儿童弥漫性中线胶质瘤伴H3 K27改变95例临床病理分析

doi:10.12372/jcp.2023.22e0347

摘要/Abstract

摘要：

目的探讨儿童弥漫性中线胶质瘤伴H3 K27改变的临床病理特征。方法回顾性分析2016年9月至2021年7月首次诊断为弥漫性中线胶质瘤伴H3 K27改变患儿的临床和病理资料。结果共纳入95例患儿，男54例、女41例，中位年龄6.0（5.0~9.0）岁；脑干为好发部位（82.1%）。肿瘤WHO组织学分级1~4级皆有分布，以高级别胶质瘤为多数（65.3%）。免疫组织化学检测显示所有病例的H3 K27M（组蛋白H3第27位赖氨酸改变为甲硫氨酸）均为阳性表达，89.0%患儿的H3 K27Me3（组蛋白H3第27位赖氨酸的三甲基化）表达下降。55.6%患儿表达突变型肿瘤蛋白53（P53）；异柠檬酸脱氢酶1（IDH1）表达率和α地中海贫血/智力低下综合征X 连锁（ATRX）表达缺失率均低，分别为8.5%和18.6%；而鼠类肉瘤滤过性病毒致癌同源体B1（BRAF）仅有1例表达（1.2%）。47.1%（8/17）患儿出现O-6-甲基鸟嘌呤-DNA甲基转移酶（MGMT）基因甲基化阳性。2.1%（1/48）患儿发生BRAF基因变异。结论弥漫性中线胶质瘤伴H3 K27改变患儿的好发部位为脑干，组织学分级以高级别为多数，ATRX蛋白缺失率较低，且与肿瘤发生部位无关。

关键词: 弥漫性中线胶质瘤伴H3 K27改变, 临床病理, 儿童

Abstract:

Objective To investigate the clinicopathological characteristics of pediatric H3 K27-altered diffuse midline gliomas (DMG). Methods The clinical and pathological data of children first diagnosed with H3 K27-altered DMG from September 2016 to July 2021 were retrospectively analyzed. Results A total of 95 patients (54 boys and 41 girls) were included, and the median age was 6.0 (5.0-9.0) years. Brainstem was the predilection site (82.1%). WHO histological grade 1-4 tumors were found in all cases and high-grade gliomas were found in most cases (65.3%). Immunohistochemical detection showed that H3 K27M (the 27th lysine of histone H3 changed to methionine) was positively expressed in all cases, and H3 K27Me3 (the trimethylation of the 27th lysine of histone H3) was decreased in 89.0% of the children. Mutant p53 (P53) was expressed in 55.6% of the children. The expression rate of isocitrate dehydrogenase 1 (IDH1) and loss expression rate of alpha-thalassemia/mental retardation syndrome X-linked (ATRX) were low (8.5% and 18.6%, respectively). V-Raf murine sarcoma viral oncogene homolog B1 (BRAF) was positive in only 1 case (1.2%). Molecular tests showed that O-6-methylguanine-DNA methyltransferase (MGMT) methylation was detected in 8 cases (47.1%, 8/17), and BRAF variation was detected in 1 case (2.1%, 1/48). Conclusions The commonest location of H3 K27-altered DMG children is the brainstem, and the histological grade is mostly high. ATRX loss in pediatric cases is less common and had no relationship with the tumor location.

Key words: H3 K27-altered diffuse midline glioma, clinicopathological characteristics, child

周琦, 王佳, 李金华. 儿童弥漫性中线胶质瘤伴H3 K27改变95例临床病理分析[J]. 临床儿科杂志, 2023, 41(3): 210-214.

ZHOU Qi, WANG Jia, LI Jinhua. Clinicopathological characteristics of H3 K27-altered diffuse midline gliomas: an analysis of 95 pediatric cases[J]. Journal of Clinical Pediatrics, 2023, 41(3): 210-214.

