H3K27M突变型弥漫性中线胶质瘤30例临床病理学特征和预后分析

Clinicopathological characteristics and prognosis of diffuse midline gliomas with histone H3K27M mutation: an analysis of 30 cases

目的探讨H3K27M突变型弥漫性中线胶质瘤(DMG)的临床病理特征,并分析DMG患者预后相关因素。方法收集广东三九脑科医院2016年10月至2018年5月确诊的30例DMG,分析其临床病理特点,根据年龄、发病部位和组织学分级等因素分层,结合患者治疗和随访资料,分析不同因素对患者预后的影响。结果 30例DMG,男性21例,女性9例,平均诊断年龄26岁(5~53岁);丘脑发病14例,脑干发病12例(其中1例同时累及丘脑),鞍区、下丘脑、第四脑室各1例,多部位弥漫性中线病变2例。肿瘤组织学分级WHOⅠ级3例(10.0%),Ⅱ级10例(33.3%),Ⅲ级8例(26.7%),Ⅳ级9例(30.0%)。WHO Ⅰ级患者年龄均>20岁,组织学呈现毛细胞星形细胞瘤样特征。免疫组织化学检测显示所有病例IDH1均为阴性;28例弥漫表达H3K27M,2例仅个别瘤细胞表达;H3K27me3在21例表达缺失(21/21,100.0%);16例(57.1%,16/28)p53强阳性;8例(38.1%,8/21)ATRX表达缺失;Ki-67阳性指数5%~40%。8例(包括2例H3K27M个别细胞表达者)行基因检测均显示H3F3A基因发生K27M突变。6例(20.0%,6/30)在治疗过程中发生颅内及脊髓播散。30例患者中位无进展生存期为9.5个月,中位总生存期34.0个月,平均无进展生存时间11.2个月,平均总生存时间24.3个月。儿童/青少年(≤20岁)与成人(>20岁)相比较,中位总生存期(8个月比34个月)均明显缩短(P=0.013),中位无进展生存期(6个月比11个月),两者差异无统计学意义。肿瘤位于脑干/丘脑与其他中线部位、WHO不同分级的无进展生存期和总生存期差异无统计学意义(均P>0.05)。结论 DMG多见于儿童和青少年,男性多见,好发的中线部位是丘脑和脑干。组织学可表现为WHO Ⅰ~Ⅳ级样肿瘤,毛细胞星形细胞瘤样病变在成人更多见。肿瘤细胞表达H3K27M同时伴有H3K27me3表达缺失有助于诊断DMG。儿童/青少年患者预后明显较成人差,组织学分级和肿瘤部位对预后的影响无统计学意义。

Objective To analyze the clinicopathological characteristics and prognosis of diffuse midline glioma (DMG) with H3K27M mutation.Methods Thirty cases of DMG were collected in Guangdong Sanjiu Brain Hospital from October 2016 to May 2018. The patients′ clinicopathological data including age, tumor site and histological grade, treatment and follow-up data were collected and analyzed.Results There were 21 males and 9 females, with a mean age of 26 years (range 5-53 years). Fourteen tumors were located in thalamus, 12 in brainstem (one involved both thalamus and brainstem), and one each in hypothalamus, fourth ventricle, and sellar region, respectively. Two cases presented as diffuse intracranial lesions. Three cases (10.0%) were of WHO grade Ⅰ, 10 cases (33.3%) were grade Ⅱ, eight cases (26.7%) were grade Ⅲ, and nine cases (30.0%) were grade Ⅳ.All patients with gradeⅠ tumors were older than 20 years. Histologically, all were pilocytic astrocytoma-like. Immunohistochemical staining demonstrated that all tumors were IDH1 negative. Twenty-eight tumors showed diffuse expression of H3K27M, and two showed focal expression. Twenty-one tumors(100.0%, 21/21) showed absent expression of H3K27me3. Sixteen tumors (57.1%, 16/28) showed strongly positive expression of p53, and ATRX was negative in eight tumors (38.1%, 8/21). The Ki-67 proliferation index ranged from 5% to 40%. Eight cases (including two cases of H3K27M expression of individual cells) showed K27M mutation in H3F3A gene. Intracranial and spinal cord dissemination occurred in six cases (20.0%, 6/30). Median progression-free survival (PFS) was 9.5 months and median overall survival (OS) was 34 months. Mean PFS was 11.2 months and mean OS was 24.3 months. Compared with adults (>20 years old), children/adolescents (no more than 20 years old) had significantly shorter median OS (8 months vs. 34 months, P=0.013). There was no significant difference in PFS and OS between DMGs located in the brain stem/thalamus and other sites within midline (P>0.05). There was no significant difference in PFS and OS between WHO grade ⅠDMGs and WHO grade Ⅱ-Ⅳ DMGs (P>0.05).Conclusions DMGs occur more commonly in children and adolescents with male predominance. DMGs present with WHO Ⅰ-Ⅳ tumors morphologically, and pilocytic astrocytoma-like lesions with WHO Ⅰ are more common in adults. Expression of H3K27M but not H3K27me3 is helpful for diagnosis of DMG. The prognosis of children/adolescents is significantly worse than that of adults, whereas histological grade and tumor location do not affect prognosis.