Chronic Lymphoproliferative Disorder of NK Cells

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Primary Author(s)*

Michelle Don, MD

Cancer Category/Type

Lymphoproliferative disorder (provisional entity)[1]

Cancer Sub-Classification / Subtype

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Definition / Description of Disease[1]

  • Persistent (>6 months) increase in peripheral blood NK-cell count without a clearly identifiable cause
  • NK-cell count usually >2x109/L
  • Indolent

Synonyms / Terminology[1]

  • Chronic NK-lymphocytosis
  • Chronic NK large granular lymphocyte lymphoproliferative disorder
  • Indolent large granular NK-cell lymphoproliferative disorder

Epidemiology / Prevalence[1]

  • Adults (median age 60 years old)
  • No known racial or genetic predisposition

Sites of Involvement[1]

  • Peripheral blood
  • Bone marrow

Morphologic Features[1]

  • NK-cells are typically intermediate in size
  • Monotonous cells with round nuclei and moderate cytoplasm with fine or coarse azurophilic granules
  • Intrasinusoidal and interstitial infiltration of bone marrow

Immunophenotype[1]


Finding Marker
Positive CD16
Positive cytoplasmic CD3-epsilon
Positive (frequent) weak 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)

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Chromosomal Rearrangement Genes in Fusion (5’ or 3’ Segments) Pathogenic Derivative Prevalence
EXAMPLE t(9;22)(q34;q11.2) EXAMPLE 3'ABL1 / 5'BCR EXAMPLE der(22) EXAMPLE 5%
EXAMPLE t(8;21)(q22;q22) EXAMPLE 5'RUNX1 / 3'RUNXT1 EXAMPLE der(8) EXAMPLE 5%

Characteristic Chromosomal Aberrations / Patterns

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Genomic Gain/Loss/LOH

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Chromosome Number Gain/Loss/Amp/LOH Region
EXAMPLE 8 EXAMPLE Gain EXAMPLE chr8:0-1000000
EXAMPLE 7 EXAMPLE Loss EXAMPLE chr7:0-1000000

Gene Mutations (SNV/INDEL)

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Gene Mutation Oncogene/Tumor Suppressor/Other Presumed Mechanism (LOF/GOF/Other; Driver/Passenger) Prevalence Additional information
STAT3
  • exons 12-21
  • encoding the Src homology 2 (SH2) domain
EXAMPLE Tumor Suppressor Driver mutation[2] variable: 9%[3] to 30%[4]
STAT5b[2]
  • Exon 16
  • Missense N642H mutation in the SH2 domain[2]
Driver mutation[2] 1 patient[2]
  • Progressed to aggressive disease[2]

Other Mutations

Type Gene/Region/Other
Concomitant Mutations EXAMPLE IDH1 R123H
Secondary Mutations EXAMPLE Trisomy 7
Mutually Exclusive EXAMPLE EGFR Amplification

Epigenomics (Methylation)

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Genes and Main Pathways Involved

  • Most patients carry heavy mutational burden

Diagnostic Testing Methods

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Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)

  • Presence of STAT mutations could imply therapeutic targets

Familial Forms

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Other Information

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Links

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References

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  1. 1.0 1.1 1.2 1.3 1.4 1.5 1.6 Villamor N, et al., (2017). Chronic lymphoproliferative disorder of NK cells, 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, p 3351-352
  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. (04 22, 2020). "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). Check date values in: |date= (help)
  4. 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.

EXAMPLE Book

  1. Arber DA, et al., (2017). Acute myeloid leukaemia with recurrent genetic abnormalities, 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, p129-171.

Notes

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