Aggressive NK-cell leukaemia

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editHAEM5 Conversion Notes

This page was converted to the new template on 2023-11-30. The original page can be found at HAEM4:Aggressive NK-cell Leukemia.

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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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)

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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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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)

Put your text here and fill in the table (Instructions: This table is not meant to be an exhaustive list; please include only genes/alterations that are recurrent and common as well either disease defining and/or clinically significant. Can include references in the table. For clinical significance, denote associations with FDA-approved therapy (not an extensive list of applicable drugs) and NCCN or other national guidelines if applicable; Can also refer to CGC workgroup tables as linked on the homepage if applicable as well as any high impact papers or reviews of gene mutations in this entity.)

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

editv4:Genes and Main Pathways Involved

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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

(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 ^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)
↑ ^2.0 ^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)
↑ ^3.0 ^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.
↑ 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.
↑ 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)
↑ 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)
↑ ^7.0 ^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)
↑ 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 11/30/2023, https://ccga.io/index.php/HAEM5:Aggressive_NK-cell_leukaemia.

[:0-1] 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] 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)

[:1-3] 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)

[:3-7] 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)

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