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  • Updated 04.17.2023
  • Released 06.13.1995
  • Expires For CME 04.17.2026

Rare brain embryonal tumors in infancy and early childhood



Embryonal brain tumors account for approximately 13% of primary brain tumors of childhood, following gliomas as the second most common CNS tumor type in children up to 14 years of age (65; 70).

Brain tumors may be congenital in children younger than 3 years of age and range from benign complex lesions to highly malignant neoplasms. They differ from those in older children with regard to histology, presentation symptoms, and treatment options, with historically lower survival outcomes. The most recent Central Brain Tumor Registry of the United States (CBTRUS) statistical report estimated brain tumor incidence in children 0 to 4 years of age to be 6.18/100,000 population, which exceeds the incidence in children aged 4 to 14 years (5.5/10000) (70). Approximately 10% to 15% of all childhood brain tumors will appear in the first 2 years of life, and about half occur in the first 6 months; overall, they are considered rare. Embryonal tumors represent 25% of brain tumors in infants younger than 1 year of age (71; 22).

The World Health Organization 2021 Classification (WHO CNS5), based on an integrated taxonomy with a strong emphasis on molecular profiling, established two types of embryonal tumors: medulloblastomas and other CNS embryonal tumors. Medulloblastoma is the most common embryonal brain tumor, whereas other embryonal tumor types are considered “rare” and typically affect infants and very young children. In contrast to medulloblastomas, which by definition originate from the cerebellum or dorsal brainstem, other CNS embryonal tumors may arise across the neuraxis.

Rare embryonal tumors were previously classified as either medulloblastomas or supratentorial primitive neuroectodermal tumors “sPNET,” and they represent approximately 34% of all embryonal brain tumors of children and adolescents (71; 70). The term sPNET is now obsolete and was removed from the WHO 2016 Classification of CNS tumors, thanks to an increased understanding of the heterogeneity and biology of these tumors and the emergence of a classification based on molecular characteristics.

Due to the unique features of the population affected by these entities, rare embryonal tumors deserve specific understanding, comprehensive diagnostic tools, and the development of much-needed novel tailored treatment approaches prioritizing less-toxic therapies to the immature nervous system.

In this article, the authors provide an overview of current concepts of clinicopathologic characteristics, specific molecular diagnosis, and general treatment strategies for these rare embryonal tumors of childhood. WHO CNS5 defines three main entities: embryonal tumor with multilayered rosettes (ETMR), CNS neuroblastoma FOXR2-activated, and CNS tumor with BCOR internal tandem duplication. Recent advances in the molecular diagnosis and treatment of pineoblastoma, a rare embryonal tumor of the pineal gland with particular penetrance in infants and young children, are also highlighted in this review. The common embryonal brain tumor medulloblastoma and the rare atypical rhabdoid teratoid tumor are well-defined entities in terms of their histopathological features, immunophenotype, and genetic profiles, as are other brain tumors occurring in this age range, including choroid plexus tumors and infant gliomas, and they are discussed in separate articles.

Key points

• Although uncommon in children younger than 2 years of age, primary CNS tumors at this age comprise almost 15% of all childhood brain tumors.

• Non-medulloblastoma embryonal brain tumors are considered rare entities; however, they account for 25% of central nervous system tumors affecting children under 1 year of age.

• Rare embryonal tumors may be congenital and can arise along the neuraxis. They can present as large tumors occupying contiguous cerebral lobes or as primary pineal, brainstem, or spinal cord tumors.

• Main new entities of embryonal brain tumors with defined genetic driver events include embryonal tumor internal tandem duplication.

• Molecularly defined aggressive pineoblastoma subgroups affect mainly infants and very young children.

• Due to varied diagnostic practices and scarce clinical data, disease features and determinants of outcomes for these tumors are poorly defined. Moreover, the development of much-needed innovative therapies is warranted for rare pediatric embryonal tumors.

Historical note and terminology

Over the past decade, genomic, transcriptomic, and proteomic profiling on large collections of embryonal brain tumors has revealed tumor heterogeneity, with proposed subgroups characterized by distinct molecular drivers (93; 89). The introduction of increasingly specific tumor groups is an effort to create more internally homogeneous categories, to allow more precise prognostication, and potentially to develop targeted therapies. New entities of embryonal brain tumors affect predominantly infants and very young children and were originally included in the WHO 2016 classification and further reviewed and updated in the latest WHO CNS5 (Table 1).

Table 1. Embryonal Brain Tumors of Infant and Young Children

Infant medulloblastoma

Medulloblastoma, SHH activated
Medulloblastoma non-WNT, non-SHH (Groups 3 and 4)

Rare embryonal brain tumors

Atypical teratoid or rhabdoid tumor
Cribriform neuroepithelial tumor (CRINET)
Embryonal tumor with multilayered rosettes (ETMR)
CNS neuroblastoma, FOXR2-activated
CNS tumor with BCOR internal tandem duplication (BCOR-ITD)
CNS embryonal tumor not elsewhere classified/not otherwise classified

Embryonal tumors of the pineal gland


Pineoblastoma, MYC/FOXR2 activated
Pineoblastoma, RB1-altered (pineal retinoblastoma)
Pineoblastoma miRNA-1 and miRNA-2


Whereas ETMR was included in previous WHO classifications, CNS neuroblastoma, FOXR2-activated, and CNS tumor with BCOR-ITD are new to WHO CNS5. In addition, CNS5 recognizes an ETMR with DICER1 alteration (in addition to the more common ETMR, C19MC altered). CNS tumors with BCOR-ITD are now included in WHO CNS5 as embryonal tumors, but these neoplasms are not definitively neuroectodermal.

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