Clinical Pearls & Morning Reports

Posted by Carla Rothaus

Published May 18, 2022


Has therapy targeted to molecular alterations prolonged survival in children with high-grade gliomas?

Brain tumors are the most common solid neoplasms and the leading cause of death from cancer in children. The fifth edition of the World Health Organization Classification of Tumors of the Central Nervous System (CNS5), published in 2021, introduced major changes in brain tumor taxonomy, emphasizing molecular diagnostic features. Read the NEJM Review Article here.

Clinical Pearls

Q: Have advances in our knowledge of molecular alterations in pediatric brain tumors led to therapeutic advances?

A: Genome sequencing and DNA methylome profiling have greatly altered the categorization of brain tumors in children. Although the prognosis for selected tumors has improved as a result of refinements in surgical and adjunctive treatment, molecular diagnostic insights have thus far provided only limited therapeutic advances. 

Q: What are some of the features of low-grade gliomas in children?

A: Unlike low-grade gliomas in adults, low-grade gliomas in children rarely transform into higher-grade tumors. Molecular alterations have been targeted with the use of drugs that may be more effective and less toxic than conventional chemotherapy. Alterations in the downstream signaling pathway of the rat sarcoma virus–mitogen-activated protein kinase (MAPK) pathway have generated considerable attention. Most low-grade gliomas have one or more alterations in the MAPK pathway, including mutation or fusion of the BRAF oncogene, NF1 mutation, fibroblast growth factor receptor 1 (FGFR1) mutation, and neurotrophic tyrosine receptor kinase (NTRK) family fusions.

Morning Report Questions

Q: Has therapy targeted to molecular alterations prolonged survival in children with high-grade gliomas?

A: Pediatric-type high-grade gliomas account for 10% of brain tumors in children and have a poor prognosis. Despite surgery and adjuvant therapy, 70 to 90% of affected children die within 2 years after diagnosis. An advance in understanding high-grade gliomas has been the identification of driver mutations in the chromatin-remodeling gene family, histone H3. The diffuse midline glioma is a particularly lethal tumor that affects young children and is unresectable. A new term, “H3K27-altered,” has been substituted for the prior term, “H3K27M-mutant,” since additional molecular changes have been identified. The H3K27 alteration appears to be specific for diffuse midline high-grade gliomas in children. A second subtype, diffuse hemispheric glioma, H3G34-mutant, arises in the cerebral hemispheres in older children and young adults. A third subtype is diffuse pediatric-type high-grade glioma, H3 wild type and IDH wild type. This is an aggressive tumor, usually found in the cerebral hemispheres, with a poor prognosis. The fourth subtype, a clinically distinct neoplasm in newborns and infants, is the infant-type hemispheric glioma, which often harbors receptor tyrosine kinase gene fusions, including ALK, NTRK 1/2/3, ROS1, and MET4. Targeted therapy driven by mutations has thus far not had substantial effect, but it has only recently been introduced into clinical practice.

Q: Describe some of the features of medulloblastomas in children.

A: Medulloblastomas usually arise in the cerebellum, and patients present with signs of increased intracranial pressure or cerebellar dysfunction. They account for more than 60% of childhood embryonal tumors, and 70% occur in children under the age of 10 years, affecting boys more than girls, though age and sex differences vary according to tumor subtype. One third of cases arise in children under the age of 3 years. The CNS5 system now recognizes two types of medulloblastoma: medulloblastoma molecularly defined and medulloblastoma histologically defined. Factors associated with a poor outcome for children with medulloblastoma include large size, disseminated disease at presentation, young age (<3 years), and residual tumor of more than 1.5 cm2 on postoperative imaging.

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