HAEM5:NK-large granular lymphocytic 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: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

Related Terminology

Acceptable	Chronic lymphoproliferative disorder of NK cells; chronic NK-large granular lymphocyte lymphoproliferative disorder
Not Recommended	Chronic NK-cell lymphocytosis; indolent leukaemia of NK cells

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		Variable: 9% to 30%			Yes	Higher frequency of symptomatic disease; no difference in overall survival	No current approved therapeutic targets	- Also seen in T-LGL - Commonly associated  with CD16high/CD57low or cytotoxic memory NK-LGL's
TET2; loss of function	Other: TET2 induces an oxidation of 5mC into 5hmc in active DNA demethylation	28% - 34%	STAT3		Yes	Unknown	Resistance to immunosuppressive agents have been observed; no current therapeutic target	- Also seen in T-LGL - Commonly associated with CD16 low phenotype - Associated with thrombocytopenia
CCL22; gain of function		21.5%			No	No	No	- Specific to NK-LGL
TNFAIP3; loss of function	TSG	6% - 10%			No	No	No
PI3K pathway genes; PIK3CD activating mutation, PIK3AP1 mutation not previously described		3 patients (5%)			No	No	No	PIK3CD mutations are observed as de novo germline mutations causing activated PI3 kinase delta syndrome
STAT5b; exon 16 missense N642H mutation in the SH2 domain, driver mutation		1 patient			Unknown	Unknown; progressed to aggressive disease and died due to disease	No current approved therapeutic targets

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

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.

Genetic Diagnostic Testing Methods

• Assessing for restricted expression of KIR isoforms, is often used as a surrogate for clonality .

• Mutational screen for STAT3, STAT5b, TET2, TNFAIP3 and CCL22 mutations may be more helpful when compared to KIR analysis on diagnostic work-up .

• Absence of T-cell receptor gene rearrangement studies .

• 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.

The epidemiology/prevalence of this disease is detailed below:

• Median age: 60 years

• Does not show sex, racial, geographical, or genetic predisposition

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
• Laboratory findings - Lymphocytosis, variable neutropenia and/or anemia

The sites of involvement of this disease are detailed below:

• Peripheral blood and bone marrow

• Uncommon: spleen

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.

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

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 07/3/2025, https://ccga.io/index.php/HAEM5:NK-large_granular_lymphocytic_leukaemia.