Aggressive NK-cell leukaemia
Haematolymphoid Tumours (5th ed.)
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Primary Author(s)*
Rabail Aslam, MD, Shanelle De Lancy, MD, Shashirekha Shetty, PhD
Case Western Reserve University, Cleveland, OH
WHO Classification of Disease
Mature T- and NK-cell neoplasms
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 | Constitutional symptoms (weight loss, fever, night sweats)
Hepatosplenomegaly common[3] Frequently complicated by multiorgan failure, coagulopathy and haemophagocytic syndrome *EBV-negative cases may occur de novo or transform from chronic lymphoproliferative disorder of NK cells[4] |
| Laboratory Findings | Markedly elevated serum lactate dehydrogenase (LDH) levels
Circulating FASL Variable % of circulating leukemic cells Anemia, neutropenia, thrombocytopenia |
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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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Sites of Involvement
Peripheral blood, bone marrow, liver, spleen, and lymph nodes. Extranodal involvement of any organ including skin, lungs, soft tissue and omentum can be seen.[5]
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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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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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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)The content below was from the old template. Please incorporate above.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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Characteristic Chromosomal Patterns
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| 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 / PatternsThe content below was from the old template. Please incorporate above.
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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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)The content below was from the old template. Please incorporate above.
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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Epigenomic Alterations
Mutations seen in epigenetic regulatory molecules:
- RNA helicase DDX3X (28%)
- TET2 (28%)
- CREBBP (21%)
- MLL2 (21%)
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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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Genetic Diagnostic Testing Methods
Foundation of diagnosis based on morphology with immunophenotyping via flow cytometry +/- immunohistochemistry.
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Familial Forms
N/A
Additional Information
N/A
Links
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 3.5 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.
- ↑ 4.0 4.1 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.
- ↑ 5.0 5.1 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 07/8/2024, https://ccga.io/index.php/HAEM5:Aggressive_NK-cell_leukaemia.