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New Advances in Molecular Diagnostics Redefine How Pediatric Brain Tumors are Classified and Treated

The newly released 2021 WHO Classification of Tumors of the Central Nervous System (CNS) introduces major changes that advance the role of molecular profiling in CNS tumor classification and includes many new pediatric brain tumor subtypes.

We talked to David Solomon, MD, PhD, a neuropathologist and cancer researcher at the UCSF Brain Tumor Center, about the significance of the new WHO Classification, major advances in pediatric brain tumors, and what clinicians need to know.

David Solomon, MD, PhD

 

How many new pediatric brain tumor entities are there?

Approximately 25 new brain tumor types or subtypes that most commonly occur in the pediatric and young adult populations are being newly recognized since the last edition of the World Health Organization (WHO) Classification of CNS Tumors in 2016.  These include:

  • Diffuse astrocytoma, MYB- or MYBL1-altered1
  • Polymorphous low-grade neuroepithelial tumor of the young (PLNTY)2
  • Diffuse low-grade glioma, MAPK pathway-altered3
  • Diffuse midline glioma, H3-wildtype with EZHIP overexpression
  • Diffuse midline glioma, EGFR-mutant4
  • Diffuse hemispheric glioma, H3 G34-mutant5
  • Diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype6
  • Infant-type hemispheric glioma7
  • Astroblastoma, MN1-altered8
  • Diffuse glioneuronal tumor with oligodendroglioma-like features and nuclear clusters
  • Myxoid glioneuronal tumor9, 10
  • Multinodular and vacuolating neuronal tumor11
  • Supratentorial ependymoma, YAP1 fusion-positive
  • Posterior fossa group A (PFA) ependymoma12
  • Posterior fossa group B (PFB) ependymoma
  • Spinal ependymoma, MYCN-amplified
  • Cribriform neuroepithelial tumor
  • Embryonal tumor with multilayered rosettes, DICER1-mutant subtype
  • CNS neuroblastoma, FOXR2-activated13
  • CNS tumor with BCOR internal tandem duplication14
  • Intracranial mesenchymal tumor, FET-CREB fusion-positive15
  • CIC-rearranged sarcoma
  • Primary intracranial sarcoma, DICER1-mutant16

For several of these, our neuro-oncology team at UCSF has led or contributed to the landmark studies that initially defined the new tumor type, identified the underlying molecular pathogenesis, or helped refine their diagnostic classification.

 

What are the major findings that influence the new classification?

The newest tumor entities and updates to existing tumor entities in the 2021 WHO Classification are in large part based on advances in our understanding of brain tumor molecular pathogenesis, which has been driven by studies using next-generation sequencing, DNA methylation profiling, single cell analysis, and other new 'omics technologies.  These technologies have refined the way we classify brain tumors beyond just how they visually appear under the microscope (i.e. conventional histopathology).  In other words, we are now able to more accurately classify brain tumors when histopathology is combined with the latest in genomic and epigenomic profiling, which have now become standard-of-care for the diagnosis and management of pediatric neuro-oncology patients.

 

What do physicians need to know?

Accurate diagnostic classification, and therefore oncologic management, of pediatric brain tumors can no longer be accomplished by conventional histopathology alone (i.e. microscopic evaluation of tissue sections), and now absolutely requires integration with one or more molecular technologies such as next-generation sequencing and DNA methylation profiling.

 

Will any of the new classifications affect treatment?

The very foundation of precision medicine for pediatric brain tumor patients is an accurate diagnosis and prognosis for each patient's individual brain or spinal cord tumor.  The decision of whether or not to use radiation or chemotherapy, what chemotherapy agents and dosage to use, and whether any of the newest targeted therapy drugs may be indicated for each pediatric brain tumor patient is entirely predicated upon accurate diagnostic classification.  The new 5th edition of the WHO Classification represents a major step forward in the accurate diagnostic classification of pediatric brain tumors, as it now further stratifies these tumors into much more uniform entities with more homogenous patient outcomes based on molecular profiling.  Better diagnostic and prognostic classification of pediatric brain tumors will enable more informed decision-making regarding treatment choices by oncologists and other clinical team members, leading to improved patient outcomes.

 

What are the most exciting avenues for research?

