Chronic Natural Killer Cell Lymphoproliferative Disorders Treated with Interferon-Α: A Case Report

1. Abstract

Chronic natural killer cell lymphoproliferative disorders are a hematological disorder which is characterized bythe proliferation ofCD3- cytotoxic natural killer cells. So far, the pathogenesis ofCLPDNK is still unclear, and there is no consensus on the effectiveness of drug therapy. Here, we report a case of a 52-year-old female who presented with asymptomatic and was initially diagnosed with

2. Key words

chronic natural killer cell lymphoproliferative disorders; interferon-α; signal transducers and activators of transcription 3

3. Abbreviations:

ASO: Anti-Streptolysin O; BM: Bone Marrow; CLPD-NK: Chronic Natural Killer Cell Lymphoproliferative Disorders; CRP: C-Reactive Protein; CyA: Cyclosporin A; EBV: Epstein-Barr Virus; ESR: Erythrocyte Sedimentation Rate; G-CSF: Granulocyte Colony-Stimulating Factor; IFNs: Interferons; MTX: Methotrexate; NK: Natural Killer; PB: Peripheral Blood; PCR: Polymerase Chain Reaction; SH2: Src homology 2; STAT3: signal transducers and activators of transcription 3; WBC: white blood cells

4. Introduction

Chronic natural killer (NK) cell lymphoproliferative disorders (CLPD-NK) is an uncommon but probably underestimated disease caused by clonal proliferation of CD3- cytotoxic NK cells [1]. Diagnosis is typically based on the high number of morphologically characteristic lymphoid cells and finding of an abnormalimmunopheno type by flow cytometry. Because of its relatively indolent clinical behavior, observation is often an appropriate therapy. However, there is still no standard regimen for drug treatment. This study was approved by the Ethics Committee of the First Affiliated Hospital of Chongqing Medical University and was performed according to the Declaration of Helsinki. Patient has provided informed consent for publication of thecase.

5. Case report

Our patient, a 52-year-old woman, was admitted to our hospital with complaints of lymphocytosis with asymptomatic of a year's duration in October 2017. The complete blood count in a physical examination a year ago revealed atypical lymphocytes that constituted 72.74% of the white blood cell population. During the course of the disease, a high proportion of lymphocytes was indicated in peripheral blood (PB) smears without treatment. The patient was hospitalized for further diagnosis and treatment for this reason. No abnormality was found in the patient's past history and family history. Her physical examination revealed a well-developed female with normal temperature, hemodynamics and respirations. She had no palpable peripheral lymphadenopathy, splenomegaly or hepatomegaly. Her peripheral blood smear displayed a white blood cells (WBC) of 15.74×109/L, with 78.5% atypical lymphocytes, 15.8% neutrophils, 4.4% monocytes, hemoglobin of 12g/ dl, and a platelet count of 189×10^9/L. Bone marrow (BM) smear indicated that abnormal lymphocyte was 30%. Large granular lymphocyte could be seen in the peripheral blood (Figure 1a) and bone marrow (Figure 1b), which were characterized by an eccentricnucleus and a slightly basophilic cytoplasm containing azurophilic granules. Lymphocyte subtype analysis by flow cytometry showed prominently exceptional elevated ratio of the total lympocytes with 72.76%, increased number of CD2+CD56+CD94+ cells with 53.91%, and slightly elevated proportion ofCD7+CD8+CD16+CD57+CD161+cells. Besides, afewcellsexpressedspecificmarkers, such as Ki-67, CD158a/h, CD158b and CD 158e (Figure 2). Cytogenetic studies using GTG banding revealed a normal karyotype, 46 XX (Figure 3). No clonal T-cell receptor gene rearrangements.

6. Discussion

CLPD-NK used to be called chronic natural killer cell lymphocytosis. It isseldom known because of itslow incidence rate. Only a few cases of CLPD-NK have been published at home and abroad since Tefferi et al. first discovered and named in 1994[2]. CLPD-NK has no special clinical manifestations, with a long disease course and a good prognosis. Men are affected more common, and the median age is about 60 years [3-6]. CLPD-NK is characterized bychronic expansion of mature NK cells in peripheral blood [7]. The diagnosis of CLPD-NK needs to combine with peripheral blood smear, immunophenotypes and clinical manifestations. As to this patient, the most common presentation was persistent lymphocytosis without symptomatic. Besides, the patient did not present with anemia or splenomegaly. Her bone marrow smears were mainly lymphocyte elevation, and the immunophenotype showed CD3-CD56+CD94+. In addition, EBV genome, chromosomal karyotype and other laboratory test results were negative. Consequently, the patient was diagnosed as chronic natural killer cell lymphoproliferative disorders. CLPD-NK is a clinically indolent disorder. Most patients do not need treatment. Only a few can be transformed into aggressive NK cell leukemia [8]. Patients with moderate to severe cytopenia require therapeutic intervention. Immunosuppressive therapy is the foundation of treatment of chronic NK cell lymphoproliferative disorders. The most frequent therapy relies on the use ofsingle immunosuppressive oral agents such as methotrexate (MTX), cyclophosphamide, or cyclosporin A (CyA)[7, 9]. For patients suffering from anemia or neutropenia, supportive care could be considered, such as using erythropoietin or granulocyte colony-stimulating.

7. Conclusion

protein, have been identified in 10% to 70% of CLPD-NK. Downstream target genes of STAT3 pathway (eg, IFNGR2, JAK2, and Bcl2L1) are up-regulated in patients with CLPD-NK[5,6][15-17]. Unfortunately, activating STAT3 somatic mutation was negativein our patient. In addition, some studies suggest that STAT3-mutated patients require more frequent treatment and have better overall survival [18]. It is conceivable that STAT3 inhibitors might be ideal targeted therapies for CLPD-NK. It was reported that STA-21, a novel synthetic inhibitor of STAT3 dimerization, DNA binding, and STAT3-dependent luciferase reporter activity, might induce apoptosis of chronic natural killer cell lymphoproliferative disorders’ cells [6]. Therefore, although STAT3 mutations are not required for a diagnosis of CLPD-NK, detection of the mutation should prompt additional evaluation for the disease if unsuspected. Our study presents that whether interferon-α is effective in the treatment of CLPD-NK remains to be further explored. What’s more, this highlights the essentiality of sequencing STAT3 gene and raisesthe necessity ofsystematic long-term follow-up studies.

8. Acknowledgements

The authors would like to thank Dr Qian Zhan and Dr Qing Li for their help with image acquisition.

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Tang X. Chronic Natural Killer Cell Lymphoproliferative Disorders Treated with Interferon-Α: A Case Report. Annals of Clinical and Medical Case Reports 2020