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Haematolymphoid Tumours (WHO Classification, 5th ed.)

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editContent Update To WHO 5th Edition Classification Is In Process; Content Below is Based on WHO 4th Edition Classification

This page was converted to the new template on 2023-12-07. The original page can be found at HAEM4:Hepatosplenic T-cell Lymphoma.

(General Instructions – The main focus of these pages is the clinically significant genetic alterations in each disease type. Use HUGO-approved gene names and symbols (italicized when appropriate), HGVS-based nomenclature for variants, as well as generic names of drugs and testing platforms or assays if applicable. Please complete tables whenever possible and do not delete them (add N/A if not applicable in the table and delete the examples); to add (or move) a row or column to a table, click within the table and select the > symbol that appears to be given options. Please do not delete or alter the section headings. The use of bullet points alongside short blocks of text rather than only large paragraphs is encouraged. Additional instructions below in italicized blue text should not be included in the final page content. Please also see Author_Instructions and FAQs as well as contact your Associate Editor or Technical Support)

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 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)	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

HAEM5:T-large granular lymphocytic leukaemia

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.)

↑ ^1.0 ^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.
↑ ^2.00 ^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)
↑ ^3.00 ^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
↑ 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)
↑ ^5.00 ^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.
↑ 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)
↑ ^7.0 ^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.
↑ 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).
↑ 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).
↑ 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)
↑ ^11.0 ^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.
↑ ^12.0 ^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)
↑ ^13.0 ^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

*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. *Citation of this Page: “Hepatosplenic T-cell lymphoma”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 09/6/2024, https://ccga.io/index.php/HAEM5:Hepatosplenic_T-cell_lymphoma.

[:0-1] 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.

[:1-2] 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)

[:2-3] 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)

[:4-5] 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)

[:3-7] 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)

[:5-11] 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.

[:6-12] 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)

[:7-13] 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)

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