NK-large granular lymphocytic leukaemia

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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:Chronic Lymphoproliferative Disorder of NK Cells.


Primary Author(s)*

Hailee St. Louis, MD, UC San Diego

Michelle Don, MD, UC San Diego

WHO Classification of Disease

Structure Disease
Book Haematolymphoid Tumours (5th ed.)
Category T-cell and NK-cell lymphoid proliferations and lymphomas
Family Mature T-cell and NK-cell neoplasms
Type Mature T-cell and NK-cell leukaemias
Subtype(s) NK-large granular lymphocytic leukaemia

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

None

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

None

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

Characteristic Chromosomal or Other Global Mutational Patterns

None

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

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 or common as well either disease defining and/or clinically significant. If a gene has multiple mechanisms depending on the type or site of the alteration, add multiple entries 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. Details on clinical significance such as prognosis and other important information such as concomitant and mutually exclusive mutations can be provided in the notes section. Please include references throughout the table. Do not delete the table.)

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.

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
STAT3; exons 12-21 encoding the Src homology 2 (SH2 domain on two hotspots: D661 and Y640), driver mutation [1] Variable: 9% [2] to 30% [3] Yes Higher frequency of symptomatic disease; no difference in overall survival [3] No current approved therapeutic targets [1] - Also seen in T-LGL [3]

- Commonly associated  with CD16high/CD57low or cytotoxic memory NK-LGL's [4]

TET2; loss of function [5] Other: TET2 induces an oxidation of 5mC into 5hmc in active DNA demethylation [5] 28% [6] - 34% [5] STAT3 [5] Yes Unknown Resistance to immunosuppressive agents have been observed; no current therapeutic target [6] - Also seen in T-LGL

- Commonly associated with CD16 low phenotype

- Associated with thrombocytopenia [5]

CCL22; gain of function [7] 21.5% [7] No No No - Specific to NK-LGL [4]
TNFAIP3; loss of function [5] TSG 6% [8] - 10% [5] No No No
PI3K pathway genes; PIK3CD activating mutation, PIK3AP1 mutation not previously described [6] 3 patients (5%) [6] No No No PIK3CD mutations are observed as de novo germline mutations causing activated PI3 kinase delta syndrome [6]
STAT5b; exon 16 missense N642H mutation in the SH2 domain, driver mutation [1] 1 patient [1] Unknown Unknown; progressed to aggressive disease and died due to disease [1] No current approved therapeutic targets [1]

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

  • TET2 shows increased methylated regions in clonal NK-LGLs compared to normal NK-cells [6]

Genes and Main Pathways Involved

Pathways involved include anti-apoptotic signaling and cell survival pathways. This includes the JAK/STAT pathway with constitutive activation of STAT3 and an activating mutation in STAT3. Also involved are RAS/MAPK and Pi3K/AKT pathways, which are constitutionally activated. [4]

Genetic Diagnostic Testing Methods

  • Assessing for restricted expression of KIR isoforms, is often used as a surrogate for clonality [9].
  • Mutational screen for STAT3, STAT5b, TET2, TNFAIP3 and CCL22 mutations may be more helpful when compared to KIR analysis on diagnostic work-up [4].
  • Absence of T-cell receptor gene rearrangement studies [9].
  • Sanger Sequencing.
  • Whole Genome Sequencing.

Familial Forms

None

Additional Information

This disease is defined/characterized as detailed below:

  • A neoplasm characterized by a persistent (>6 months) increase in peripheral NK cells (> 2 x 10^9/L) and a chronic indolent clinical course. Additional essential diagnostic criteria include flow cytometric evidence of peripheral blood or bone marrow involvement by a uniform population of sCD3(-), CD16(+) NK cells and demonstration of a restricted pattern of KIR expression.
  • The differential diagnosis includes other mature T-cell neoplasms with a leukemic presentation. T-cell large granular lymphocytic leukemia is a disorder with clinical and pathological overlap; NK-LGL cannot be distinguished from T-LGL by cytological features. If there is prominent lymphocytosis, an aggressive NK-cell leukemia can be considered and NK-LGL is distinguished by an indolent clinical presentation and lack of nuclear EBV positivity.[10]

The epidemiology/prevalence of this disease is detailed below:

  • Median age: 60 years
  • Does not show sex, racial, geographical, or genetic predisposition[10]

The clinical features of this disease are detailed below:

  • Signs and symptoms - Asymptomatic (incidental finding on complete blood counts); May occur in association with autoimmune disorders, solid tumors, hematological neoplasms, and neuropathy; Uncommon/atypical: splenomegaly, hepatomegaly, lymphadenopathy, skin involvement[10]
  • Laboratory findings - Lymphocytosis, variable neutropenia and/or anemia[10]

The sites of involvement of this disease are detailed below:

  • Peripheral blood and bone marrow
  • Uncommon: spleen[10]

