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

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:

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).

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.

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).

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.

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

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

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).

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