at this time
*No known chromosomal rearrangements at this time
+
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
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!Clinical Relevance Details/Other Notes
!Clinical Relevance Details/Other Notes
|-
|-
−|<span class="blue-text">EXAMPLE:</span> ''ABL1''||<span class="blue-text">EXAMPLE:</span> ''BCR::ABL1''||<span class="blue-text">EXAMPLE:</span> The pathogenic derivative is the der(22) resulting in fusion of 5’ BCR and 3’ABL1.||<span class="blue-text">EXAMPLE:</span> t(9;22)(q34;q11.2)
+|N/A
−|<span class="blue-text">EXAMPLE:</span> Common (CML)
+|
−|<span class="blue-text">EXAMPLE:</span> D, P, T
+|
−|<span class="blue-text">EXAMPLE:</span> Yes (WHO, NCCN)
+|
+|
+|
+|
+|
+|}
+==Individual Region Genomic Gain/Loss/LOH==
+{| class="wikitable sortable"
+|-
+!Chr #!!'''Gain, Loss, Amp, LOH'''!!'''Minimal Region Cytoband and/or Genomic Coordinates [Genome Build; Size]'''!!'''Relevant Gene(s)'''
+!'''Diagnostic, Prognostic, and Therapeutic Significance - D, P, T'''
+!'''Established Clinical Significance Per Guidelines - Yes or No (Source)'''
+!'''Clinical Relevance Details/Other Notes'''
+|-
+|<span class="blue-text">EXAMPLE:</span>
+7
+|<span class="blue-text">EXAMPLE:</span> Loss
+|<span class="blue-text">EXAMPLE:</span>
+chr7
+|<span class="blue-text">EXAMPLE:</span>
+Unknown
+|<span class="blue-text">EXAMPLE:</span> D, P
+|<span class="blue-text">EXAMPLE:</span> No
|<span class="blue-text">EXAMPLE:</span>
|<span class="blue-text">EXAMPLE:</span>
−Presence of monosomy 7 (or 7q deletion) is sufficient for a diagnosis of AML with MDS-related changes when there is ≥20% blasts and no prior therapy (add reference). Monosomy 7/7q deletion is associated with a poor prognosis in AML (add references).
|-
|-
−|<span class="blue-text">EXAMPLE:</span> ''CIC''
+|<span class="blue-text">EXAMPLE:</span>
−|<span class="blue-text">EXAMPLE:</span> ''CIC::DUX4''
+8
−|<span class="blue-text">EXAMPLE:</span> Typically, the last exon of ''CIC'' is fused to ''DUX4''. The fusion breakpoint in ''CIC'' is usually intra-exonic and removes an inhibitory sequence, upregulating ''PEA3'' genes downstream of ''CIC'' including ''ETV1'', ''ETV4'', and ''ETV5''.
+|<span class="blue-text">EXAMPLE:</span> Gain
−|<span class="blue-text">EXAMPLE:</span> t(4;19)(q25;q13)
+|<span class="blue-text">EXAMPLE:</span>
−chr8
−|<span class="blue-text">EXAMPLE:</span> D
+|<span class="blue-text">EXAMPLE:</span>
+Unknown
+|<span class="blue-text">EXAMPLE:</span> D, P
|
|
|<span class="blue-text">EXAMPLE:</span>
|<span class="blue-text">EXAMPLE:</span>
−Common recurrent secondary finding for t(8;21) (add references).
−|-
|-
−|<span class="blue-text">EXAMPLE:</span>
|<span class="blue-text">EXAMPLE:</span>
−17
−|<span class="blue-text">EXAMPLE:</span> Amp
−|<span class="blue-text">EXAMPLE:</span>
−|<span class="blue-text">EXAMPLE:</span> ''ABL1''
+17q12; chr17:39,700,064-39,728,658 [hg38; 28.6 kb]
−|<span class="blue-text">EXAMPLE:</span> N/A
+|<span class="blue-text">EXAMPLE:</span>
−''ERBB2''
−|<span class="blue-text">EXAMPLE:</span> N/A
−|<span class="blue-text">EXAMPLE:</span> D, P, T
|<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.
