Molecular and Clinical Heterogeneity in Histologically Diagnosed CNS-PNET


Key Points

  • Molecular profiling revealed that many patients had high-grade gliomas.
  • Prognosis for patients with CNS-PNET/PBL was remarkably better when patients with HGG were excluded from analysis.

As reported by Hwang et al in the Journal of Clinical Oncology, subsequent molecular profiling of histologically diagnosed central nervous system supratentorial primitive neuroectodermal tumors (CNS-PNET) in patients showed molecular and clinical heterogeneity that strongly affected prognosis.

The phase III Children’s Oncology Group ACNS0332 trial included patients aged 3 to 22 years with histologically diagnosed high-risk medulloblastoma, CNS-PNET, and pineoblastoma. After standard intensive therapy, patients were randomly assigned to receive carboplatin during radiation, adjuvant isotretinoin, both, or neither.

Molecular profiling later identified tumor heterogeneity that was not detectable at the start of the study. Enrollment of patients with CNS-PNET/pineoblastoma was then discontinued. The current analysis examines outcomes among this group of patients. The molecular tumor classification was retrospectively performed using DNA methylation profiling.  

The primary endpoint for the study was event-free survival.

Molecular Heterogeneity and Outcomes

Overall, 85 patients with institutionally diagnosed CNS-PNETs/pineoblastomas were enrolled. Among 60 patients with sufficient tissue for analysis, 31 had tumors that were nonpineal in location; of these, 22 (71%) had tumors that were not intended to be included in the trial, including 18 with high-grade gliomas, 2 with atypical teratoid rhabdoid tumors, and 2 with ependymomas.

Outcomes by tumor type differed markedly: patients with supratentorial embryonal tumors/PBLs had 5-year event-free survival and overall survival of 62.8% and 78.5%, with no significant difference in outcomes between those with supratentorial embryonal tumors and those with pineoblastomas. By comparison, 5-year event-free and overall survival were 5.6% and 12.0% among patients with molecularly classified high-grade glioma. No significant association of outcome with carboplatin or isotretinoin was observed among all patients. As noted by the investigators, the survival outcomes for patients with high-grade gliomas were similar to that in historic studies that did not include craniospinal irradiation and intensive chemotherapy.

The investigators concluded, “For patients with CNS-PNET/[pineoblastoma], prognosis is considerably better than previously assumed when molecularly confirmed [high-grade gliomas] are removed. Identification of molecular HGGs may spare affected children from unhelpful intensive treatment. This trial highlights the challenges of a histology-based diagnosis for pediatric brain tumors and indicates that molecular profiling should become a standard component of initial diagnosis.”

The study was supported by the National Institutes of Health, St. Baldrick’s Foundation, German Childhood Cancer Foundation, and German Cancer Consortium.

James M. Olson, MD, of the Fred Hutchinson Cancer Research Center, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: See study authors’ full disclosures at  

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.