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

Definition / Description of Disease

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. [1]

Synonyms / Terminology

  • Chronic lymphoproliferative disorder of NK cells
  • Chronic NK-large granular lymphocyte lymphoproliferative disorder
  • Chronic NK-cell lymphocytosis (historical)
  • Indolent leukemia of NK cells (historical) [1]

Epidemiology / Prevalence

  • Median age: 60 years
  • Does not show sex, racial, geographical, or genetic predisposition [1]

Clinical Features

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 [1]

Laboratory Findings Lymphocytosis, variable neutropenia and/or anemia [1]

Sites of Involvement

  • Peripheral blood and bone marrow
  • Uncommon: spleen [1]

Morphologic Features

  • 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. [1]

Immunophenotype [1]

Finding Marker
Positive CD16
Positive cytoplasmic CD3-epsilon
Positive (frequent) CD56
Positive Cytotoxic markers

(TIA1, granzyme B & granzyme M)

Positive CD94
Decreased to negative CD2, CD7, CD57, CD161
Negative surface CD3
Restricted or lack of expression KIR isoforms (CD158a, b, c)
Negative EBV

Chromosomal Rearrangements (Gene Fusions)

None

Individual Region Genomic Gain / Loss / LOH

None

Characteristic Chromosomal Patterns

None

Gene Mutations (SNV / INDEL)

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 [2] Variable: 9% [3] to 30% [4] Yes Higher frequency of symptomatic disease; no difference in overall survival [4] No current approved therapeutic targets [2] - Also seen in T-LGL [4]

- Commonly associated  with CD16high/CD57low or cytotoxic memory NK-LGL's [5]

TET2; loss of function [6] Other: TET2 induces an oxidation of 5mC into 5hmc in active DNA demethylation [6] 28% [7] - 34% [6] STAT3 [6] Yes Unknown Resistance to immunosuppressive agents have been observed; no current therapeutic target [7] - Also seen in T-LGL

- Commonly associated with CD16 low phenotype

- Associated with thrombocytopenia [6]

CCL22; gain of function [8] 21.5% [8] No No No - Specific to NK-LGL [5]
TNFAIP3; loss of function [6] TSG 6% [9] - 10% [6] No No No
PI3K pathway genes; PIK3CD activating mutation, PIK3AP1 mutation not previously described [7] 3 patients (5%) [7] No No No PIK3CD mutations are observed as de novo germline mutations causing activated PI3 kinase delta syndrome [7]
STAT5b; exon 16 missense N642H mutation in the SH2 domain, driver mutation [2] 1 patient [2] Unknown Unknown; progressed to aggressive disease and died due to disease [2] No current approved therapeutic targets [2]

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 [7]

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. [5]

Genetic Diagnostic Testing Methods

  • Assessing for restricted expression of KIR isoforms, is often used as a surrogate for clonality [10].
  • Mutational screen for STAT3, STAT5b, TET2, TNFAIP3 and CCL22 mutations may be more helpful when compared to KIR analysis on diagnostic work-up [5].
  • Absence of T-cell receptor gene rearrangement studies [10].
  • Sanger Sequencing.
  • Whole Genome Sequencing.

Familial Forms

None

Additional Information

None

Links


References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 Cite error: Invalid <ref> tag; no text was provided for refs named :0
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 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.
  3. ↑ 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).
  4. ↑ 4.0 4.1 4.2 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.
  5. ↑ 5.0 5.1 5.2 5.3 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).
  6. ↑ 6.0 6.1 6.2 6.3 6.4 6.5 6.6 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).
  7. ↑ 7.0 7.1 7.2 7.3 7.4 7.5 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).
  8. ↑ 8.0 8.1 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)
  9. ↑ 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)
  10. ↑ 10.0 10.1 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.


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: “NK-large granular lymphocytic leukaemia”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 09/6/2024, https://ccga.io/index.php/HAEM5:NK-large_granular_lymphocytic_leukaemia.

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