Pediatric high-grade gliomas, H3-wildtype, IDH-wildtype: Refining diagnostic criteria and exploring clinical associations.

IF 2.5 Q2 CLINICAL NEUROLOGY

Neuro-oncology practice Pub Date : 2025-08-03 eCollection Date: 2026-02-01 DOI:10.1093/nop/npaf079

Supriya Bhardwaj, Jyotsna Singh, Swati Singh, Charli Roy, Hemlata Jangir, Srinidhi Vasant, Shweta Kedia, Ajay Garg, Ashish Suri, Mehar Chand Sharma, Chitra Sarkar, Vaishali Suri

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引用次数: 0

Abstract

Background: Diffuse pediatric-type high-grade gliomas (pHGGs), H3-wildtype (H3 WT), and IDH-wildtype (IDH WT), represent a newly recognized, highly malignant brain tumor entity with unique molecular and epigenetic profiles. Despite their recent inclusion in the WHO 2021 classification, their histological and molecular diversity presents significant diagnostic and therapeutic challenges.

Methods: This study analyzed 12 cases of pHGGs, H3 WT and IDH WT, identified through whole-genome methylation profiling. Clinical, radiological, and histopathological evaluations were complemented by immunohistochemical profiling, employing an extended spectrum of antibodies, and molecular studies. Methylation profiling enabled precise tumor classification and correlation with known subtypes such as RTK-1, RTK-2, and MYCN.

Results: Among the 12 cases, 7 were classified under the RTK-1 subtype, 3 under RTK2 subtype, and a case each under MYCN, pHGGs, H3 WT, and IDH WT subtype B. Notably, 5/12 cases demonstrated a loss of H3K27me3 expression, contradicting the WHO 2021 recommendation for its retention as a diagnostic criterion. Furthermore, 6/7 RTK-1 subtype cases were linked to either mismatch-repair (MMR) deficiency or radiation-induced gliomas, highlighting an enrichment of these clinical scenarios within this subgroup. MGMT promoter methylation was observed in only 4/12 of these cases, consistent with its low prevalence in this tumor category.

Conclusions: This study provides a comprehensive characterization of pHGGs, H3 WT, IDH WT, and emphasizes the clinical and molecular complexity of this rare tumor entity. The findings challenge current WHO diagnostic criteria regarding H3K27me3 retention and demonstrate the critical role of molecular diagnostics, particularly methylation profiling, in refining classification and guiding clinical management. These results advocate for re-evaluation of existing diagnostic frameworks to better accommodate the observed variability and associations in this challenging tumor subtype.

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小儿高级别胶质瘤，h3 -野生型，idh -野生型：改进诊断标准和探索临床关联

背景：弥漫性儿科型高级别胶质瘤（pHGGs）， H3野生型（H3 WT）和IDH野生型（IDH WT）是一种新发现的高度恶性脑肿瘤实体，具有独特的分子和表观遗传学特征。尽管它们最近被列入世卫组织2021年分类，但其组织学和分子多样性给诊断和治疗带来了重大挑战。方法：本研究分析了通过全基因组甲基化分析鉴定的12例pHGGs、H3 WT和IDH WT。临床，放射学和组织病理学评估辅以免疫组织化学分析，采用扩展的抗体谱和分子研究。甲基化分析能够精确地对肿瘤进行分类，并与已知亚型（如RTK-1、RTK-2和MYCN）进行关联。结果：12例患者中，7例属于RTK-1亚型，3例属于RTK2亚型，MYCN、pHGGs、H3 WT和IDH WT b亚型各1例。值得注意的是，5/12例患者表现出H3K27me3表达缺失，这与WHO 2021年保留其作为诊断标准的建议相矛盾。此外，6/7的RTK-1亚型病例与错配修复（MMR）缺陷或辐射诱导的胶质瘤有关，突出了该亚组中这些临床情况的丰富性。MGMT启动子甲基化仅在这些病例中的4/12中观察到，这与MGMT启动子甲基化在该肿瘤类别中的低患病率一致。结论：本研究提供了pHGGs、H3 WT、IDH WT的全面特征，并强调了这种罕见肿瘤实体的临床和分子复杂性。这些发现挑战了世卫组织目前关于H3K27me3保留的诊断标准，并证明了分子诊断，特别是甲基化谱分析在改进分类和指导临床管理方面的关键作用。这些结果提倡重新评估现有的诊断框架，以更好地适应在这种具有挑战性的肿瘤亚型中观察到的变异性和相关性。

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来源期刊

Neuro-oncology practice CLINICAL NEUROLOGY-

CiteScore

5.30

自引率

11.10%

发文量

期刊介绍： Neuro-Oncology Practice focuses on the clinical aspects of the subspecialty for practicing clinicians and healthcare specialists from a variety of disciplines including physicians, nurses, physical/occupational therapists, neuropsychologists, and palliative care specialists, who have focused their careers on clinical patient care and who want to apply the latest treatment advances to their practice. These include: Applying new trial results to improve standards of patient care Translating scientific advances such as tumor molecular profiling and advanced imaging into clinical treatment decision making and personalized brain tumor therapies Raising awareness of basic, translational and clinical research in areas of symptom management, survivorship, neurocognitive function, end of life issues and caregiving