Aggressive NK-cell leukaemia

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Haematolymphoid Tumours (5th ed.)

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Primary Author(s)*

Shanelle De Lancy, MD, Shashirekha Shetty, PhD

Cancer Category / Type

Mature T- and NK-cell neoplasms

Cancer Sub-Classification / Subtype

Aggressive NK-cell Leukaemia

Definition / Description of Disease

  • Proliferation of NK-cells
  • Associated with EBV infection, but EBV may be negative in a subset of patients
  • Aggressive clinical course with poor response to chemotherapy
  • Relapse common in patients that achieve complete remission (+/- bone marrow transplantation)

Synonyms / Terminology

Aggressive NK-cell leukaemia/lymphoma

Epidemiology / Prevalence

  • Young to middle-aged adults
  • Median age: 40 years; Peaks in 3rd and 5th decades
  • More prevalent in Asian, Central and South America[1]
  • No gender predilection
  • EBV-negative cases tend to occur in older patients, with no significant difference in Asian vs. non-Asian populations[2]
  • Median survival: <2 months


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[3]

Clinical Features

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Signs and Symptoms EXAMPLE Asymptomatic (incidental finding on complete blood counts)

EXAMPLE B-symptoms (weight loss, fever, night sweats)

EXAMPLE Fatigue

EXAMPLE Lymphadenopathy (uncommon)

Laboratory Findings EXAMPLE Cytopenias

EXAMPLE Lymphocytosis (low level)


editv4:Clinical Features
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Signs and Symptoms:

  • Constitutional symptoms, e.g, fever, general malaise
  • Hepatosplenomegaly common
  • Frequently complicated by multiorgan failure, coagulopathy and haemophagocytic syndrome

Laboratory Findings:

  • Markedly elevated serum lactate dehydrogenase (LDH) levels
  • Circulating FASL
  • Variable % of circulating leukaemic cells
  • Anaemia, neutropenia, thrombocytopenia


*EBV-negative cases may occur de novo or transform from chronic lymphoproliferative disorder of NK cells


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[3][4]

Sites of Involvement

  • Peripheral blood
  • Bone marrow
  • Liver
  • Spleen
  • Lymph nodes

but may involve any organ including skin, lungs, soft tissue and omentum


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[5]

Morphologic Features

Peripheral Blood:

  • Variable; May appear as:
    • Normal large granular lymphocytes or
    • Intermediate to large cells with atypical nuclei (enlarged, irregular folding, open chromatin or distinct nucleoli) and moderate pale or lightly basophilic cytoplasm containing fine, coarse or no azurophilic granules

Bone Marrow:

  • Interstitial or intrasinusoidal infiltrating pattern, which may be extensive, focal or subtle[1]
  • May have interspersed reactive histiocytes with haemophagocytosis

Tissue:

  • Diffuse or patchy destructive infiltrates
  • Monotonous medium sized cells
  • Round or highly irregular nuclei with condensed chromatin and small nucleoli
  • Frequently admixed apoptotic bodies
  • Necrosis common
  • +/- angioinvasion


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[3]

Immunophenotype

Finding Marker
Positive (universal) CD2, CD3-epsilon, CD56, CD94, cytotoxic molecules (TIA1, Granzyme B, perforin A), FASL, c-MYC
Positive (subset) CD16 (75%), CD11b, EBER, p53, pSTAT3, PD-L1, BCL2
Negative (universal) surface CD3, CD4, CD5, CD57 (usually), CD158a/b/e, TCR alpha/beta, TCR gamma/delta
Negative (subset) CD7, CD45


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[3][1]

Chromosomal Rearrangements (Gene Fusions)

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Chromosomal Rearrangement Genes in Fusion (5’ or 3’ Segments) Pathogenic Derivative Prevalence Diagnostic Significance (Yes, No or Unknown) Prognostic Significance (Yes, No or Unknown) Therapeutic Significance (Yes, No or Unknown) Notes
EXAMPLE t(9;22)(q34;q11.2) EXAMPLE 3'ABL1 / 5'BCR EXAMPLE der(22) EXAMPLE 20% (COSMIC)

EXAMPLE 30% (add reference)

Yes No Yes EXAMPLE

The t(9;22) is diagnostic of CML in the appropriate morphology and clinical context (add reference). This fusion is responsive to targeted therapy such as Imatinib (Gleevec) (add reference).


editv4:Chromosomal Rearrangements (Gene Fusions)
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N/A


editv4:Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications).
Please incorporate this section into the relevant tables found in:
  • Chromosomal Rearrangements (Gene Fusions)
  • Individual Region Genomic Gain/Loss/LOH
  • Characteristic Chromosomal Patterns
  • Gene Mutations (SNV/INDEL)


Molecular abnormalities present possible therapeutic implications.

