HAEM4:Hepatosplenic T-cell Lymphoma

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Primary Author(s)*

  • Michelle Don, MD, MS

Cancer Category/Type

Cancer Sub-Classification / Subtype

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 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]. Thus, this entity is also included in the list of the World Health Organization's post-transplant lymphoproliferative disorders[2].

Synonyms / Terminology

  • Hepatosplenic T-cell lymphoma (HSTL)

Epidemiology / Prevalence

  • 1-2% of T-natural killer cell lymphomas[2]
  • ~80% are Classic γδ type[2]
  • M:F ~ 3:1[2]
  • Median age ~ 35 years old[2]

Clinical Features

  • Splenomegaly (most common symptom)[3]
  • Diagnosed late in the course of the disease
  • B-symptoms (night sweats, fever, weight loss and fatigue)[1]
  • Hepatosplenomegaly[3]
  • Cytopenias (most commonly thrombocytopenia)[1][3]
  • Lymphadenopathy (uncommon)[3][1]

Sites of Involvement[2]

  • Spleen
  • Liver
  • Bone marrow
  • Lymph node (uncommon)
  • With or without leukemic involvement

Morphologic Features

  • Typically shows a sinusoidal pattern

Immunophenotype

Finding Marker
Positive (typically) CD3, γδ T-cell receptor, TIA1, Granzyme M[2]
Negative CD4, CD8[2]

Chromosomal Rearrangements (Gene Fusions)

  • No known chromosomal rearrangements at this time.

Characteristic Chromosomal Aberrations / Patterns

  • Most common genetic abnormalities include Isochromosome 7q and trisomy 8 (see table below "Genomic Gain/Loss/LOH")[4]
  • Isochromsome 7q[5] and chromosome 7 imbalances including ring chromosome 7
    • Variable frequency in the literature (25-58%)[3]
    • Considered to be a primary chromosomal aberration[3]
    • Cases with chromosome 7 abnormalities show:
      • Constant loss of 7p22.1p14.1 (34.88 Mb; 3506316-38406226 bp)[6]
      • Gain of 7q22.11q31.1 (38.77 Mb; 86259620–124892276 bp)[6]
    • Can be seen in conjunction with trisomy 8 (please see below)
      • 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 and gain of chromosome 1q occur in a significant minority of HSTL cases[4]

Genomic Gain/Loss/LOH

Chromosome Number Gain/Loss/Amp/LOH Notes
7q Gain Considered a primary aberration[3]
8 Gain (trisomy) Considered a secondary aberration[3]
10q Loss Seen in 19% of cases[4]
1q Gain Seen in 13% of cases[4]


Gene Mutations (SNV/INDEL)

Gene Mutation Role/function Presumed Mechanism (LOF/GOF/Other; Driver/Passenger) Prevalence[4] Notes
STAT3 Src homology 2 (SH2) domain Signaling pathway Oncogenic driver mutation 9%
  • Also seen in 40% of T-large granular lymphocyte leukemia[3]
STAT5b Src homology 2 (SH2) domain Signaling pathway Oncogenic driver mutation 31%
  • Highest functional potency: STAT5B N642H and V712E mutations[3]
  • One study showed increased CD56 expression with STAT5b[7]
  • Also seen in ~2% of T-large granular lymphocyte leukemia[3]
PIK3CD Signaling pathway Activate signaling pathways important to cell survival[4] 9%
SETD2 SET2–RPB1 interacting domain (SRI) domain ( 31 ) at the COOH-terminus of the SETD2 protein product

(other mutations interspersed among different domains have also been seen)[4]

Tumor suppressor gene, chromatin modifier*[4] Biallelic loss of function[4] 71% (cases showing at least one loss of function mutation)
  • Most frequently silenced gene and most frequent mutated chromatin modifier in HSTL[4]
  • More than 44% of patients had more than 1 mutation in SETD2.[3]
INO80 Chromatin modifier* 21%
TET3 Chromatin modifier* 15%
SMARCA2 Chromatin modifier* 10%

*Chromatin modifiers make up the most commonly mutated genes in HSTL[4]

Specific mutations in the above genes can be found elsewhere (COSMIC, cBioPortal)

Important to note:

Type Gene/Region/Other
Mutually Exclusive STAT3 and STAT5b
  • Only 1 reported case with both mutations present[4]

Epigenomics (Methylation)

