间变星形细胞少枝胶质细胞肿瘤分子病理亚型分类研究

A molecular classification system for anaplastic glioma

目的 探讨应用分子标记物拟对间变星形细胞少枝胶质细胞肿瘤进行分子病理亚型分类.方法 回顾性研究2009年5月至2011年6月手术治疗、具有完整病历记录及可靠随访资料的原发性WHO Ⅲ级间变性胶质瘤患者共161例临床资料.其中男性100例,女性61例;年龄17～68岁,平均（43±12）岁.组织学病理均通过2位资深病理科专家会诊确定,其中间变少枝胶质细胞瘤（AO）36例、间变少枝星形细胞瘤（AOA） 66例、间变星形细胞瘤（AA）59例.手术全切除116例,次全切除37例,部分切除8例.分子标记物包括：1p/19q、IDH1、O6-甲基鸟嘌呤-DNA甲基转移酶（MGMT）.生存分析采用Kaplan-Meier计算生存率,并采用Log-rank检验进行生存率比较.结果 生存分析结果显示：AO患者术后各时间点无进展生存率及总体生存率均显著优于AOA（x2=12.812和6.557,P＜0.05）及AA（x2=19.125和10.206,P＜0.05）,而AOA与AA间差异无统计学意义（P＞0.05）.依据分子标记物1p/19q、IDH1、MGMT表达状态,AOA可细分为2个亚型AOA1和AOA2;AOA1具备1p/19q联合缺失、IDH1突变、MGMT阴性表达中的1个或1个以上预后良好因子,其生存期与AO患者比较差异无统计学意义（P ＞0.05）;AOA2不具备1p/19q联合缺失、IDH1突变、MGMT阴性表达中任何1个预后良好因子,其生存期与AA比较差异无统计学意义（P＞0.05）.AO＋ AOA1组患者术后各时间点无进展生存率（x2=25.180,P＜0.001）及总体生存率（x2=15.649,P＜0.001）均优于AA＋ AOA2组.多因素分析结果显示分子病理亚型分类为预后的独立影响因子（无进展生存率：OR =0.499,95％ CI：0.381 ～0.653,P＜0.001;总体生存率：OR=0.605,95％ CI：0.450 ～0.814,P=0.001）.结论 此针对间变星形细胞少枝胶质细胞肿瘤的分子病理亚型分类可协助对间变性胶质瘤患者预后进行评估,指导临床更加合理的个体化治疗.

Objective To project a new molecular classification system for anaplastic gliomas based on the molecular biomarkers.Methods There were 161 patients with histological diagnosis of primary anaplastic gliomas after operation and complete and reliable follow-up data were enrolled in the study from May 2009 to June 2011.A total of 100 male and 61 female patients with a median age of （43 ± 12） years （range：17-68 years）.After the pathology review by 2 experienced neuro-pathologists,36 anaplastic oligodendroglioma （AO）,66 anaplastic oligoastrocytoma （AOA） and 59 anaplastic astrocytoma （AA） were confirmed.There were 116 patients underwent gross-total resection,37 sub-total resection and 8 partial resection.Molecular biomarkers evaluated included 1p/19q,IDH1 gene and O6-methylguanine-DNA-methyltransferase （MGMT）.Kaplan-Meier plots were compared by Log-rank method.Results The survival analysis results showed that the 6-month,12-month,18-month and 24-month progression-free survival （PFS） and overall survival （OS） rates of AO was significantly longer than AOA（x2 =12.812 and 6.557,P ＜ 0.05） and AA （x2 =19.125 and 10.206,P ＜ 0.05）,but no significant difference of prognosis was observed between AOA and AA （P ＞ 0.05）.According to the status of biomarkers,AOA was reclassified into two subgroups-AOA1 and AOA2.AOA1 with 1p/19q co-deletion,IDH1 mutation and/or negative MGMT expression showed similar prognosis with AO （P ＞ 0.05）.AOA2 without any biomarkers showed similar prognosis with AA （P ＞ 0.05）.Besides,the 6-month,12-month,18-month and 24-month PFS and OS rates of patients with AO and AOA1 was significantly longer than patients with AA and AOA2 （PFS：x2 =25.180,P ＜ 0.001 ; OS：x2 =15.649,P ＜ 0.001）.Multivariate analysis showed that the moecular pathology subtypes classified was an independent prognostic factor （PFS：OR =0.499,95％ CI：0.381-0.653,P ＜ 0.001 ; OS：OR =0.605,95％ CI：0.450-0.814,P =0.001）.Conclusions The molecular classification system for anaplastic gliomas will be helpful in estimating patients＇ prognosis and guiding reasonable therapy for patients with anaplastic gliomas.