成人H3K27变异型弥漫性中线胶质瘤临床病理学分析

Diffuse midline glioma with H3K27 alteration in adults:a clinicopathological analysis

目的探讨成人H3K27变异型弥漫性中线胶质瘤(diffuse midline glioma,DMG)的临床病理特征、病理诊断及预后。方法收集南京医科大学第一附属医院2017—2022年收治的经病理确诊的20例成人H3K27变异型DMG,对其临床表现、组织学形态、免疫表型及分子遗传学改变进行分析总结,并复习文献。结果患者男女比例1∶1,发病年龄25~74岁,中位发病年龄为53岁,3例(3/20,15%)位于脑干,17例(17/20,85%)位于非脑干部位(其中胸腰髓3例,松果体1例)。临床表现无特异性,多为头晕头痛、视物模糊、记忆力下降、腰背痛、肢体感觉和/或运动障碍等。光镜下肿瘤呈浸润性生长,组织学分级WHO 2级3例,3级12例,4级5例,多呈星形细胞肿瘤形态,部分病例可见少突胶质细胞样、毛细胞样、上皮样等形态。免疫组织化学:肿瘤细胞均表达胶质纤维酸性蛋白、Olig2及H3K27M,H3K27me3均不同程度表达缺失,4例ATRX表达缺失,11例p53强阳性表达,Ki-67阳性指数5%~70%。分子检测:20例均存在H3F3A基因第1号外显子p.K27M突变,2例存在BRAF突变,分别为V600E和L597Q突变。随访1~58个月,结果示脑干与非脑干部位的病例生存时间(分别为6.0个月和30.4个月)差异具有统计学意义(P<0.05)。结论H3K27变异型DMG在各年龄段均可发生,成人较少见,以非脑干部位多见,脊髓病例主要位于胸腰髓段,组织形态学谱系较宽,以星形细胞分化为主,建议中线部位胶质瘤常规行H3K27me3免疫组织化学检测并对可疑病例行分子检测避免漏诊。本文报道1例伴BRAF L597Q突变,松果体区病例伴PPM1D突变。该肿瘤总体预后较差,发生于脑干部位的病例预后更差。

Objective To investigate the clinicopathological characteristics,pathological diagnosis and prognosis of diffuse midline glioma(DMG)with H3K27 alteration in adults.Methods Twenty cases of H3K27-altered adult DMG diagnosed in the First Affiliated Hospital of Nanjing Medical University were enrolled from 2017 to 2022.All cases were evaluated by clinical and imaging presentations,HE,immunohistochemical staining and molecular genetics;and the relevant literature was reviewed.Results The ratio of male to female was 1∶1,and the median age was 53 years(range from 25 to 74 years);the tumors were located in the brainstem(3/20,15%)and non-brainstem(17/20,85%;three in thoracolumbar spinal cord and one in pineal region).The clinical manifestations were non-specific,mostly dizziness,headache,blurred vision,memory loss,low back pain,limb sensation and/or movement disorders,etc.Microscopically,the tumors showed infiltrative growth,with WHO grade 2(3 cases),grade 3(12 cases),and grade 4(5 cases).The tumors showed astrocytoma-like and oligdendroglioma-like,pilocytic astrocytoma-like and epithelioid-like patterns.Immunohistochemically,the tumor cells were positive for GFAP,Olig2 and H3K27M,and H3K27me3 expression was variably lost.ATRX expression was lost in four cases,p53 was strongly positive in 11 cases.Ki-67 index was about 5%-70%.Molecular genetics showed p.k27m mutation in exon 1 of H3F3A gene in 20 cases;BRAF mutation in two cases:V600E and L597Q mutation in one case each.Follow up intervals ranged from 1 to 58 months,and the survival time for brainstem(6.0 months)and non-brainstem(30.4 months)tumors was significantly different(P<0.05).Conclusions DMG with H3K27 alteration is uncommonly found in adults,mostly occurs in non-brainstem,and can present in adults of all ages.Owing to the wide histomorphologic features,mainly astrocytic differentiation,routine detection of H3K27me3 in midline glioma is recommended.Molecular testing should be performed on any suspected cases to avoid missed diagnosis.Concomitant BRAF L597Q mutation and PPM1D mutation are novel findings.The overall prognosis of this tumor is poor,with tumors located in the brainstem showing worse outcome.