|-
|-
−|
|
|
|
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|
|
|}
|}
−{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
!Chr #!!Gain / Loss / Amp / LOH!!Minimal Region Genomic Coordinates [Genome Build]!!Minimal Region Cytoband
!Chr #!!Gain / Loss / Amp / LOH!!Minimal Region Genomic Coordinates [Genome Build]!!Minimal Region Cytoband
−!Diagnostic Significance (Yes, No or Unknown)<ref name=":2" /><ref name=":4">McKinney, M., Moffitt, A.B., Gaulard, P., Travert, M., De Leval, L., Nicolae, A., Raffeld, M., Jaffe, E.S., Pittaluga, S., Xi, L. and Heavican, T., 2017. The genetic basis of hepatosplenic T-cell lymphoma. ''Cancer discovery'', ''7''(4), pp.369-379.</ref>
+!Diagnostic Significance (Yes, No or Unknown)<ref name=":2">Yabe M, Miranda RN, Medeiros LJ. Hepatosplenic T-cell Lymphoma: a review of clinicopathologic features, pathogenesis, and prognostic factors. ''Hum Pathol''. 2018;74:5‐16. doi:10.1016/j.humpath.2018.01.005</ref><ref name=":4">McKinney, M., Moffitt, A.B., Gaulard, P., Travert, M., De Leval, L., Nicolae, A., Raffeld, M., Jaffe, E.S., Pittaluga, S., Xi, L. and Heavican, T., 2017. The genetic basis of hepatosplenic T-cell lymphoma. ''Cancer discovery'', ''7''(4), pp.369-379.</ref>
!Prognostic Significance (Yes, No or Unknown)<ref name=":2" /><ref name=":4" />
!Prognostic Significance (Yes, No or Unknown)<ref name=":2" /><ref name=":4" />
!Therapeutic Significance (Yes, No or Unknown)
!Therapeutic Significance (Yes, No or Unknown)
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|Yes
|Yes
|No
|No
−|Considered a primary aberration<ref name=":2" />, seen in 40-70% of cases<ref name=":1" />
+|Considered a primary aberration<ref name=":2" />, seen in 40-70% of cases<ref name=":1">{{Cite journal|title=Hepatosplenic T-cell lymphoma. In: WHO Classification of Tumours Editorial Board. Haematolymphoid tumours [Internet]|url=https://tumourclassification.iarc.who.int/chaptercontent/63/229|displayauthors=1|last=Medeiros|first=Jeffrey|date=2024|journal=WHO classification of tumours series, 5th ed.|volume=vol. 11|pages=|via=Lyon (France): International Agency for Research on Cancer}}</ref>
|-
|-
|8
|8
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|Seen in 10-15% of cases<ref name=":1" />
|Seen in 10-15% of cases<ref name=":1" />
|}<br />
|}<br />
+
==Characteristic Chromosomal or Other Global Mutational Patterns==
==Characteristic Chromosomal or Other Global Mutational Patterns==
+{| class="wikitable sortable"
+|-
+!Chromosomal Pattern
+!Molecular Pathogenesis
+!'''Prevalence -'''
+'''Common >20%, Recurrent 5-20% or Rare <5% (Disease)'''
+!'''Diagnostic, Prognostic, and Therapeutic Significance - D, P, T'''
+!'''Established Clinical Significance Per Guidelines - Yes or No (Source)'''
+!'''Clinical Relevance Details/Other Notes'''
+|-
+|<span class="blue-text">EXAMPLE:</span>
+Co-deletion of 1p and 18q
+|<span class="blue-text">EXAMPLE:</span> See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference).