  • AIM1 is dramatically reduced in HSTL likely due to promoter methylation[8]
    • Suggest AIM1 may play a role as a tumor suppressor gene in HSTL oncogenesis[8]
  • Eight consistently hypermethylated genes (BCL11B, CD5, CXCR6, GIMAP7, LTA, SEPT9, UBAC2, UXS1) and four consistently hypomethylated genes (ADARB1, NFIC, NR1H3, ST3GAL3) in HSTL[9].
    • 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[9].
      • 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[9].
        • Note: This finding is not specific to HSTL and can be seen in other T-cell lymphomas[9]

Genes and Main Pathways Involved

  • HSTL (both γδ and αβ phenotypes) show a similar molecular blueprint[8]
    • Clustering of expression profiles of HSTL samples show separate clustering compared to the other T-cell lymphomas irrespective of their αβ or γδ lineage[8]
    • Overexpression of genes encoding NK-cell–associated molecules (KIRs, KLR, CD244, and NCAM1), oncogenes (FOS, VAV3, MAF, and BRAF), cell adhesion (eg, VCAM1, CD11d, and ICAM1), tsignal transduction (eg, SPRY2, RHOB, MAP4K3, and SPRY1), the sonic hedgehog pathway (eg, GLI3, PRKAR2B, PRKACB, and PRKAR1A), the WNT pathway (eg, FRZB, TCF7L2, BAMBI, TLE1, CTNNB1, APC, and FZD5), and S1PR5, and the tyrosine kinase SYK[8]
    • AIM1 (absent in melanoma 1) was among the most down-expressed genes[8]
      • Genes showing significant under expression in HSTL includes those associated with cytotoxicity (eg, Granulysin, Granzyme H, Granzyme K, and Granzyme B), cytokines (eg, LTA, TNF, and IFNG), and CD5[8]

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[4]
    • Presence of RHOA mutation, can potentially exclude HSTL from the differential diagnosis[4]

Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)

  • 7q aberrations and trisomy 8 are considered specific for HSTL, but not sensitive[3]
  • SETD2, INO80, TET3, and STAT5B - seen almost exclusively in hepatosplenic T-cell lymphoma, compared to other B and T-cell lymphoma, which can support a diagnosis of HSTL in difficult cases[4]
    • RHOA, has not been seen in HSTL cases, and is more commonly seen in peripheral T-cell lymphoma, NOS and angioimmunoblastic T- cell lymphoma[4]
  • PI3KCD, JAK1/2, and STAT5B mutations suggest potential therapeutic targets[3]
  • SyK expression was seen one study, which is not typical for normal T-cells[8]
    • Syk is a protein tyrosine kinase usually involved in B-cell receptor signaling[8]
    • Syk inhibitors may be a potential targeted therapeutic option[8]
  • A single study has shown use of IFNα2c therapy-induced changes in CpG methylation[10]
    • CpG methylation changes have the potential to serve as biomarkers of drug responses and/or disease progression[10]
  • The likely methylation of AIM1 seen in HSTL may provide rationale for demethylating agents as therapeutic options[8]

Familial Forms

  • N/A

Other Information

  • N/A

Links

References

(use "Cite" icon at top of pa

  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. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 2.8 Gaulard P, et al., (2017). Hepatosplenic T-cell lymphoma, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Arber DA, Hasserjian RP, Le Beau MM, Orazi A, and Siebert R, Editors. IARC Press: Lyon, France, p 381-382
  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 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. ↑ 4.00 4.01 4.02 4.03 4.04 4.05 4.06 4.07 4.08 4.09 4.10 4.11 4.12 4.13 4.14 4.15 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.
  5. ↑ Wlodarska, Iwona, et al. "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 and Cancer 33.3 (2002): 243-251.
  6. ↑ 6.0 6.1 Ferreiro, Julio Finalet, et al. "Integrative genomic and transcriptomic analysis identified candidate genes implicated in the pathogenesis of hepatosplenic T-cell lymphoma." PloS one 9.7 (2014): e102977.
  7. ↑ Nicolae A, Xi L, Pittaluga S, Abdullaev Z, Pack SD, Chen J, Waldmann TA, Jaffe ES, Raffeld M. Frequent STAT5B mutations in γδ hepatosplenic T-cell lymphomas. Leukemia. 2014 Nov;28(11):2244-8.
  8. ↑ 8.00 8.01 8.02 8.03 8.04 8.05 8.06 8.07 8.08 8.09 8.10 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.
  9. ↑ 9.0 9.1 9.2 9.3 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)
  10. ↑ 10.0 10.1 Bhat, Jaydeep; et al. (2020-08-20). "DNA methylation profile of a hepatosplenic gamma/delta T-cell lymphoma patient associated with response to interferon-α therapy". Cellular & Molecular Immunology. doi:10.1038/s41423-020-0518-4. ISSN 2042-0226. PMID 32820235 Check |pmid= value (help).


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