H3K27M突变型弥漫性中线胶质瘤39例临床病理特征及预后分析

Clinicopathological characteristics and prognostic analysis of 39 patients with H3K27M mutant diffuse midline glioma

目的探讨H3K27M突变型弥漫性中线胶质瘤(diffuse midline glioma,DMG)的临床病理特征、免疫表现及分子病理学改变,并分析其预后相关因素。方法选取2017年11月至2021年1月就诊于中山大学肿瘤防治中心的39例DMG患者,分析其临床病理特点,根据年龄、发病部位和组织病理学分级等因素分层,结合患者的治疗和随访资料,分析不同因素对患者预后的影响。结果39例DMG患者中,男24例,女15例,发病年龄28(3~69)岁。临床表现:累及丘脑的肿瘤多表现为头痛、恶心或嗜睡,累及脑干表现为步态不稳、肢体乏力,累及脊髓可表现为下肢麻木疼痛、无力、无法直立行走。组织病理学形态多样,主要表现为高级别胶质瘤,少见情况下呈毛细胞型星形细胞瘤和间变性室管膜瘤。肿瘤组织病理学分级WHOⅠ级2例(5.1%),Ⅱ级1例(2.6%),Ⅲ级2例(5.1%),Ⅳ级34例(87.2%)。WHOⅠ级患者年龄均>20岁,组织病理学呈毛细胞型星形细胞瘤样特征。39例行H3K27M免疫组织化学检测,38例弥漫表达H3K27M,1例仅个别瘤细胞表达;23例(82.1%,23/28)MGMT阳性表达;26例(70.3%,26/37)p53强阳性;29例(80.6%,29/36)ATRX表达缺失;Ki-67阳性指数1%~60%。39例(包括1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。所有病例IDH1基因检测均为阴性。13例发生颅内及脊髓播散。39例患者平均总生存期(12.1±8.0)个月。Log-rank单因素分析结果显示,性别、组织病理学分级、颅内/脊髓播散转移是DMG患者总生存期的影响因素(P<0.05)。Cox回归分析结果显示,颅内/脊髓播散转移是DMG患者总生存期的独立影响因素(P<0.05)。结论H3K27M突变型DMG好发于儿童和青少年,呈浸润性生长,好发的中线部位是丘脑、脑干和脊髓。组织病理学可表现为WHOⅠ~Ⅳ级样肿瘤,毛细胞型星形细胞瘤样病变在成人中更多见。

Objective To investigate the clinicopathological characteristics,immune manifestations,and molecular pathological changes of H3K27M mutant diffuse midline glioma(DMG),and to analyze the prognostic factors of DMG patients.Method A total of 39 DMG patients in the Sun Yat-sen University Cancer Center from November 2017 to January 2021 were collected,and their clinicopathological characteristics were analyzed.They were stratified according to factors such as age,location of onset,and histological grade,combined with patient treatment and follow-up data.Analyze the influence of different factors on the prognosis of patients.Result Among 39 patientsdd with DMG,24 were males and 15 were females.The average age of onset was 28(3-69)years old.The clinical manifestations mainly depended on the location of the tumor.The tumors involved in the thalamus were mostly headache,nausea or drowsiness.The brainstem is manifested as unstable walking and weakness of the limbs,and the spinal cord may be manifested as numbness and pain in the lower limbs,weakness,and inability to walk upright.Histologically,the morphology is diverse,mainly high-grade glioma,and in rare cases,pilocytic astrocytoma and anaplastic ependymoma.Tumor histological grading:WHO grade Ⅰ 2 cases(5.1%),grade Ⅱ 1 case(2.6%),grade Ⅲ 2 cases(5.1%),gradeⅣ34 cases(87.2%).The WHO grade I patients were all>20 years old,and the histology shows pilocytic astrocytoma-like features.Immunohistochemistry showed the expression of tumor cells to varying degrees.39 cases underwent H3K27M immunohistochemical detection,38 cases diffusely expressed H3K27M,1 case only expressed in individual tumor cells;23 cases(82.1%,23/28)had positive expression of MGMT;26 cases(70.3%,26/37)p53 is strongly positive;29 cases(80.6%,29/36)lack ATRX expression;Ki-67 positive index is 1%-60%.Genetic testing of 39 cases(including 1 individual H3K27M expressor)showed that the H3F3A gene had a K27M mutation.IDH1 was negative in all cases.Intracranial and spinal cord dissemination occurred in 13 cases.The average overall survival time of 39 patients was(12.1±8.0)months.Univariate log-rank analysis showed that gender,histopathological grade and intracranial/spinal metastasis were the influencing factors for overall survival of DMG patients(P<0.05).Cox regression analysis showed that intracranial/spinal cord metastasis was an independent factor influencing the overall survival of DMG patients(P<0.05).Conclusion The H3K27M mutant DMG is more likely to occur in children and adolescents,with invasive growth.The most common midline sites are the thalamus,brainstem,and spinal cord.Histology can be manifested as WHO grade Ⅰ to Ⅳ tumors,and pilocytic astrocytoma-like lesions are more common in adults.Detection of mutations in the H3K27M gene can guide clinical treatment of patients with diffuse midline glioma.