Clinicopathological Analysis And Prognostic Markers Of Extranodal NK/T Cell Lymphoma

ObjectiveThis study aimed to explore the clinicopathological features and prognostic correlation of extranodal natural killer(NK)/T-cell lymphoma(ENKTCL),and screen out the prognostic markers of ENKTCL,and to establish the molecular model of ENKTCL prognosis.MethodsA retrospective study was conducted in 99 patients from May 1999 to Dec.2013 in Chinese Academy of Medical Sciences Cancer Hospital,who were diagnosed with ENKTCL according to WHO lymphoid hematopoietic tumor classification(published in 2008).The clinical data and paraffin-embedded tissue blocks were collected.The expressions of CD56,MLH1,PDGFRA,VEGF,PD-L1,PD-1,CyclinD1,p53 and Ki-67 were detected by high-throughput tissue microarray and immunohistochemistry(IHC)staining.The relationship between nine protein expressions and the clinicopathological features and prognosis of patients with ENKTCL were analyzed.Results1.The survival time of the 53 patients with complete clinical and follow-up data was 0～189 months.The median survival time(MST)was 99.4 months,and the average survival time was 60.3 months.The survival rates of 1 year,2 years,3 year were respectively 81.1%,75.5%,67.9%.Single factor survival analysis showed that the increase of serum lactate dehydrogenase(LDH ≥240UI/L)before treatment was associated with poor prognosis,and there was a significant difference in survival rate between patients with elevated LDH levels and normal LDH levels before treatment(P =0.008).There was no statistical difference between epidemiological factors such as gender,age and other clinicopathological factors including tumor location,clinical stage,B symptoms,β2-microglobulin levels before treatment,therapy method and prognosis.2.Immunohistochemical staining showed the expressions of PDGFRA,CD56 and p53 in 53 cases with ENKTCL were respectively 75.5%(40/53),73.6%(39/53)and 73.6%(39/53).The positive expression rates of VEGF and PD-1 were only 24.5%(13/53)and 1.9%(1/53).In addition,the positive expression rate of MLH1 was 69.8%(37/53),the positive expression rate of PD-L1 was 62.3%(33/53)and the positive expression rate of CyclinD1 was 45.3%(24/53).The positive expression rate of Ki-67,more than 50%as the Ki-67 overexpression(≥50%),was 41.5%(22/53).3.Correlation analysis between 9 proteins and epidemiological factors and clinicopathological factors showed that the expression of PDGFRA protein was correlated with the level of LDH before treatment(P = 0.047).The expression of PD-L1 protein was correlated with the level of LDH and(32-microglobulin before treatment(P=0.047 and P<0.001).The expression of p53 protein was correlated with the level ofβ2-microglobulin before treatment(P<0.05).The expression level of Ki-67 protein was correlated with the sex of ENKTCL patients(P = 0.020).4.Survival analysis of single factor showed that the positive expression of PDGFRA,PD-L1 and p53 was respectively related to the poor prognosis of patients with ENKTCL(P = 0.028,0.049,0.032).The patients with Ki-67 overexpression(≥50%)had a worse prognosis than those with lower expression(<50%),and the difference of survival rate between the two groups has statistical significance(P=0.010).The expression of CD56,MLH1,VEGF,PD-1 and CyclinDl has no effect on survival rate(P>0.05).5.Multivariate survival analysis showed that the expression status of PDGFRA,PD-L1 and Ki-67 was an independent factor in the prognosis of patients with ENKTCL,and the positive expression of these 3 proteins was the risk factors for prognosis of patients with ENKTCL(PDGFRA:P = 0.047,HR = 0.226,95%CI:0.052-0.978.PD-L1:P = 0.018,HR = 0.294,95%CI:0.107-0.809.Ki-67:P= 0.015,HR = 0.339,95%CI:0.142-0.812).The expression status of p53 protein was not an independent factor in the prognosis of patients with ENKTCL(P = 0.181),but the positive expression of p53 protein suggested poor prognosis,which could be used as an adjunctive index(HR = 0.424;95%CI:0.121-1.489).Serum lactate dehydrogenase level before treatment was not an independent factor in the prognosis of patients with ENKTCL(P = 0.589),but the serum lactate dehydrogenase before treatment(LDH≥240UI/L)suggested poor prognosis,which could be also used as an adjunctive index(HR = 0.766;95%CI:0.291-2.015).Conclusion1.The elevation of serum lactate dehydrogenase(LDH ≥240UI/L)before treatment was associated with poor prognosis,which could be used as an adjunct index to the prognosis.However,it was not an independent factor for the prognosis of patients with ENKTCL.2.The expression of PDGFRA,PD-L1 and Ki-67 was an independent factor in the prognosis of patients with ENKTCL and these 3 proteins were risk factors of prognosis.The positive expression of P53 protein suggests poor prognosis,and p53 protein may be used as a supplementary indicator of prognosis.The above markers combined with clinical factors may establish the prognosis model of ENKTCL.