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

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 Genomic Coordinates [Genome Build] 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) Concomitant Mutations 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

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. ↑ 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. ↑ 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. ↑ 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)
  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)
  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)
  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.
  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)
  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)


Notes

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