Preliminary Exploration Of Clinical Features And Prognosis Of Epstein-barr Virus-associated T/Natural Killer-Cell Lymphoproliferative Diseases Patients

Objectives:The clinical features,treatment and outcomes of Epstein-Barr virus-associated T/natural killer-cell lymphoproliferative diseases(EBV-T/NK-LPDs)patients were preliminarily analyzed.Methods:The clinical data of 11 EBV-T/NK-LPDs patients who were diagnosed from the Second Affiliated Hospital of Kunming Medical University between March 2013 and October 2020 were retrospectively analyzed.Results:1.Clinical features:1.1 Age of onset:14-58,median age 24;1.2 Gender:5 males(45.45%),6 females(54.55%);1.3 Clinical manifestations:recurrent or persistent fever(10 cases,90.9%),splenomegaly(10 cases,90.9%),superficial lymph node enlargement(8 cases,72.7%),skin damage(4 cases,36.4%),hepatomegaly(4 cases,36.4%);1.4 Secondary hemophagocytic syndrome(6 cases,54.5%).2.Laboratory characteristics:2.1 Leukopenia was found in 9 cases(81.8%),thrombocytopenia in 6 cases(54.5%),lactate dehydrogenase in 6 cases(54.5%),both anemia and liver dysfuction in 4 cases(36.4%);2.2 EBV-DNA detection:all patients were positive for EBV-DNA in peripheral blood,with a median of 2.76×105 copies/ml(3.89x103～4.07×107 copies/ml);2.3 EBV-DNA sorting nucleic acid:only one patient received the test,with the results suggesting that EBV-T-DNA 4.12 × 103 copies/ml,EBV-B-DNA 1.5 × 103 copies/ml and EBV-NK-DNA 7.98 × 103 copies/ml;2.4 Detection of lymphocyte subsets infected with EBV:only one patient received the test,with the results indicating that CD3+CD4+cells 7.9×103 copies/ml,CD56+cells 3.7×103 copies/ml,and CD3+CD8+and CD3+CD19+positive cells undetected.3.Histopathological features:3.1 Bone marrow cytology:all cases were proliferative myelogram,and blood phagocytosis was detected in 6 cases(54.5%);3.2 Lymph node tissue:Lymphoid biopsy was performed in 6 cases,and pathological examination was characterized by certain reactive inflammatory changes,including lymphoid hyperplasia(5 cases),lymphoid hyperplasia with focal necrosis(1 case),small-to-medium sizes of proliferative lymphoid cells,irregular karyotype and mild-to-moderate atypia;3.3 Skin tissue:2 cases underwent skin biopsy,1 case manifested a scattered distribution of a few suspected heteromorphic cells in the background of cutaneous panniculitis,1 case indicated an infiltration of lymphoid cells and monocytes around the blood vessels,and some cells were slightly atypical;3.4 Gastrointestinal mucosal tissue:Gastroduodenal microscopic examination and mucosal biopsy were performed in 2 cases,with one showing a massive lymphocyte infiltration in the mucosal glandular stroma,and another manifesting a local intestinal mucosa with low-grade intraepithelial neoplasia and an interstitial infiltration of acute and chronic inflammatory cells;3.5 Brain tissue:brain biopsy in 1 case presented lymphoid tissue hyperplasia with focal necrosis,a consistent distribution of medium-sized lymphocytes and an infiltration around the blood vessels;3.6 Liver tissue:liver biopsy in 1 case indicated a fatty degeneration of hepatocytes,and cholestasis of hepatocytes with scattered lymphocytes in hepatic sinusoids.4.Immunohistochemistry:immunohistochemical staining showed a T-cell phenotype in 7 of 11 cases,including 3 cases with CD4+CD8+,3 cases with CD3+CD56-,and 1 case with CD3+CD4+;4 cases had an NK-cell phenotype,and the immunophenotype was CD3-CD56+.5.Molecular biology:5.1 EBER in situ hybridization detection:all test results of 9 cases were positive;5.2 TCR gene rearrangement:7 cases were successfully analyzed,and all of them were polyclonal.6.Treatment intervention and outcome:6.1 Treatment regimen:of the 11 cases,7 received chemotherapy and 3 received immunomodulatory therapy;6.2 Treatment response:6.2.1 Immunomodulatory therapy:2 patients only received immunotherapy and all died.1 patient initially received immunomodulatory therapy and progressed after self-withdrawal.Then received CHOP regimen chemotherapy,and PR was evaluated after 2 courses of chemotherapy.6.2.2 Chemotherapy:7 patients were assessed after 2 courses of chemotherapy:PR(2 cases),SD(4 cases),PD(1 cases);5 patients were assessed after 4 courses of chemotherapy:CR(1 case),PR(3 cases),PD(1 case);6.3 Outcome:the median follow-up period was 9 months(2-40 months),of which 2 patients survived,8 patients died,and 1 patient lost follow-up.Following the last follow-up,2 patients survived and 1 patient evaluated SD,1 estimated PR.Conclusions:1.EBV-T/NK-LPDs has a strong clinical invasiveness.The onset age of the patients is relatively young,and there is no significant difference between men and women.The most typical clinical features include recurrent or persistent fever,splenomegaly,systemic superficial lymph node enlargement,skin lesions and hemophagocytic syndrome.2.The EBV-DNA load in the peripheral blood of patients with EBV-T/NK-LPDs increases in varied degrees.Most of the pathological changes in the involved organs manifest reactive inflammation,with a slight increase in number of lymphocytes,small-to-medium cell size,irregular karyotype,and mild-to-moderate atypia.3.EBER is positive in all patients with EBV-T/NK-LPDs,and most TCR rearrangements are polyclonal.4.The case fatality rate of EBV-T/NK-LPDs is still high,and prognosis is poor.Presently,there is no standard treatment plan;the corresponding chemotherapy regimen is primarily based on anthracycline+etoposide+hormone approach,but it still cannot significantly improve patients’survival.