Dufva et al identified high sensitivity of ANKL cell lines to JAK and BCL2 inhibition.

Other possibly effective drug classes:

  • Heat shock protein 90 (HSP90) inhibitors
  • Polo-like kinase (PLK) inhibitors
  • Aurora kinase (AURK) inhibitors
  • Cyclin-dependent kinase inhibitors
  • Histone deacetylase inhibitors


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[6]

Individual Region Genomic Gain / Loss / LOH

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Chr # Gain / Loss / Amp / LOH Minimal Region Genomic Coordinates [Genome Build] Minimal Region Cytoband Diagnostic Significance (Yes, No or Unknown) Prognostic Significance (Yes, No or Unknown) Therapeutic Significance (Yes, No or Unknown) Notes
EXAMPLE

7

EXAMPLE Loss EXAMPLE

chr7:1- 159,335,973 [hg38]

EXAMPLE

chr7

Yes Yes No EXAMPLE

Presence of monosomy 7 (or 7q deletion) is sufficient for a diagnosis of AML with MDS-related changes when there is ≥20% blasts and no prior therapy (add reference).  Monosomy 7/7q deletion is associated with a poor prognosis in AML (add reference).

EXAMPLE

8

EXAMPLE Gain EXAMPLE

chr8:1-145,138,636 [hg38]

EXAMPLE

chr8

No No No EXAMPLE

Common recurrent secondary finding for t(8;21) (add reference).

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Chromosome Gain/Loss/Amp/LOH
1q23.1-q23.2 Gain
1q31.3-q44 Gain
7p15.1-q22.3 Loss
17p13.1 Loss


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[1][3]

Characteristic Chromosomal Patterns

Put your text here (EXAMPLE PATTERNS: hyperdiploid; gain of odd number chromosomes including typically chromosome 1, 3, 5, 7, 11, and 17; co-deletion of 1p and 19q; complex karyotypes without characteristic genetic findings; chromothripsis)

Chromosomal Pattern Diagnostic Significance (Yes, No or Unknown) Prognostic Significance (Yes, No or Unknown) Therapeutic Significance (Yes, No or Unknown) Notes
EXAMPLE

Co-deletion of 1p and 18q

Yes No No EXAMPLE:

See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference).

editv4:Characteristic Chromosomal Aberrations / Patterns
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Due to rare nature of disease, cytogenetics data is limited. However, common abnormalities include del(6)(q21q25) and del(11q).

Complex karyotypes with unbalanced rearrangements are frequently seen.


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[2]

Gene Mutations (SNV / INDEL)

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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) Prognostic Significance (Yes, No or Unknown) Therapeutic Significance (Yes, No or Unknown) Notes
EXAMPLE: TP53; Variable LOF mutations

EXAMPLE:

EGFR; Exon 20 mutations

EXAMPLE: BRAF; Activating mutations

EXAMPLE: TSG EXAMPLE: 20% (COSMIC)

EXAMPLE: 30% (add Reference)

EXAMPLE: IDH1 R123H EXAMPLE: EGFR amplification EXAMPLE:  Excludes hairy cell leukemia (HCL) (add reference).


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 content.


editv4:Gene Mutations (SNV/INDEL)
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Gene Oncogene/Tumor Suppressor/Other Presumed Mechanism (LOF/GOF/Other; Driver/Passenger) Prevalence [2]
JAK/STAT/c-MYC pathway (including STAT3, STAT5B, STAT5A, JAK2, JAK3, STAT6, SOCS31, SOCS3 and PTPN11) Oncogene Gain of function 21 - 66.6%
RAS/MAPK pathway Oncogene Gain of function 16.7 - 29%
TP53 Tumor suppressor Loss of function 7 -50%
BCL2 Oncogene Gain of function N/A

JAK/STAT/c-MYC

  • Mutations in the JAK-STAT pathway appear to be mutually exclusive[7]
  • Most STAT3 and STAT5B mutations localized to exons 20 and 21 encoding the Src homology 2 (SH2) domain, which causes STAT dimerization
  • Other mutations identified:
    • 9p copy gains (containing JAK2)
    • point mutation in protein tyrosine phosphatase (PTPRK) (tumor suppressor that negatively regulates STAT3)
    • mutations in PTPN4 and PTPN23


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[2][8][7]

Epigenomic Alterations

Mutations seen in epigenetic regulatory molecules:

