Difference between revisions of "HAEM5:Hepatosplenic T-cell lymphoma"
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==Primary Author(s)*== | ==Primary Author(s)*== |
Revision as of 18:15, 18 October 2024
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] |
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:
Can be seen in conjunction with trisomy 8 |
Yes | Yes | No | See table under "Genomic Gain/Loss/LOH"
|
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]
| |
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
| ||
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].
- 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.)
- ↑ 1.0 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 10/18/2024, https://ccga.io/index.php/HAEM5:Hepatosplenic_T-cell_lymphoma.