Pediatric brain tumor research is such an exciting field to be working in right now.  The latest 'omics technologies being employed – including DNA methylation profiling, single cell sequencing, and metabolomic analysis – are leading to major breakthroughs at an incredibly rapid pace.  We are better understanding the molecular pathogenesis of pediatric brain tumors, their cellular composition at single cell resolution, the tumor microenvironment, and how the immune system interfaces with tumor cells.  Precision medicine clinical trials using genomically-tailored therapies are being conducted by nationwide consortia (such as the Pacific Pediatric Neuro-Oncology Consortium led by UCSF pediatric neuro-oncologist Sabine Mueller, MD, PhD) to bring the latest discoveries from the research labs into the clinics.  The future is bright for pediatric neuro-oncology and, most importantly, our patients.

 

References

  1. Chan E, et al. Angiocentric glioma with MYB-QKI fusion located in the brainstem, rather than cerebral cortex. Acta Neuropathol. 2017 Oct;134(4):671-673.
  2. Gupta R, et al. Low-grade glioneuronal tumors with FGFR2 fusion resolve into a single epigenetic group corresponding to 'Polymorphous low-grade neuroepithelial tumor of the young'. Acta Neuropathol. 2021 Sep;142(3):595-599. 
  3. Lucas CG, et al. Comprehensive analysis of diverse low-grade neuroepithelial tumors with FGFR1 alterations reveals a distinct molecular signature of rosette-forming glioneuronal tumor. Acta Neuropathol Commun. 2020 Aug 28;8(1):151. 
  4. Mondal G, et al. Pediatric bithalamic gliomas have a distinct epigenetic signature and frequent EGFR exon 20 insertions resulting in potential sensitivity to targeted kinase inhibition. Acta Neuropathol. 2020 Jun;139(6):1071-1088. 
  5. Lucas CG, et al. Diffuse hemispheric glioma, H3 G34-mutant: genomic landscape of a new tumor entity and prospects for targeted therapy. Neuro-Oncology 2021. 2021 Nov 2;23(11):1974-1976.
  6. Sloan EA, et al. Gliomas arising in the setting of Li-Fraumeni syndrome stratify into two molecular subgroups with divergent clinicopathologic features. Acta Neuropathol. 2020 May;139(5):953-957. 
  7. Clarke M, et al. Infant High-Grade Gliomas Comprise Multiple Subgroups Characterized by Novel Targetable Gene Fusions and Favorable Outcomes. Cancer Discov. 2020 Jul;10(7):942-963. 
  8. Wood MD, et al. Multimodal molecular analysis of astroblastoma enables reclassification of most cases into more specific molecular entities. Brain Pathol. 2018 Mar;28(2):192-202. 
  9. Solomon DA, et al. Myxoid glioneuronal tumor of the septum pellucidum and lateral ventricle is defined by a recurrent PDGFRA p.K385 mutation and DNT-like methylation profile. Acta Neuropathol. 2018 Aug;136(2):339-343.
  10. Lucas CG, et al. Myxoid glioneuronal tumor, PDGFRA p.K385-mutant: clinical, radiologic, and histopathologic features. Brain Pathol. 2020 May;30(3):479-494. 
  11. Pekmezci M, et al. Multinodular and vacuolating neuronal tumor of the cerebrum is a clonal neoplasm defined by genetic alterations that activate the MAP kinase signaling pathway. Acta Neuropathol. 2018 Mar;135(3):485-488.
  12. Panwalkar P, et al. Immunohistochemical analysis of H3K27me3 demonstrates global reduction in group-A childhood posterior fossa ependymoma and is a powerful predictor of outcome. Acta Neuropathol. 2017 Nov;134(5):705-714. 
  13. Sturm D, et al. New Brain Tumor Entities Emerge from Molecular Classification of CNS-PNETs. Cell. 2016 Feb 25;164(5):1060-1072. 
  14. Ferris SP, et al. High-grade neuroepithelial tumor with BCOR exon 15 internal tandem duplication-a comprehensive clinical, radiographic, pathologic, and genomic analysis. Brain Pathol. 2020 Jan;30(1):46-62.
  15. Sloan EA, et al. Intracranial mesenchymal tumor with FET-CREB fusion-A unifying diagnosis for the spectrum of intracranial myxoid mesenchymal tumors and angiomatoid fibrous histiocytoma-like neoplasms. Brain Pathol. 2021 Jul;31(4):e12918. 
  16. Lee JC, et al. Primary intracranial sarcomas with DICER1 mutation often contain prominent eosinophilic cytoplasmic globules and can occur in the setting of neurofibromatosis type 1. Acta Neuropathol. 2019 Mar;137(3):521-525.