HAEM5:Hepatosplenic T-cell lymphoma

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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

Related Terminology

Acceptable N/A
Not Recommended Erythrophagocytic Tγ lymphoma

Gene Rearrangements

No known chromosomal rearrangements at this time.

Driver Gene Fusion(s) and Common Partner Genes Molecular Pathogenesis Typical Chromosomal Alteration(s) 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
N/A N/A N/A N/A N/A N/A N/A N/A

Individual Region Genomic Gain/Loss/LOH

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
7 Gain 7q, chr7 Unknown D, P No Considered a primary aberration[1], seen in 40-70% of cases[2]
8 Gain (trisomy) Chr8 Unknown D, P No Considered a secondary aberration[1], seen in 10-50% of cases[2]
Y Loss ChrY Unknown Unknown No Seen in 20-25% of cases[2]
10 Loss 10q, chr10 Unknown P No Seen in 10-20% of cases[2]
1 Gain 1q, chr1 Unknown P No Seen in 10-15% of cases[2]

Characteristic Chromosomal or Other Global Mutational Patterns

7q aberrations and trisomy 8 are considered specific for HSTL, but not sensitive[1]

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
Isochromosome 7q[3] and chromosome 7 imbalances including ring chromosome 7.

Can be seen in conjunction with trisomy 8

Cases with chromosome 7 abnormalities show:
  • Constant loss of 7p22.1p14.1 (34.88 Mb; 3506316-38406226 bp)[4]
  • Gain of 7q22.11q31.1 (38.77 Mb; 86259620–124892276 bp)[4]
 Common D, P No See table under "Genomic Gain/Loss/LOH"


Co-occurrence of Isochromosome 7q and trisomy 8 can be seen in 8-53% of cases[1]


Cases without diagnostic detection of i(7q) or trisomy 8, often have detection of these abnormalities at the time of relapse or disease progression[1]

Loss of chromosome 10q

Gain of chromosome 1q

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

Gene Mutations (SNV/INDEL)

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

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
STAT3; missense mutation missense mutation Oncogenic driver mutation Recurrent T No Also seen in 40% of T-large granular lymphocyte leukemia[1]
STAT5b; missense mutation missense mutation Oncogenic driver mutation Common D, T No Highest functional potency: STAT5B N642H and V712E mutations[1]


One study showed increased CD56 expression with STAT5b[6]


Also seen in ~2% of T-large granular lymphocyte leukemia[1]

PIK3CD Activating mutations Activate signaling

pathways important to cell survival[5]

Recurrent T No
SETD2; biallelic LOF biallelic LOF Tumor suppressor gene, chromatin modifier*[5] Common D, T No 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[1]

INO80 Chromatin modifier* Common D, P, T No
ARID1B Chromatin modifier* Recurrent Unknown No
TET3 Chromatin modifier* Recurrent D, T No
SMARCA2 Chromatin modifier* Recurrent Unknown No

Note: A more extensive list of mutations can be found in cBioportal, COSMIC, and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.

Epigenomic Alterations

  • AIM1 is dramatically reduced in HSTL likely due to promoter methylation[7]
    • Suggest AIM1 may play a role as a tumor suppressor gene in HSTL oncogenesis[7]
  • Eight consistently hypermethylated genes (BCL11B, CD5, CXCR6, GIMAP7, LTA, SEPT9, UBAC2, UXS1) and four consistently hypomethylated genes (ADARB1, NFIC, NR1H3, ST3GAL3) in HSTL[8].
    • 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[8].
      • 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[8].
        • Note: This finding is not specific to HSTL and can be seen in other T-cell lymphomas[8]
  • A single study has shown use of IFNα2c therapy-induced changes in CpG methylation[9]
    • CpG methylation changes have the potential to serve as biomarkers of drug responses and/or disease progression[9]

Genes and Main Pathways Involved

Gene; Genetic Alteration[5][7] Pathway[5][7] Pathophysiologic Outcome[5][7]
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[7] Syk is a protein tyrosine kinase usually involved in B-cell receptor signaling[7]

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[7]
    • Presence of RHOA mutation, can potentially exclude HSTL from the differential diagnosis[7]

Familial Forms

  • N/A

Additional Information

HSTL is an aggressive subtype of extranodal, peripheral T-cell lymphoma with 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, this lymphoma can consist of a proliferation of αβ expressing cytotoxic T-cells [10][2][1]. Most cases occur de novo, with a subset of approximately 20-30% occurring in the setting of iatrogenic immunosuppression [1].

Epidemiology/prevalence:

  • 1.4-2% of peripheral T-cell lymphomas[2]
  • ~75% are classic γδ type[2]
  • Male predominance in γδ subtype[2]
  • Median age ~35 years old[1], 51% with age >60 years old[11]

Clinical features: Splenomegaly (most common symptom); B-symptoms (night sweats, fever, weight loss and fatigue); hepatomegaly; uncommonly lymphadenopathy; cytopenias (most commonly thrombocytopenia); elevated serum levels of B2M and LDH

Sites of involvement: Spleen, liver, bone marrow, with or without leukemia involvement; uncommonly lymph nodes; rarely skin, usually in relapse cases

Immunophenotype:

Positive (typically) - CD2, CD3, γδ T-cell receptor, TIA1, Granzyme M[2]

Negative (subset) – CD5, CD4, CD8[2]

Links

References

  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 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
  2. ↑ 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 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. ↑ 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)
  4. ↑ 4.0 4.1 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.
  5. ↑ 5.00 5.01 5.02 5.03 5.04 5.05 5.06 5.07 5.08 5.09 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. ↑ 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)
  7. ↑ 7.0 7.1 7.2 7.3 7.4 7.5 7.6 7.7 7.8 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.
  8. ↑ 8.0 8.1 8.2 8.3 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)
  9. ↑ 9.0 9.1 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)
  10. ↑ 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.
  11. ↑ 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)

Notes

*Citation of this Page: Sargolzaeiaval F, Don M. “Hepatosplenic T-cell lymphoma”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 01/6/2026, https://ccga.io/index.php/HAEM5:Hepatosplenic_T-cell_lymphoma.


*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 Associate Editor 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): N/A

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