Aggressive NK-cell leukaemia
Haematolymphoid Tumours (WHO Classification, 5th ed.)
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Primary Author(s)*
Shanelle De Lancy, MD, Rabail Aslam, MD, Shashirekha Shetty, PhD
Case Western Reserve University, Cleveland, OH
WHO Classification of Disease
Aggressive NK-cell Leukaemia
Definition / Description of Disease
Aggressive NK-cell leukaemia is a malignant proliferation of NK-cells, often associated with EBV infection, however, a subset of cases could be EBV negative. The disease has an extremely aggressive clinical course with poor response to chemotherapy, frequent relapses noted in patient who have had previously achieved complete remission (+/- bone marrow transplantation).
Synonyms / Terminology
Aggressive NK-cell leukaemia/lymphoma
Epidemiology / Prevalence
Aggressive NK-cell leukaemia impacts young to middle-aged adults with peak incidence during 3rd and 5th decades of life (Mean age: 40 years).[1] There is no gender predilection and most prevalent in Asia, Central and South America.[2] Median survival is very short, <2 months. EBV-negative cases tend to occur in older patients, with no significant difference in Asian vs. non-Asian populations.[3] EBV-negative cases may occur de novo or transform from chronic lymphoproliferative disorder of NK cells.[4]
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Clinical Features
Most common presentation is with constitutional symptoms and frequently associated hepatosplenomegaly is noted on physical examination.[1][4]
| Signs and Symptoms | Constitutional symptoms (weight loss, fever, night sweats)
Hepatosplenomegaly common Frequently complicated by multiorgan failure, coagulopathy and haemophagocytic syndrome |
| Laboratory Findings | Markedly elevated serum lactate dehydrogenase (LDH) levels
Circulating FASL Variable percentage of circulating leukemic cells Anemia, neutropenia, thrombocytopenia |
editv4:Clinical FeaturesContent Update To WHO 5th Edition Classification Is In Process; Content Below is Based on WHO 4th Edition Classification
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 are frequently involved. Extranodal involvement sites are organs including skin, lungs, soft tissue and omentum has also been reported.[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.[1]
Bone Marrow:
- Interstitial or intrasinusoidal infiltrating pattern, which may be extensive, focal or subtle[2]
- 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
The leukaemic cells show demonstrate the following phenotypic expression.[1][2]
| 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)
Due to the rarity of this lymphoma the data in recurrent chromosomal rearrangement is extremely scant. There have been chromosomal rearrangements reported in association with the aggressive NK-cell leukaemia, however, none of them are considered specific for the disease.
| 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 |
|---|
editv4:Chromosomal Rearrangements (Gene Fusions)Content Update To WHO 5th Edition Classification Is In Process; Content Below is Based on WHO 4th Edition ClassificationN/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
There have been a few chromosomal abnormalities associated with aggressive NK-cell leukaemia as listed below, however, the specificity along with prognostic and therapeutic significance is unknown.[3]
| 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 |
|---|---|---|---|---|---|---|---|
| 1 | Gain | 1q23.1-q23.2 | No | Unknown | Unknown | ||
| 1 | Gain | 1q31.3-q44 | No | Unknown | Unknown | ||
| 7 | Loss | 7p15.1-q22.3 | No | Unknown | Unknown | ||
| 17 | Loss | 17p13.1 | No | Unknown | Unknown | ||
| 6 | Loss | 6q16.1–q27 | No | Unknown | Unknown |
editv4:Genomic Gain/Loss/LOHContent Update To WHO 5th Edition Classification Is In Process; Content Below is Based on WHO 4th Edition Classification
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
Due to rare nature of disease, cytogenetics data is limited. The common abnormalities include del(6)(q21q25) and del(11q), however, none of these abnormalities are specific and their clinical significance is unknown.[3] Complex karyotypes with unbalanced rearrangements are frequently seen.
| Chromosomal Pattern | Diagnostic Significance (Yes, No or Unknown) | Prognostic Significance (Yes, No or Unknown) | Therapeutic Significance (Yes, No or Unknown) | Notes |
|---|
editv4:Characteristic Chromosomal Aberrations / PatternsContent Update To WHO 5th Edition Classification Is In Process; Content Below is Based on WHO 4th Edition Classification
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)
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.[3][8]
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 are heat shock protein 90 (HSP90) inhibitors, polo-like kinase (PLK) inhibitors, aurora kinase (AURK) inhibitors, cyclin-dependent kinase inhibitors, and histone deacetylase inhibitors.[6]
| 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 |
|---|---|---|---|---|---|---|---|---|
| JAK/STAT/c-MYC pathway (including STAT3, STAT5B, STAT5A, JAK2, JAK3, STAT6, SOCS31, SOCS3 and PTPN11) | Oncogene | 21 - 66.6% | Gain of function
| |||||
| RAS/MAPK pathway | Oncogene | 16.7 - 29% | Gain of function | |||||
| TP53 | Tumor suppressor gene | 7 -50% | Loss of function | |||||
| BCL2 | Oncogene | NA | Gain of function |
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)Content Update To WHO 5th Edition Classification Is In Process; Content Below is Based on WHO 4th Edition Classification
Gene Oncogene/Tumor Suppressor/Other Presumed Mechanism (LOF/GOF/Other; Driver/Passenger) Prevalence [3] 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 including RNA helicase DDX3X (28%), TET2 (28%), CREBBP (21%), and MLL2 (21%) have been reported.[3][7]
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Genes and Main Pathways Involved
The disease pathogenesis is regulated by a complex interplay between diverse molecular pathways especially that involving the upregulated JAK/STAT-MYC biosynthesis axis due to upstream STAT3 activation of the MYC transcription program. Thought in some cases to be as a result of highly expressed EBV-encoded small RNAs (EBERs) causing release of IL-10.[3]
| Gene; Genetic Alteration | Pathway | Pathophysiologic Outcome |
|---|---|---|
| STAT3 activation of the MYC transcription program | JAK/STAT-MYC biosynthesis axis | Increased cell survival and proliferation |
| Alterations in RAS-MAPK pathway | RAS-MAPK pathway | Increased cell survival and proliferation |
| BCOR, KMT2D/MLL2, SETD2, PRDM9, CREBBP, and TET2 | Epigenetic modifier genes | Altering the epigenetic landscape |
| TP53, ASXL1, ASXL2, BRINP3 | DNA damage repair | ?? |
| PRPF40B | mRNA splicing factors | ?? |
editv4:Genes and Main Pathways InvolvedContent Update To WHO 5th Edition Classification Is In Process; Content Below is Based on WHO 4th Edition Classification
- 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.[3]
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Genetic Diagnostic Testing Methods
Foundation of diagnosis based on morphology with immunophenotyping via flow cytometry +/- immunohistochemistry.[2]
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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 1.5 1.6 1.7 1.8 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.
- ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 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) - ↑ 3.00 3.01 3.02 3.03 3.04 3.05 3.06 3.07 3.08 3.09 3.10 3.11 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) - ↑ 4.0 4.1 4.2 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) - ↑ 6.0 6.1 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 7.3 7.4 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) - ↑ 8.0 8.1 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 09/1/2024, https://ccga.io/index.php/HAEM5:Aggressive_NK-cell_leukaemia.