Chronic lymphoproliferative disorders of NK cells ICD-10: C91.7

Last updated on: 08.12.2021

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HistoryThis section has been translated automatically.

The World Health Organization (WHO) divides chronic proliferations of LGLs into two entities according to their cell lineage:

  • Chronic lymphoproliferative disorders of NK cells (CLPD-NKs)

and

  • T-cell large granular lymphocytic leukemia (T-LGL).

although there are no significant differences between them in terms of clinical features or therapeutic approaches (Swerdlow SH et al. 2008; Bareau B et al. 2010; Epling-Burnette PK et al. 2008). STAT3 gene mutations occur in both T and NK diseases:

DefinitionThis section has been translated automatically.

Chronic lymphoproliferative disorder of NK cells (CLPD-NK) is a provisional entity listed in the 2017 WHO classification. It is a rare, heterogeneous, indolent disorder in which the number of natural killer cells in peripheral blood is constant at ≥2 × 10/L over a period of more than 6 months (Semenzato G et al. 2012; Lamy T et al. 2017).

EtiopathogenesisThis section has been translated automatically.

There are few data on the pathogenesis of this indolent disease. It is likely that constitutive activation of anti-apoptotic pathways plays an important role (Lamy T et al. 2017). The discovery in 2012 of somatic STAT3 mutations occurring in approximately 40% of T-cell lymphocytic leukemia (T-LGLL = large granular lymphocytic leukemia) and in approximately 30% of CLPD-NK suggests a constitutive activation of the Janus kinase signal transduction pathway (Jerez A et al. 2012) for both diseases.

However, the frequency of patients with STAT3 mutations is lower in CLPD-NK compared to T-LGLL. It is in versch. It is between 8-10% in different cohorts (Barcena P, et al. 2015). STAT3 mutated patients usually present with severe neutropenia and often require specific therapy. Note: The STAT3 pathway is considered an important intrinsic pathway for inflammatory responses in tumor diseases. This pathway can induce a large number of downstream genes that are critical for tumor promotion.

ManifestationThis section has been translated automatically.

Chronic expansion of LGLs mainly affects the elderly. The sometimes accompanying severe cytopenias and other comorbidities, including autoimmune diseases, often make diagnosis difficult due to the overlap between reactive processes and clearly malignant lymphoproliferations (Posnett DN et al. 1994; Bigouret V et al. 2003).

Whereas in T-LGL, objective molecular characterization is based on the detection of clonal expansions by the restructured TCR, detection of the clonal nature of CLPD-NKs is difficult. In both types, the autoimmune phenomena are mediated by clonal immune cells (Koskela HL et al. 2012).

Clinical featuresThis section has been translated automatically.

CLPD-NK generally has an indolent course, with most patients being asymptomatic. Hematologic findings are often incidental.

Evidence of NK cell lymphocytosis.

Neutropenia (absolute neutrophil count < 1500/mm3) is often the most important hematologic feature (detectable in about 40% of patients). A proportion of patients present with severe neutropenia (ANC < 500/mm3) (Semenzato G et al. 2012).

Anemia and thrombocytopenia: These are usually mild.

Splenomegaly and MGUS is detected in about 20% of patients.

Skin manifestations have been described only very occasionally (Ní Mhaolcatha S et al. 2019). They occurred in the form of a painful papular exanthema.

TherapyThis section has been translated automatically.

Clinical controls if patients are otherwise asymptomatic. Gfl. low-dose cyclophosphamide or methotrexate.

Progression/forecastThis section has been translated automatically.

Some patients are and remain completely asymptomatic. Others require specific treatment.

Note(s)This section has been translated automatically.

Natural killer (NK) cells are a distinct class of lymphocytes with large granular morphology and cytotoxic functions characterized by the CD3-/CD16+/CD56+ phenotype. They are traditionally considered part of innate immunity. A specific subset of NK cells can respond to specific antigens, e.g. viral infections or best. Cytokines (IL-12, IL-15 and IL-18) like adaptive immune cells react (Min-Oo G et al. 2013). These NK cells, are also called "NK memory cells". Based on CD56 expression, two major subsets of NK cells can be distinguished:

CD56high/CD16dim/neg NK cells with the ability to release cytokines.

and

CD56dim/CD16high NK cells with cytotoxic capabilities towards virus-infected or neoplastic cells ( Campbell KS et al (2013).

LiteratureThis section has been translated automatically.

  1. Barcena P, et al. (2015) Phenotypic profile of expanded NK cells in chronic lymphoproliferative disorders: a surrogate marker for NK-cell clonality. Oncotarget 6:42938-42951.
  2. Bareau B et al. (2010) Analysis of a French cohort of patients with large granular lymphocyte leukemia: a report on 229 cases. Haematologica 95 1534-1541.
  3. Bigouret V et al. (2003) Monoclonal T-cell expansions in asymptomatic individuals and in patients with large granular leukemia consist of cytotoxic effector T cells expressing the activating CD94:NKG2C/E and NKD2D killer cell receptors. Blood 101: 3198-3204.
  4. Campbell KS et al (2013) Natural killer cell biology: an update and future directions. J Allergy Clin. Immunol 132:536-544.
  5. Cerwenka A et al. (2016) Natural killer cell memory in infection, inflammation and cancer. Nat Rev Immunol 16:112-123.
  6. Epling-Burnette PK et al (2008) Clinical improvement by farnesyltransferase inhibition in NK large granular lymphocyte leukemia associated with imbalanced NK receptor signaling. Blood112: 4694-4698.
  7. Grivennikov S et al (2008) Autocrine IL-6 signaling: a key event in tumorigenesis?, Cancer Cell131: 7-9.
  8. Jerez A et al. (2012) STAT3 mutations unify the pathogenesis of chronic lymphoproliferative disorders of NK cells and T-cell large granular lymphocyte leukemia. Blood 120:3048-3057.
  9. Koskela HL et al (2012) Somatic STAT3 mutations in large granular lymphocytic leukemia., N Engl J Med 366: 1905-1913.
  10. Epling-Burnette PK et al (2004) Dysregulated NK receptor expression in patients with lymphoproliferative disease of granular lymphocytes., Blood103: 3431-3439.
  11. Lamy T et al. (2017) LGL leukemia: from pathogenesis to treatment. Blood129:1082-1094.
  12. Loughran TP et al (1985) Leukemia of large granular lymphocytes: association with clonal chromosomal abnormalities and autoimmune neutropenia, thrombocytopenia, and hemolytic anemia. Ann Intern Med 102: 169-175.
  13. Min-Oo G et al (2013) Natural killer cells: walking three paths down memory lane. Trends Immunol 34:251-258.
  14. Morice WG et al (2010) Chronic lymphoproliferative disorder of natural killer cells: a distinct entity with subtypes correlating with normal natural killer cell subsets. Leukemia 24:881-884.
  15. Ní Mhaolcatha S et al (2019) An Unusual Case of Cutaneous Neural Infiltration as a Manifestation of Chronic Lymphoproliferative Disorder of Natural Killer Cells. Am J Dermatopathol 41:378-381.

  16. Posnett DN et al. (1994) Clonal populations of T cells in normal elderly humans: the T cell equivalent to "benign monoclonal gammapathy.", J Exp Med 179: 609-618.
  17. Semenzato G et al (2012) State of the art in natural killer cell malignancies. Int J Lab. Hematol 34:117-128.
  18. Swerdlow SH et al. (2008) WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues4th Ed Lyon, France International Agency for Research on Cancer.

Last updated on: 08.12.2021