SNUH study reclassifies childhood brain tumors under new WHO criteria

A research team at Seoul National University Hospital has reclassified pediatric malignant brain tumors according to the latest World Health Organization (WHO) standards, revealing that more than half of cases previously diagnosed as glioblastoma or primitive neuroectodermal tumor (PNET) should now be categorized as “pediatric-type diffuse high-grade glioma (pHGG).”

Alluvial plot (https://rawgraphs.io/) for revisiting the previous diagnosis of pHGGs and PNETs according to the WHO CNS5. The cohort includes a total of 78 patients, comprising 41 with pHGG and 37 with other diagnoses. Abbreviations: GBM, glioblastoma; AA, anaplastic astrocytoma; AOA, anaplastic oligoastrocytoma; GC, gliomatosis cerebri; PNET, primitive neuroectodermal tumor; pHGG, pediatric-type diffuse high-grade glioma; DMG-H3K27, diffuse midline glioma, H3 K27-altered; DHG-H3G34, diffuse hemispheric glioma, H3 G34-mutant; DpHGG-H3wt/IDHwt, diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype; IHG, infant-type hemispheric glioma; ST-EPN, supratentorial ependymoma; AT/RT, atypical teratoid/rhabdoid tumor; WHO CNS5, The 2021 WHO Classification of Tumors of the Central Nervous System, 5th edition. (Credit: Neuro-Oncology Advances)

The findings mark Korea’s first large-scale analysis of the clinical and molecular characteristics of pHGG and are expected to contribute to developing more personalized treatment strategies for pediatric brain cancer patients.

The study, led by Professors Kim Seung-ki and Kim Joo-hwan from the Department of Pediatric Neurosurgery and Park Sung-hye from the Department of Pathology, reviewed 78 cases of children treated for malignant brain tumors at Seoul National University Children’s Hospital between 1997 and 2023.

A research team from Seoul National University Hospital led a study reclassifying pediatric malignant brain tumors under the latest WHO criteria. From left are Professors Kim Seung-ki, Kim Joo-hwan, and Park Sung-hye. (Credit: SNUH)

Tumor samples previously diagnosed as glioblastoma, anaplastic astrocytoma, anaplastic oligodendroglioma, diffuse cerebral gliomatosis, or PNET were re-examined pathologically using immunohistochemistry and next-generation sequencing (NGS) to apply the integrated diagnostic framework of the 2021 WHO Classification of Tumors of the Central Nervous System (WHO CNS5).

The re-evaluation found that 41 of the 78 cases (52.6 percent) were reclassified as pediatric-type diffuse high-grade gliomas.

These included 11 cases of H3 K27-altered diffuse midline glioma (DMG-H3K27), 5 cases of H3 G34-mutant diffuse hemispheric glioma (DHG-H3G34), 15 cases of H3/IDH-wild-type pediatric-type diffuse high-grade glioma (DpHGG-H3wt/IDHwt), and 10 cases of infant-type hemispheric glioma (IHG).

The results demonstrate that applying the updated WHO classification improves diagnostic precision and helps distinguish prognostic differences that were previously unclear under older diagnostic systems.

When the reclassified cohort was combined with 20 newly diagnosed pHGG cases identified under the WHO CNS5 criteria, the team analyzed clinical and genomic data from a total of 61 patients.

Among the 48 cases with available genomic data (excluding infant-type gliomas), TP53 mutations were detected in 34 patients (70.8 percent).

Notably, in the H3/IDH-wild-type subgroup, half of the patients (50 percent) were found to have underlying cancer predisposition syndromes such as Li-Fraumeni syndrome, neurofibromatosis type 1 (NF1), or constitutional mismatch repair deficiency (cMMRD), underscoring the need for germline genetic testing and family counseling during diagnosis.

Prognostic analysis showed that infant-type hemispheric glioma had a significantly better survival outcome compared with other subtypes.

The two-year and five-year survival rates were 92.3 percent and 73.8 percent, respectively. Patients who underwent gross total resection (GTR) also demonstrated superior survival compared to those who did not.

The researchers suggested that due to the distinct biological features and relatively favorable prognosis of infant-type tumors, treatment intensity should be tailored carefully to minimize long-term side effects from unnecessary radiation therapy.

“By re-analyzing cases previously diagnosed as pediatric glioblastoma through integrated molecular pathology, this study provides meaningful insights into the precise classification and prognosis of pediatric high-grade gliomas,” said Professor Kim Seung-ki. “We expect the findings to help establish more personalized treatment strategies and ultimately improve outcomes for pediatric brain tumor patients.”

The study was supported by the Lee Kun-Hee Pediatric Cancer and Rare Disease Project and was published in the latest issue of the international journal Neuro-Oncology Advances.