Brain tumors represent the most common solid tumor of childhood, with gliomas comprising the largest fraction of these cancers. Pediatric high-grade gliomas (pHGG) are different from those that arise in adults, and represent a diverse group of aggressive glial tumors with distinct genetic subgroups characterized by unique tumor locations, age of onset, gender predilection, and importantly survival outcomes.
Available Sub Types
This group of tumors harbors a pathogenic K27M mutation in one of the histone H3 genes and tends to occur in midline locations (thalamus, pons, and spinal cord). An H3.3 (H3F3A) K27M mutation is seen in most cases. H3.1 (HIST1H3B/C/A) K27M mutations occur at a lower frequency and have a predilection for pontine location in young children. H3.2 K27M mutations are infrequent. Histone H3 K27M mutation is one of the defining features of a new entity termed ‘diffuse midline glioma’ (WHO grade IV). Rare non-midline examples have also been encountered. Histologic findings may include diffuse astrocytoma, anaplastic astrocytoma, and glioblastoma.
This group of tumors harbors a pathogenic G34R, which is the most common, or G34V mutation in the H3F3A (H3.3) gene. H3 G34 R/V-mutant high-grade gliomas have a strong predilection for cerebral cortical location and are most commonly seen in adolescents. There are frequently concomitant TP53 and ATRX alterations. Histologic findings may include anaplastic astrocytoma and glioblastoma.
Most pediatric high-grade gliomas belong to this group, which harbors no pathogenic mutations in histone H3, IDH1, IDH2, and BRAF. The underlying genetic/genomic alterations are very heterogeneous and vary based on the age of the patients and the location of the tumors. Histologic findings may include anaplastic astrocytoma, glioblastoma, and high-grade glioma, not otherwise specified (NOS)/not elsewhere classified (NEC).
This group of tumors harbors a pathogenic BRAF V600E mutation. Homozygous CDKN2A deletion is frequently identified in high-grade tumors or tumors that have undergone malignant transformation from a low-grade precursor lesion. Histologic findings may include anaplastic ganglioglioma, anaplastic pleomorphic xanthoastrocytoma, epithelioid glioblastoma, and conventional glioblastoma.
This group of tumors commonly harbors alterations in one of the DNA mismatch repair genes (MLH1, PMS2, MSH2, or MSH6), which may be germline in association with Lynch syndrome or constitutional mismatch repair deficiency (CMMRD). Alterations in DNA polymerase (POLE) are occasionally identified. Histologic findings may include anaplastic astrocytoma and glioblastoma.