HAEM5:Aggressive NK-cell leukaemia

Haematolymphoid Tumours (WHO Classification, 5th ed.)

editContent Update To WHO 5th Edition Classification Is In Process; Content Below is Based on WHO 4th Edition Classification

This page was converted to the new template on 2023-12-07. The original page can be found at HAEM4:Aggressive NK-cell Leukemia.

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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). There is no gender predilection and most prevalent in Asia, Central and South America. 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. EBV-negative cases may occur de novo or transform from chronic lymphoproliferative disorder of NK cells.

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Clinical Features

Most common presentation is with constitutional symptoms and frequently associated hepatosplenomegaly is noted on physical examination.

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

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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 are frequently involved. Extranodal involvement sites are organs including skin, lungs, soft tissue and omentum has also been reported.

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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
• 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.

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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WHO Essential and Desirable Genetic Diagnostic Criteria

(Instructions: The table will have the diagnostic criteria from the WHO book autocompleted; remove any non-genetics related criteria. If applicable, add text about other classification systems that define this entity and specify how the genetics-related criteria differ.)

WHO Essential Criteria (Genetics)*
WHO Desirable Criteria (Genetics)*
Other Classification

*Note: These are only the genetic/genomic criteria. Additional diagnostic criteria can be found in the WHO Classification of Tumours.

Related Terminology

(Instructions: The table will have the related terminology from the WHO autocompleted.)

Acceptable
Not Recommended

Gene Rearrangements

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.

Driver Gene	Fusion(s) and Common Partner Genes	Molecular Pathogenesis	Typical Chromosomal Alteration(s)	Prevalence -Common >20%, Recurrent 5-20% or Rare <5% (Disease)	Diagnostic, Prognostic, and Therapeutic Significance - D, P, T	Established Clinical Significance Per Guidelines - Yes or No (Source)	Clinical Relevance Details/Other Notes

Individual Region Genomic Gain/Loss/LOH

Chr #	Gain, Loss, Amp, LOH	Minimal Region Cytoband and/or Genomic Coordinates [Genome Build; Size]	Relevant Gene(s)	Diagnostic, Prognostic, and Therapeutic Significance - D, P, T	Established Clinical Significance Per Guidelines - Yes or No (Source)	Clinical Relevance Details/Other Notes
EXAMPLE: 7	EXAMPLE: Loss	EXAMPLE: chr7	EXAMPLE: Unknown	EXAMPLE: D, P	EXAMPLE: 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 references).
EXAMPLE: 8	EXAMPLE: Gain	EXAMPLE: chr8	EXAMPLE: Unknown	EXAMPLE: D, P		EXAMPLE: Common recurrent secondary finding for t(8;21) (add references).
EXAMPLE: 17	EXAMPLE: Amp	EXAMPLE: 17q12; chr17:39,700,064-39,728,658 [hg38; 28.6 kb]	EXAMPLE: ERBB2	EXAMPLE: D, P, T		EXAMPLE: Amplification of ERBB2 is associated with HER2 overexpression in HER2 positive breast cancer (add references). Add criteria for how amplification is defined.

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.

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

Characteristic Chromosomal or Other Global Mutational 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. Complex karyotypes with unbalanced rearrangements are frequently seen.

Chromosomal Pattern	Molecular Pathogenesis	Prevalence - Common >20%, Recurrent 5-20% or Rare <5% (Disease)	Diagnostic, Prognostic, and Therapeutic Significance - D, P, T	Established Clinical Significance Per Guidelines - Yes or No (Source)	Clinical Relevance Details/Other Notes
EXAMPLE: Co-deletion of 1p and 18q	EXAMPLE: See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference).	EXAMPLE: Common (Oligodendroglioma)	EXAMPLE: D, P
EXAMPLE: Microsatellite instability - hypermutated		EXAMPLE: Common (Endometrial carcinoma)	EXAMPLE: P, T

Gene Mutations (SNV/INDEL)

Gene	Genetic Alteration	Tumor Suppressor Gene, Oncogene, Other	Prevalence - Common >20%, Recurrent 5-20% or Rare <5% (Disease)	Diagnostic, Prognostic, and Therapeutic Significance - D, P, T	Established Clinical Significance Per Guidelines - Yes or No (Source)	Clinical Relevance Details/Other Notes
EXAMPLE:EGFR	EXAMPLE: Exon 18-21 activating mutations	EXAMPLE: Oncogene	EXAMPLE: Common (lung cancer)	EXAMPLE: T	EXAMPLE: Yes (NCCN)	EXAMPLE: Exons 18, 19, and 21 mutations are targetable for therapy. Exon 20 T790M variants cause resistance to first generation TKI therapy and are targetable by second and third generation TKIs (add references).
EXAMPLE: TP53; Variable LOF mutations	EXAMPLE: Variable LOF mutations	EXAMPLE: Tumor Supressor Gene	EXAMPLE: Common (breast cancer)	EXAMPLE: P		EXAMPLE: >90% are somatic; rare germline alterations associated with Li-Fraumeni syndrome (add reference). Denotes a poor prognosis in breast cancer.
EXAMPLE: BRAF; Activating mutations	EXAMPLE: Activating mutations	EXAMPLE: Oncogene	EXAMPLE: Common (melanoma)	EXAMPLE: T

Note: A more extensive list of mutations can be found in cBioportal, COSMIC, and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.

Mutations in the JAK-STAT pathway appear to be mutually exclusive. 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.

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.

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.

Epigenomic Alterations

Mutations seen in epigenetic regulatory molecules including RNA helicase DDX3X (28%), TET2 (28%), CREBBP (21%), and MLL2 (21%) have been reported.

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.

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	??

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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

Extranodal NK/T-cell lymphoma

Hepatosplenic T-cell Lymphoma (HSTCL)

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

References

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Notes

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Prior Author(s):

*Citation of this Page: “Aggressive NK-cell leukaemia”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 02/13/2025, https://ccga.io/index.php/HAEM5:Aggressive_NK-cell_leukaemia.