Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
Pathology center, Seegene Medical Foundation, Seoul 04805, Republic of Korea.
Brain Pathol. 2024 Sep;34(5):e13234. doi: 10.1111/bpa.13234. Epub 2024 Jan 12.
The accurate diagnosis and classification of gliomas are essential for appropriate treatment planning and prognosis prediction. This study aimed to investigate the molecular diagnostics of IDH-wildtype diffuse astrocytic gliomas and identify potential genetic variants that could differentiate glioblastoma (GBM) from lower-grade gliomas when DNA methylation analysis is not feasible. In total, 479 H3-and IDH-wildtype diffuse astrocytic gliomas were included in this study. All the cases were diagnosed according to the 2021 World Health Organization (WHO) classification of central nervous system (CNS) tumors. Panel sequencing data were collected, and clinicopathological information was retrieved from medical records. Genetic alterations and histological findings were analyzed to determine their diagnostic utility and prognostic implications. Out of 479 cases, 439 (91.6%) were diagnosed with GBM, including 28 cases that were molecularly diagnosed as GBM. However, 40 (8.4%) cases could not be classified according to the 2021 WHO classification and were diagnosed as lower-grade diffuse astrocytic glioma, IDH-wildtype, not elsewhere classified (LGNEC). In addition to the three genetic alterations included in the diagnostic criteria of GBM, PTEN and EGFR mutations were found to be enriched in GBM. Patients harboring mTOR pathway mutations demonstrated a more favorable prognosis and often exhibited morphology resembling subependymal giant cell astrocytoma, along with a high tumor mutational burden. Among patients with mTOR pathway mutations, those lacking molecular diagnostic features of GBM exhibited outstanding survival outcomes, even in the presence of grade 4 histology. Integration of molecular features enhanced the diagnostic accuracy of IDH-wildtype gliomas. Some molecular alterations enriched in GBM offer valuable insights for molecular diagnosis and glioma classification. Furthermore, high-grade diffuse astrocytic gliomas featuring mTOR pathway mutations in the absence of molecular diagnostic features of GBM could represent more favorable tumor types distinct from GBM.
明确诊断和分级对于恰当的治疗方案制定和预后预测至关重要。本研究旨在探究 IDH 野生型弥漫性星形细胞瘤的分子诊断，并确定潜在的遗传变异，以便在无法进行 DNA 甲基化分析时，将其与低级别胶质瘤区分开来。共纳入 479 例 H3 和 IDH 野生型弥漫性星形细胞瘤患者。所有病例均根据 2021 年世界卫生组织（WHO）中枢神经系统（CNS）肿瘤分类进行诊断。收集了面板测序数据，并从病历中提取了临床病理信息。分析遗传改变和组织学发现，以确定其诊断效用和预后意义。在 479 例病例中，439 例（91.6%）诊断为 GBM，其中 28 例分子诊断为 GBM。然而，40 例（8.4%）病例无法根据 2021 年 WHO 分类进行分级，诊断为低级别弥漫性星形细胞瘤，IDH 野生型，未另分类（LGNEC）。除了 GBM 诊断标准中包含的三种遗传改变外，还发现 PTEN 和 EGFR 突变在 GBM 中更为丰富。携带 mTOR 通路突变的患者预后更有利，其形态常类似于室管膜下巨细胞星形细胞瘤，且具有较高的肿瘤突变负担。在携带 mTOR 通路突变的患者中，那些缺乏 GBM 的分子诊断特征的患者表现出出色的生存结果，即使存在 4 级组织学。整合分子特征提高了 IDH 野生型胶质瘤的诊断准确性。一些在 GBM 中富集的分子改变为分子诊断和胶质瘤分类提供了有价值的见解。此外，在缺乏 GBM 的分子诊断特征的情况下，伴有 mTOR 通路突变的高级别弥漫性星形细胞瘤可能代表与 GBM 不同的更有利的肿瘤类型。
