A Study Of Clinical Pathological Features And EGFR, HER-2, β-catenin Expressions In Pediatric Central Nervous Small Cell Tumors

【Objective】Central nervous system(CNS) tumors are the most common solid tumors that occur in children,and the incidence is increasing year by year.Our research focused on pediatric CNS small cell tumors,which include medulloblastoma(MB),small cell glioblastoma(GB) and PNET.Our assey was to study the pathological features of childhood central nervous system(CNS) tumors,and to analyze the clinical and pathological features that might have relationships with small cell tumors prognosis. Moreover,the research was to focus on detecting the protein expressions of EGFR,HER-2,β-catenin and gene amplification of HER-2,and discussing the potential roles they might play in the tumorigenesis and the relathionships they have with the prognosis.【Methods】According to the 2007 WHO classification of the tumors of the nervous system,a retrospective analysis were performed on children(age≤16 years) diagnosed as CNS tumors in Qilu Hospital,Shandong University from 1995 to 2007.Statistics analysis and 12-year survival analysis were employed in epidemiological and clinical treatment datas of CNS small cell tumors between 1996 and 2008.The expression of EGFR,HER-2, ki-67,β-catenin were detected by immunohistochemistry.The fluorescence in situ hybridization(FISH) have been used to observe the amplification of HER-2 gene in tumor cells.All datas were analyzed by the SPSS 13.0 software for windows.【Results】1.330 cases(196 males and 134 females) were diagnosed as CNS tumors over 13 years. It accounted for 6.89%of total 4,788 cases in Qilu hospital during the same period. There were 299 cases of intracranial tumors,among which the supratentorial tumors were 192 cases and infratentorial tumors were 107 cases.There were 31 cases of intraspinal tumors.The top three histological types were:astrocytoma in 94(28.48%), embryonal tumors in 58(17.58%) and craniopharyngioma in 49(14.85%).Most of the pediatric CNS tumors are the low grades(gradeⅠorⅡ),except embryonal tumors and germ cell tumors.2.71 cases of CNS small tumors were diagnosed,including 44 cases of MB,19 cases of small cell GB and 8 cases of PNET.The average ages were 10,11.4 and 10.5 years old respectively.The male to female sex ratios were 1.59:1,2.17:1 and 1:1.The rates of surgical total resection in MBs,small cell GBs and PNETs respectively were 50%, 36.84%and 50%.The children who received postoperative PFI and CSI radiotherapy of three groups were 17 cases(38.64%),7 cases(36.84%) and 4 cases(50%). Follow-up survey was employed in 71 cases,among which 65 cases were followed. The follow-up rate was 91.55%.45 patients died,and 20 cases survived.The mean follow-up time was 84 months(range,4 to 156 months).Median survival times of MBs, GBs and PNETs were 23±6.7months,8±4.7months and 10±1.4months.3.Necrosis was obeserved in 20 cases of MBs,among which 12 cases had large-area necrosises.Tumor necrosis was observed in every cases of small cell GBs,among which 14 cases owned small-area necrosises.Large-area necrosises were observed in 4 cases of PNETs.The single-factor survival analysis demonstrated the children with turnors necrosis,especially large-area necrosis,had poor outcomes(P＜0.05). Angiogenesis,glial differentiation and rosette structure has no relationship to outcome in three groups(P＞0.05).4.There was no statisitical difference between the ki67 expressions of MBs,small cell GB and PNET(P＞0.05).The single-factor survival analysis demonstrated ki67 was no related to prognosis of three groups(P＞0.05).The mitotic counts of MBs,PNETs and small cell GBs varied over a broad range(5～50/10HPF).The mitotic counts of MBs, small cell GBs and PNETs were 6.81,6.33 and 10/10HPF on average respectively.The overall survival time of three groups had no relationship with the mitotic counts (P＞0.05).The expression of ki67 was associated with mitotic counts in MBs and small cell GBs(P＜0.05). 5.There was no statistical distinction between the EGFR expressions of every subtypes (P＞0.05).The single-factor survival analysis suggested that the overexpression of EGFR predicted poor prognosis in three groups(P＜0.05).No positive expression of HER-2 was detected in all cases.6.There is no statistical distinction between the cytoplasmicβ-catenin expressions of every subtypes(P＞0.05).The overexpression ofβ-catenin in cytoplasm predicted poor progrosis in three groups(P＜0.05).The expression of nuclears occoured in about 38.24%,6.67%and 28.57%of MBs,small cell GBs and PNETs.The nuclear expression ofβ-catenin had been associated with a favourable prognosis(P＜0.05). Moreover,a significant negative correlation was found between cytoplasmic and nuclear expression(spearman correlation coefficient -0.6417,P=0.000043).The nuclear expression ofβ-catenin was not related with outcome of PNETs,however two distict nuclear staining patterns were observed,whose survival time had overpassed 4.5 years.The nuclear expression ofβ-catenin is no related with outcome of small cell GBs.7.Fluorescence in situ hybridization was employed to detect the HER-2 gene in 10 cases MBs.No amplifications of HER-2 gene were observed in every cases.8.The multi-factor Cox regression analysis suggested that the negative prognostic factors of MBs included the overexpression of EGFR,the high expression ofβ-catenin in cytoplasm and necrosis.The positive factors were the expression ofβ-catenin in nuclei and radiotherapy.The necrosis and the overexpression of EGFR were emerging as the negative factors in small cell GBs,and radiotherapy predicted good outcome. The overall survival times were shorter in PNETs cases with the necrosis and the overexpression of EGFR.The expression ofβ-catenin in nuclei and radiotherapy were associated with a favourable prognosis.【Conclusions】1.Astrocytoma,embryonal tumors and craniopharyngioma are the most common types of CNS minors in childhood.The incidence is male predominant.The incidence of CNS tumors is increasing with age.2.The incidences are male predominant in MBs and small cell GBs,and there is no significant sex distinction in PNETs.The three tumor types are high grade and have poor prognosis.3.The significant favourable prognosis factor is whole neuraxis radiotherapy in every groups.4.Tumor necrosis predicts poor outcomes of MBs,small cell GBs and PNETs.The vascular proliferation,glial differentiation and rosette have no relationships with the prognosis.5.The expression of ki67 and mitotic counts have no significant relationships with the prognosis.6.The positive expression rates of EGFR are high in MBs,PNETs and small cell GBs. This data suggest the hypothesis that EGFR signalling might play particular significant role in the tumorigenesis of MBs and small cell GBs.The overexpression of EGFR has been associated with poor prognosis in three types,so EGFR could be prognostic marker of central nervous small cell tumors.7.No expression and amplification of HER-2 in every case.Whether this gene contribute to the development or progression of central nervous small cell tumor remains to be determined.8.The high expression ofβ-catenin in cytoplasm has been associated with a poor clinical outcomes of MBs,GBs and PNETs.The nuclear expression ofβ-catenin predicts favourable outcome of MBs.These datas interpret that Writ signalling might have a role in MBs,PNETs and small cell GBs formation.β-catenin could be prognositic marker of central nervous small cell tumors.