Dr. Packer of George Washington University and Children’s National Health System received honorariums from Boehringer and Novartis as an advisory board member.)
This article includes discussion of brainstem gliomas in childhood, brainstem astrocytomas in childhood, brainstem tumors in childhood, pontine gliomas in childhood, DIPG, cervicomedullary masses, diffuse pontine gliomas, tectal lesions, and tectal gliomas. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.
The management of brainstem gliomas remains problematic. Approximately 80% of children have diffuse, intrinsic pontine tumors, which carry a dismal prognosis. Children with cervicomedullary and tectal tumors have markedly better outcomes. The author reviews outcomes after clinical trials and new biological insights that open exciting innovative avenues of molecularly-targeted treatment.
• Brainstem gliomas occur most frequently in children, with the majority being diffuse pontine gliomas.
• Approximately 20% of childhood brainstem gliomas are not diffuse pontine tumors; these non-diffuse pontine lesions, such as tectal gliomas and exophytic cervicomedullary tumors, are often low-grade gliomas and have a relatively good prognosis.
• Over 90% of children with diffuse pontine gliomas will die of disease within 18 months of diagnosis.
• Radiotherapy remains the only effective, albeit transient, therapy for diffuse pontine gliomas.
• Biopsy and autopsy studies have disclosed biological subtypes of diffuse pontine gliomas, which most frequently have mutations of chromatin remodeling genes.
Historical note and terminology
Brainstem gliomas are, by definition, glial tumors that primarily arise within the brainstem. Concepts concerning brainstem gliomas have changed remarkably since the advent of MRI. Although the majority of brainstem gliomas arise in the pons, subsets of patients have been identified with more caudal or rostral tumors (Packer et al 1993a; Packer et al 1993b). In addition, MR has more clearly identified the extent of lesions and the tendency of some brainstem tumors to infiltrate the diencephalon, the cervical cord, and even the cerebellum (Barkovich et al 1991).
The pathology of brainstem gliomas is complex. Although pure low-grade and high-grade tumors do exist, more commonly a mixed glial pattern is seen, with areas of low-grade glioma in contiguity with regions of frank anaplasia (Littman et al 1980). For unclear reasons, the location of the tumor within the brainstem is often related to pathology, as benign lesions tend to occur more frequently in the mesencephalon and the low medulla. Therefore, brainstem gliomas are separated into 3 relatively distinct, but overlapping, groups: (1) diffuse pontine gliomas, (2) tectal lesions, and (3) cervicomedullary masses. As of 2016, due to the recognition that nearly 80% of diffuse intrinsic gliomas of the brainstem have a H3K27M mutation and that infiltrating gliomas of pons behave similarly to those of the midbrain or thalamus, the WHO created a new tumor category: diffuse midline glioma, H3 K27M; this essentially replaces the nomenclature of these tumors as diffuse intrinsic pontine gliomas (DIPGs) (Louis et al 2016).
Diffuse intrinsic brainstem gliomas almost always involve the pons, with or without extension to other brainstem sites, and constitute the majority of childhood tumors. These primarily pontine or diffuse intrinsic tumors make up approximately 80% of all brainstem gliomas and are highly resistant to treatment. Pathologically intrinsic diffuse brainstem tumors usually display mixed features, including areas of malignancy.
Up to 10% of brainstem gliomas arise in the medulla or at the cervicomedullary junction (Epstein and McCleary 1986; Stroink et al 1987). These tumors tend to be dorsally exophytic and histopathologically low-grade—the majority being pilocytic astrocytomas. Such cervicomedullary tumors carry a more favorable prognosis and may be amenable to total, or near-total, surgical resection.
Focal, or localized, tumors of the mesencephalon may also occur. Such lesions, especially those of the tectum, are often indolent and histopathologically low-grade (Vandertop et al 1992).
Children with neurofibromatosis type 1 are at increased risk to develop apparent brainstem gliomas (Milstein et al 1989; Pollack et al 1996). The patterns of growth and presentation for children with brainstem lesions and neurofibromatosis are variable, with some patients being asymptomatic at the time when lesions are radiographically identified and others having stable neurologic deficits. Once again, the understanding of brainstem gliomas in children with neurofibromatosis has changed dramatically since the advent of MRI, especially with routine screening of asymptomatic newly diagnosed patients with neurofibromatosis. It is now believed that many such lesions are hamartomas that will not grow over time. In any event, all lesions in children with neurofibromatosis should be evaluated circumspectly, and treatment should only follow documented progression.
Despite the initial variability in clinical presentation and histopathologic features at the time of diagnosis, later in the course of disease, the majority of patients with progressive brainstem gliomas will be found to harbor tumors that show areas of malignancy. It is unclear whether this finding represents a dedifferentiation of the tumor or whether malignant foci were present in the tumor at the time of diagnosis. At the time of progression, intrinsic brainstem gliomas tend to be extremely bulky and infiltrative, essentially destroying the normal architecture of the brainstem. Leptomeningeal dissemination is not rare at the time of disease progression, occurring in up to one third of patients at initial relapse.
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