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参考文献 16

[1]	Hawkins C, Ellison DW, Sturm D. Diffuse midline glioma, H3 K27M-mutant[M]// Louis DN, Ohgaki H, Wiestler OD, et al. The 2016 WHO classification of tumors of the central nervous system (4th ed). Lyon: IARC, 2016: 57-59.
[2]	WHO Classification of Tumours Editorial Board. The 2021 WHO classification of tumors of the central nervous system (5th ed)[M]. Lyon: IARC, 2021.
[3]	马东林, 姚晶晶, 尹洪芳. 弥漫中线胶质瘤伴H3 K27M突变的研究进展[J]. 中华病理学杂志, 2018, 47(4): 314-317.
[4]	Chi AS, Tarapore RS, Hall MD, et al. Pediatric and adult H3 K27M-mutant diffuse midline glioma treated with the selective DRD2 antagonist ONC201[J]. J Neurooncol, 2019, 145(1): 97-105. doi: 10.1007/s11060-019-03271-3
[5]	曹亚先, 王芮, 陈臻, 等. 儿童弥漫性中线胶质瘤,H3K27M 突变型的MRI 表现[J]. 影像诊断与介入放射学, 2020, 29(5): 343-348.
[6]	Ferris SP, Hofmann JW, Solomon DA, et al. Charac-terization of gliomas: from morphology to molecules[J]. Virchows Arch, 2017, 471(2): 257-269. doi: 10.1007/s00428-017-2181-4
[7]	Huang T, Garcia R, Qi J, et al. Detection of histone H3 K27M mutation and post-translational modifications in pediatric diffuse midline glioma via tissue immunohistochemistry informs diagnosis and clinical outcomes[J]. Oncotarget, 2018, 9(98): 37112-37124. doi: 10.18632/oncotarget.26430 pmid: 30647848
[8]	Wang L, Li Z, Zhang M, et al. H3 K27M-mutant diffuse midline gliomas in different anatomical locations[J]. Hum Pathol, 2018, 78: 89-96. doi: S0046-8177(18)30144-8 pmid: 29727696
[9]	Schulte JD, Buerki RA, Lapointe S, et al. Clinical, radiologic, and genetic characteristics of histone H3 K27M-mutant diffuse midline gliomas in adults[J]. Neurooncol Adv, 2020, 2(1): vdaa142.
[10]	李海南, 山常国, 范冲竹, 等. 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[J]. 中华病理学杂志, 2019, 48(3): 192-198.
[11]	Castel D, Kergrohen T, Tauziede-Espariat A, et al. Histone H3 wild-type DIPG/DMG overexpressing EZHIP extend the spectrum diffuse midline gliomas with PRC2 inhibition beyond H3-K27M mutation[J]. Acta Neuropathol, 2020, 139(6): 1109-1113. doi: 10.1007/s00401-020-02142-w pmid: 32193787
[12]	Erker C, Lane A, Chaney B, et al. Characteristics of patients≥ 10 years of age with diffuse intrinsic pontine glioma: a report from the International DIPG registry[J]. Neuro Oncol, 2022, 24(1): 141-152. doi: 10.1093/neuonc/noab140
[13]	Enomoto T, Aoki M, Hamasaki M, et al. Midline glioma in adults: clinicopathological, genetic, and epigenetic analysis[J]. Neurol Med Chir (Tokyo), 2020, 60(3): 136-146. doi: 10.2176/nmc.oa.2019-0168
[14]	Meyronet D, Esteban-Mader M, Bonnet C, et al. Characteristics of H3 K27M-mutant gliomas in adults[J]. Neuro Oncol, 2017, 19(8): 1127-1134. doi: 10.1093/neuonc/now274
[15]	Cohen KJ, Heideman RL, Zhou T, et al. Temozolomide in the treatment of children with newly diagnosed diffuse intrinsic pontine gliomas: a report from the Children's Oncology Group[J]. Neuro Oncol, 2011, 13(4): 410-416. doi: 10.1093/neuonc/noq205
[16]	Wu G, Diaz AK, Paugh BS, et al. The genomic landscape of diffuse intrinsic pontine glioma and pediatric non-brainstem high-grade glioma[J]. Nat Genet, 2014, 46(5): 444-450. doi: 10.1038/ng.2938 pmid: 24705251

临床特征	例数 (%)
性别
男	54(56.8)
女	41(43.2)
发生部位
脑干	78(82.1)
丘脑	6(6.3)
脊髓	4(4.2)
其他部位	7(7.4)
WHO组织学分级
低级别	33(34.7)
1级	9(9.5)
2级	24(25.3)
高级别	62(65.3)
3级	44(46.3)
4级	18(18.9)

项目	检测例数	阳性[n(%)]
IHC检测
H3 K27M	95	95(100.0)
H3 K27me3表达下降	73	65(89.0)
IDH₁	82	7(8.5)
P53>10.0%	90	50(55.6)
BRAF	82	1(1.2)
ATRX蛋白缺失	86	16(18.6)
分子学检测
BRAF基因变异	48	1(2.1)
EGFR基因变异	9	0(0)
MGMT基因甲基化	17	8(47.1%)
TERT基因变异	16	0(0)

部位	例数	ATRX蛋白缺失	P¹⁾
脑干	64	15(23.4)	0.087
脊髓和丘脑	7	1(14.3)
其他	15	0(0.0)