  • RNA helicase DDX3X (28%)
  • TET2 (28%)
  • CREBBP (21%)
  • MLL2 (21%)


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[2][7]

Genes and Main Pathways Involved

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Gene; Genetic Alteration Pathway Pathophysiologic Outcome
EXAMPLE: BRAF and MAP2K1; Activating mutations EXAMPLE: MAPK signaling EXAMPLE: Increased cell growth and proliferation
EXAMPLE: CDKN2A; Inactivating mutations EXAMPLE: Cell cycle regulation EXAMPLE: Unregulated cell division
EXAMPLE:  KMT2C and ARID1A; Inactivating mutations EXAMPLE:  Histone modification, chromatin remodeling EXAMPLE:  Abnormal gene expression program
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  • Upregulated JAK/STAT-MYC biosynthesis axis due to upstream STAT3 activation of the MYC transcription program. *
  • Alterations in RAS-MAPK pathway also identified
  • Epigenetic modifier genes (e.g BCOR, KMT2D/MLL2, SETD2, PRDM9, CREBBP, and TET2)
  • DNA damage repair (TP53, ASXL1, ASXL2, BRINP3)
  • mRNA splicing factors (PRPF40B)


*Thought in some cases to be as a result of highly expressed EBV-encoded small RNAs (EBERs) causing release of IL-10.


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[2]

Genetic Diagnostic Testing Methods

Foundation of diagnosis based on morphology with immunophenotyping via flow cytometry +/- immunohistochemistry.


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[1]

Familial Forms

N/A

Additional Information

N/A

Links

Extranodal NK/T-cell lymphoma

Hepatosplenic T-cell Lymphoma (HSTCL)

Chronic lymphoproliferative disorder of natural killer cells (CLPD-NK)

References

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  1. ↑ 1.0 1.1 1.2 1.3 1.4 El Hussein, Siba; et al. (09 2020). "Genomic and Immunophenotypic Landscape of Aggressive NK-Cell Leukemia". The American Journal of Surgical Pathology. 44 (9): 1235–1243. doi:10.1097/PAS.0000000000001518. ISSN 1532-0979. PMID 32590457 Check |pmid= value (help). Check date values in: |date= (help)
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 El Hussein, Siba; et al. (10 09, 2020). "Aggressive NK Cell Leukemia: Current State of the Art". Cancers. 12 (10). doi:10.3390/cancers12102900. ISSN 2072-6694. PMC 7600035 Check |pmc= value (help). PMID 33050313 Check |pmid= value (help). Check date values in: |date= (help)
  3. ↑ 3.0 3.1 3.2 3.3 3.4 Chan, JKC et al., (2017). Aggressive NK-cell leukaemia, 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, p353-354.
  4. ↑ Kim, Wook Youn; et al. (2019). "Epstein-Barr Virus-Associated T and NK-Cell Lymphoproliferative Diseases". Frontiers in Pediatrics. 7: 71. doi:10.3389/fped.2019.00071. ISSN 2296-2360. PMC 6428722. PMID 30931288.
  5. ↑ Hue, Susan Swee-Shan; et al. (2020-01). "Epstein–Barr virus-associated T- and NK-cell lymphoproliferative diseases: an update and diagnostic approach". Pathology. 52 (1): 111–127. doi:10.1016/j.pathol.2019.09.011. Check date values in: |date= (help)
  6. ↑ Dufva, Olli; et al. (04 19, 2018). "Aggressive natural killer-cell leukemia mutational landscape and drug profiling highlight JAK-STAT signaling as therapeutic target". Nature Communications. 9 (1): 1567. doi:10.1038/s41467-018-03987-2. ISSN 2041-1723. PMC 5908809. PMID 29674644. Check date values in: |date= (help)
  7. ↑ 7.0 7.1 7.2 Huang, Liang; et al. (2018-02). "Integrated genomic analysis identifies deregulated JAK/STAT-MYC-biosynthesis axis in aggressive NK-cell leukemia". Cell Research. 28 (2): 172–186. doi:10.1038/cr.2017.146. ISSN 1001-0602. PMC 5799812. PMID 29148541. Check date values in: |date= (help)CS1 maint: PMC format (link)
  8. ↑ Gao, Juehua; et al. (2020-11). "Comprehensive molecular genetic studies of Epstein-Barr virus-negative aggressive Natural killer-cell leukemia/lymphoma". Human Pathology. 105: 20–30. doi:10.1016/j.humpath.2020.08.008. 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: “Aggressive NK-cell leukaemia”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 12/13/2023, https://ccga.io/index.php/HAEM5:Aggressive_NK-cell_leukaemia.

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