+|<span class="blue-text">EXAMPLE:</span> Common (Oligodendroglioma)
+|<span class="blue-text">EXAMPLE:</span> D, P
+|
+|
+|-
+|<span class="blue-text">EXAMPLE:</span>
+Microsatellite instability - hypermutated
+|
+|<span class="blue-text">EXAMPLE:</span> Common (Endometrial carcinoma)
+|<span class="blue-text">EXAMPLE:</span> P, T
+|
+|
+|-
+|
+|
+|
+|
+|
+|
+|}
*7q aberrations and trisomy 8 are considered specific for HSTL, but not sensitive<ref name=":2" />
*7q aberrations and trisomy 8 are considered specific for HSTL, but not sensitive<ref name=":2" />
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|occur in a significant minority of HSTL cases<ref name=":4" />
|occur in a significant minority of HSTL cases<ref name=":4" />
|}<br />
|}<br />
+
==Gene Mutations (SNV/INDEL)==
==Gene Mutations (SNV/INDEL)==
+Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: This table is not meant to be an exhaustive list; please include only genes/alterations that are recurrent or common as well either disease defining and/or clinically significant. If a gene has multiple mechanisms depending on the type or site of the alteration, add multiple entries in the table. For clinical significance, denote associations with FDA-approved therapy (not an extensive list of applicable drugs) and NCCN or other national guidelines if applicable; Can also refer to CGC workgroup tables as linked on the homepage if applicable as well as any high impact papers or reviews of gene mutations in this entity. Details on clinical significance such as prognosis and other important information such as concomitant and mutually exclusive mutations can be provided in the notes section. Please include references throughout the table. Do not delete the table.'') </span>
+{| class="wikitable sortable"
+|-
+!Gene!!'''Genetic Alteration'''!!'''Tumor Suppressor Gene, Oncogene, Other'''!!'''Prevalence -'''
+'''Common >20%, Recurrent 5-20% or Rare <5% (Disease)'''
+!'''Diagnostic, Prognostic, and Therapeutic Significance - D, P, T '''
+!'''Established Clinical Significance Per Guidelines - Yes or No (Source)'''
+!'''Clinical Relevance Details/Other Notes'''
+|-
+|<span class="blue-text">EXAMPLE:</span>''EGFR''
+
+<br />
+|<span class="blue-text">EXAMPLE:</span> Exon 18-21 activating mutations
+|<span class="blue-text">EXAMPLE:</span> Oncogene
+|<span class="blue-text">EXAMPLE:</span> Common (lung cancer)
+|<span class="blue-text">EXAMPLE:</span> T
+|<span class="blue-text">EXAMPLE:</span> Yes (NCCN)
+|<span class="blue-text">EXAMPLE:</span> Exons 18, 19, and 21 mutations are targetable for therapy. Exon 20 T790M variants cause resistance to first generation TKI therapy and are targetable by second and third generation TKIs (add references).
+|-
+|<span class="blue-text">EXAMPLE:</span> ''TP53''; Variable LOF mutations
+<br />
+|<span class="blue-text">EXAMPLE:</span> Variable LOF mutations
+|<span class="blue-text">EXAMPLE:</span> Tumor Supressor Gene
+|<span class="blue-text">EXAMPLE:</span> Common (breast cancer)
+|<span class="blue-text">EXAMPLE:</span> P
+|
+|<span class="blue-text">EXAMPLE:</span> >90% are somatic; rare germline alterations associated with Li-Fraumeni syndrome (add reference). Denotes a poor prognosis in breast cancer.
+|-
+|<span class="blue-text">EXAMPLE:</span> ''BRAF''; Activating mutations
+|<span class="blue-text">EXAMPLE:</span> Activating mutations
+|<span class="blue-text">EXAMPLE:</span> Oncogene
+|<span class="blue-text">EXAMPLE:</span> Common (melanoma)
+|<span class="blue-text">EXAMPLE:</span> T
+|
+|
+|-
+|
+|
+|
+|
+|
+|
+|
+|}Note: A more extensive list of mutations can be found in [https://www.cbioportal.org/ <u>cBioportal</u>], [https://cancer.sanger.ac.uk/cosmic <u>COSMIC</u>], and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.
{| class="wikitable sortable"
{| class="wikitable sortable"
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Note: A more extensive list of mutations can be found in cBioportal (https://www.cbioportal.org/), COSMIC (https://cancer.sanger.ac.uk/cosmic), ICGC (https://dcc.icgc.org/) and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external conten
Note: A more extensive list of mutations can be found in cBioportal (https://www.cbioportal.org/), COSMIC (https://cancer.sanger.ac.uk/cosmic), ICGC (https://dcc.icgc.org/) and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external conten
+
==Epigenomic Alterations==
==Epigenomic Alterations==
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==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:
−*N/A
+Signs and symptoms - Splenomegaly (most common symptom); B-symptoms (night sweats, fever, weight loss and fatigue); Hepatomegaly; Lymphadenopathy (uncommon)
+Laboratory findings - Cytopenias (most commonly thrombocytopenia); Elevated serum levels of B2M; Elevated serum levels of LDH
+The <u>sites of involvement</u> of this disease are detailed below:
+*Spleen
+*Liver
+*Bone marrow
+*Lymph node (uncommon)
+*Skin (rarely, in relapse cases)
+*With or without leukemic involvement
+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==