Embryonal brain tumors in infancy and early childhood

Roger J Packer MD (Dr. Packer of George Washington University; Senior Vice President, Center for Neuroscience and Behavioral Medicine; and Gilbert Endowed Distinguished Professor in Neurofibromatosis and Director, Gilbert Neurofibromatosis Institute and Brain Tumor Institute, Children’s National Health System, has no relevant financial relationships to disclose.)
Originally released June 13, 1995; last updated July 26, 2017; expires July 26, 2020

This article includes discussion of embryonal brain tumors in infancy and early childhood, brain tumors in infancy and early childhood, primitive neuroectodermal tumors, and medulloepithelioma embryonal tumor with multilayered rosettes CNS neuroblastoma. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.

Overview

Approximately 10% to 15% of all childhood brain tumors will arise in the first 2 years of life. These tumors, which may be congenital, range from benign complex lesions that can be difficult to classify to highly malignant tumors that are often unresponsive to treatment. Embryonal tumors often arise in children younger than 2 years of age, and in the past decade an increasing incidence of the atypical teratoid/rhabdoid tumor has been reported. Although outcome is far from optimal, increasing evidence indicates that there are distinct molecular subtypes of these embryonal tumors, which require different managements. In this article, the author reviews current concepts of treatment for these diverse lesions, including the use of molecularly targeted therapy and novel radiation therapy techniques. Other brain tumors occurring in this age range, including medulloblastomas, choroid plexus tumors, lower grade neuro-glial tumors, and atypical teratoid tumors, are discussed in separate articles.

Key points

 

• Although uncommon in children less than 2 years of age, primary central nervous system tumors still comprise almost 15% of all childhood brain tumors.

 

• Many infantile brain tumors are congenital, may be large at diagnosis, and can be difficult to classify.

 

• Treatment options for infantile brain tumors may be limited because of the immaturity of the nervous system and resultant risk of treatment-related neurotoxicity.

 

• Embryonal brain tumors are comprised of molecular distinct entities.

Historical note and terminology

Primary central nervous system tumors occurring in children younger than 2 years of age constitute approximately 10% to 15% of all childhood nervous system tumors (Cohen et al 1993). Tumors that arise during this time period are probably congenital in origin and differ (to some degree) in presentation, histology subtype, and location of origin, from neoplasms that arise in older children. At times, neoplasms in young children are difficult to classify because they are composed of immature elements. Lumping these neoplasms into standard classification schemas has obscured the unique nature of these tumors and possibly their differing responses to therapy. With the wider utilization of immunohistochemical and molecular genetic techniques, the complexity of some infantile tumors is just now being recognized (Sturm et al 2016). Improvements in neuroimaging have led to the earlier diagnosis of intracranial neoplasms. Determining exactly when a brain tumor first arose is virtually impossible. Many tumors diagnosed early in life have been considered to be congenital; an alternative terminology is to classify these tumors as “connatal,” designating the tumor as present or producing symptoms at birth or within the first 2 weeks of life.

Another factor that has increased interest in tumors occurring in young children is the recognition that prognosis may not be as dire as outcome documented in series collected over the past 50 years (Duffner et al 1986b). Studies from multiple centers have demonstrated that some malignant brain tumors arising in children younger than 3 years of age are responsive to chemotherapy (Duffner et al 1993), although outcome is far from optimal (Duffner et al 1993; Bode et al 2014). This has led to the hope that infantile brain tumors could more effectively be treated and that children who survive will have fewer long-term sequelae.

The terminology and classification of childhood embryonal tumors has been significantly altered. Tumor designations such as primitive neuro-ectodermal tumor, supratentorial primitive neuro-ectodermal tumor, CNS neuroblastoma, embryonal tumor with abundant neuropil rosettes (ETANR) (Gessi et al 2009), ependymoblastoma, and medulloepithelioma have all been terms that have been utilized over the past decades. In the most recent WHO classification of central nervous system tumors, the term primitive neuro-ectodermal tumor has been removed (Louis et al 2016). Medulloblastomas are classified separately and remain a form of embryonal tumor which arises in the region of the fourth ventricle. Atypical teratoid/rhabdoid tumors, a form of embryonal tumor, are a clearcut separate entity. Some historic terms, such as medulloepithelioma and CNS neuroblastoma have been maintained and a tumor termed embryonal tumor with multilayered rosettes has been added and is further subdivided on the basis of whether there is a demonstrable genetic abnormality.

Although this is a major change in classification, it is likely that further molecular subclassification will occur in the near future. Work by multiple authors has demonstrated that such central nervous system embryonal tumors of infancy and early childhood are comprised of multiple molecular subtypes (Li et al 2009; Pfister et al 2009; Korshunov et al 2010; Schwalbe et al 2013; Korshunov et al 2014; Sturm et al 2016). Some tumors that were initially considered embryonal tumors are molecularly high-grade gliomas and require alternative classification. Others may fall under the ependymal tumor grouping, whereas still others are molecularly more similar to medulloblastomas. It is likely that for more effective treatment therapy, treatment will need to be guided by these molecular findings.

Table 1. Embryonal Tumor Classification

 

• Embryonal tumor with multilayered rosettes, C19MC-altered
• Embryonal tumor with multilayered rosettes, NOS
• Medulloepithelioma
• CNS neuroblastoma
• CNS ganglioneuroblastoma
• CNS embryonal tumor, NOS
• Atypical teratoid/rhabdoid tumor
• CNS embryonal tumor with rhabdoid features

(Louis et al 2016)

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