HAEM5:Hepatosplenic T-cell lymphoma

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

Characteristic Chromosomal or Other Global Mutational Patterns

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

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 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) Gain of 7q22.11q31.1 (38.77 Mb; 86259620–124892276 bp)	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 Cases without diagnostic detection of i(7q) or trisomy 8, often have detection of these abnormalities at the time of relapse or disease progression
Loss of chromosome 10q Gain of chromosome 1q		Recurrent	P	No	occur in a significant minority of HSTL cases

Gene Mutations (SNV/INDEL)

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

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
STAT5b; missense mutation	missense mutation	Oncogenic driver mutation	Common	D, T	No	Highest functional potency: STAT5B N642H and V712E mutations One study showed increased CD56 expression with STAT5b Also seen in ~2% of T-large granular lymphocyte leukemia
PIK3CD	Activating mutations	Activate signaling pathways important to cell survival	Recurrent	T	No
SETD2; biallelic LOF	biallelic LOF	Tumor suppressor gene, chromatin modifier*	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 71% of cases showing at least one LOF mutation, and more than 44% of patients with SETD2 mutations had more than 1 mutation detected
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
  • Suggest AIM1 may play a role as a tumor suppressor gene in HSTL oncogenesis

• Eight consistently hypermethylated genes (BCL11B, CD5, CXCR6, GIMAP7, LTA, SEPT9, UBAC2, UXS1) and four consistently hypomethylated genes (ADARB1, NFIC, NR1H3, ST3GAL3) in HSTL.
  • 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.
    • 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.
      • Note: This finding is not specific to HSTL and can be seen in other T-cell lymphomas

• A single study has shown use of IFNα2c therapy-induced changes in CpG methylation
  • CpG methylation changes have the potential to serve as biomarkers of drug responses and/or disease progression

Genes and Main Pathways Involved

Gene; Genetic Alteration	Pathway	Pathophysiologic Outcome
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)

**SyK expression was seen one study, which is not typical for normal T-cells Syk is a protein tyrosine kinase usually involved in B-cell receptor signaling

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

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 . Most cases occur de novo, with a subset of approximately 20-30% occurring in the setting of iatrogenic immunosuppression .

Epidemiology/prevalence:

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

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

Negative (subset) – CD5, CD4, CD8

Links

• HAEM5:T-large granular lymphocytic leukaemia

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