Study On The Grading And Prognosis Of CD24 And PRAME In Pineal Parenchymal Tumors Of Intermediate Differentiation

BACKGROUND:The pineal parenchymal tumors of intermediate differentiation(PPTIDs)are extremely rare tumor entities of central nervous system(CNS).According to the classification criteria of World Health Organization(WHO),They exhibit low risk(grade Ⅱ)and high risk(grade Ⅲ)malignancies,which may lead to different therapies and prognosis.However,the criteria of WHO for grading PPTID remains elusive,and the relevance of these criteria,including mitotic count,Neurofilament protein(NF)immunoexpression,and Ki-67 proliferation index,is still controversial.In 2006,a cDNA study of brain tumors showed that Cluster of differentiation 24(CD24),Preferentially expressed antigen in Melanomas(PRAME),POU Class 4 Homeobox 2(POU4F2)and Homeobox protein D13(HOXD13)were deleted or very low expressed in Pineocytoma(PC),PPTIDs grade Ⅱ,normal pineal gland and brain tissues,while these four genes were significantly elevated in pineoblastoma(PB)and PPTIDs gradeⅢ.Therefore,through the analysis of the expression and prognosis of biomarkers(CD24,PRAME,POU4F2 and HOXD13)which are helpful to distinguish PPTIDs grade,we can find out the biomarkers which are useful for PPTID grade and prognosis,so as to provide more reliable evidences for the prognosis and treatment of PPTIDs patients.METHODS:Twenty-nine cases of PPTIDs with complete clinical and prognostic information between Jan 2008 and Dec 2017 were collected in Nanfang Hospital,Southern Medical University and General Hospital of Southern Theater Command,People’s Liberation Army of China.At the same time,cases of PC,PB,diffuse astrocytoma(DA),anaplastic astrocytoma(AA),glioblastoma(GB)and medulloblastoma(MB)are collected too.Immunohistochemical staining for CD24,PRAME,POU4F2 and HOXD13 and their clinicopathologic analyses were performed in pineal parenchymal tumors of intermediate differentiation and other tumors in the pineal region.Using the x 2 test or the Spearman rank test assesses the correlations between expression of biological indicators and clinicopathologic parameters.We use the ROC curve to assess the sensitivity and specificity of CD24 and PRAME for PPTIDs’ grade diagnosis,and the cut-off value for grade diagnosis.Progression-free survival(PFS)and overall survival(OS)were estimated using the Kaplan-Meier method and compared using log-rank tests.RESULTS:1.CD24 and PRAME were expressed in 9/11(81.8%)and 8/11(72,7%)cases of PPTIDs grade Ⅲ,compared to 6/18(33.3%)and 5/18(27.8%)cases of PPTIDs gradeⅡ.The levels of CD24 and PRAME were significantly higher in PPTIDs grade Ⅲthan grade Ⅱ(p=0.02 1,p=0.027 respectively).However,there were no differences of HOXD13 and POU4F2 expression levels in PPTIDs grade Ⅱ and grade Ⅲ(p=0.671,p=1.000 respectively).Patients with high expression levels of CD24 and PRAME exhibited a significant shorter survival time(p=0.049,p=0.004 respectively)by univariate prognostic analysis.2.Campared to low-grade tumors of central nervous system(including PC,DA and AA),high expression of CD24 and PRAME were prevalently found in high-grade tumors of central nervous system(including PB and MB).By the ROC curve,the sensitivity and specificity of CD24 and PRAME in the diagnosis of PPTIDs was 81.8%and 72.7%,66.7%and 72.2%respectively.3.The PPTIDs grading results of CD24 and PRAME were basically consistent with the WHO criteria.Case15 was diagnosed as PPTIDs Ⅱ according to the histological grading criteria of WHO,but CD24 was strongly positive in the tumor cells of this case,while PRAME was locally positive in the tumor cells of this case.According to the follow-up data,the patient had tumor recurrence 6 months after operation and survived for 16 months,which suggested a poor prognosis,and his biological behavior was more inclined to PPTIDs grade Ⅲ.Case21 was diagnosed as PPTIDs Ⅲ according to WHO histological grading criteria,but CD24 and PRAME were negative in the tumor cells of this patient.The patient survived for 20 months without recurrence,and the prognosis was good,suggesting that its biological behavior was more inclined to PPTIDs grade Ⅱ.According to the results above,we found that the combination of CD24 and PRAME expression for grading PPTIDs might be more valuable than WHO criteria only.CONCLUSIONS:CD24 and PRAME are novel markers for grading and prognostic evaluation of PPTIDs,and their expressions are highly consistent with WHO ’s PPTIDs grading criteria.At the same time,the expressions of CD24 and PRAME may be important supplementary indicators of the grading criteria,that may be helpful to determine therapeutic decision for PPTIDs patients.