The morphologic features of this disease are detailed below:

  • NK-cells are typically intermediate to large in size with small, round nuclei and moderate cytoplasm with fine or coarse azurophilic granules.
  • Intrasinusoidal and sometimes interstitial infiltration of bone marrow and possibly spleen.[10]

The immunophenotype of this disease is detailed below:

Positive - CD16, cytoplasmic CD3-epsilon, Cytotoxic markers (TIA1, granzyme B & granzyme M), CD94

Positive (frequent) - CD56

Decreased to negative - CD2, CD7, CD57, CD161

Restricted or lack of expression - KIR isoforms (CD158a, b, c)

Negative - surface CD3, EBV

Links

N/A

References

  1. Jump up to: 1.0 1.1 1.2 1.3 1.4 1.5 Rajala, Hanna L. M.; et al. (2013-05-30). "Discovery of somatic STAT5b mutations in large granular lymphocytic leukemia". Blood. 121 (22): 4541–4550. doi:10.1182/blood-2012-12-474577. ISSN 1528-0020. PMC 3668487. PMID 23596048.
  2. Gasparini, Vanessa Rebecca; et al. (2020-04-22). "A high definition picture of somatic mutations in chronic lymphoproliferative disorder of natural killer cells". Blood Cancer Journal. 10 (4): 42. doi:10.1038/s41408-020-0309-2. ISSN 2044-5385. PMC 7176632 Check |pmc= value (help). PMID 32321919 Check |pmid= value (help).
  3. Jump up to: 3.0 3.1 3.2 Jerez, Andres; et al. (2012-10-11). "STAT3 mutations unify the pathogenesis of chronic lymphoproliferative disorders of NK cells and T-cell large granular lymphocyte leukemia". Blood. 120 (15): 3048–3057. doi:10.1182/blood-2012-06-435297. ISSN 1528-0020. PMC 3471515. PMID 22859607.
  4. Jump up to: 4.0 4.1 4.2 4.3 Drillet, Gaëlle; et al. (2022). "Toward a Better Classification System for NK-LGL Disorders". Frontiers in Oncology. 12: 821382. doi:10.3389/fonc.2022.821382. ISSN 2234-943X. PMC 8843930 Check |pmc= value (help). PMID 35178350 Check |pmid= value (help).
  5. Jump up to: 5.0 5.1 5.2 5.3 5.4 5.5 5.6 Pastoret, Cédric; et al. (2021-06-10). "Linking the KIR phenotype with STAT3 and TET2 mutations to identify chronic lymphoproliferative disorders of NK cells". Blood. 137 (23): 3237–3250. doi:10.1182/blood.2020006721. ISSN 1528-0020. PMC 8351897 Check |pmc= value (help). PMID 33512451 Check |pmid= value (help).
  6. Jump up to: 6.0 6.1 6.2 6.3 6.4 6.5 Olson, Thomas L.; et al. (2021-08-26). "Frequent somatic TET2 mutations in chronic NK-LGL leukemia with distinct patterns of cytopenias". Blood. 138 (8): 662–673. doi:10.1182/blood.2020005831. ISSN 1528-0020. PMC 8394905 Check |pmc= value (help). PMID 33786584 Check |pmid= value (help).
  7. Jump up to: 7.0 7.1 Baer, Constance; et al. (2022-05). "CCL22 mutations drive natural killer cell lymphoproliferative disease by deregulating microenvironmental crosstalk". Nature Genetics. 54 (5): 637–648. doi:10.1038/s41588-022-01059-2. ISSN 1546-1718. PMC 9117519 Check |pmc= value (help). PMID 35513723 Check |pmid= value (help). Check date values in: |date= (help)
  8. Kawakami, Toru; et al. (2019-05). "STAT3 mutations in natural killer cells are associated with cytopenia in patients with chronic lymphoproliferative disorder of natural killer cells". International Journal of Hematology. 109 (5): 563–571. doi:10.1007/s12185-019-02625-x. ISSN 1865-3774. PMID 30859397. Check date values in: |date= (help)
  9. Jump up to: 9.0 9.1 Lamy, Thierry; et al. (2017-03-02). "LGL leukemia: from pathogenesis to treatment". Blood. 129 (9): 1082–1094. doi:10.1182/blood-2016-08-692590. ISSN 1528-0020. PMID 28115367.
  10. Jump up to: 10.0 10.1 10.2 10.3 10.4 10.5 Cite error: Invalid <ref> tag; no text was provided for refs named :0


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 Associate Editor or other CCGA representative.  When pages have a major update, the new author will be acknowledged at the beginning of the page, and those who contributed previously will be acknowledged below as a prior author.

Prior Author(s):


*Citation of this Page: “NK-large granular lymphocytic leukaemia”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 02/19/2025, https://ccga.io/index.php/HAEM5:NK-large_granular_lymphocytic_leukaemia.