Intrinsic brainstem tumor
Brainstem tumors were first described by Kummel in 1881 1) and Monakow 2). The first nosological classification was reported in 1926 by Bailey and Cushing who emphasized, for the first time, that brainstem gliomas could develop from certain embryological cells 3).
Primary brainstem tumors are a group of diseases that may be located in the mesencephalon, pons, and medulla oblongata. They are generally considered as diseases with a poor prognosis, because surgery nearby such eloquent structures within the brainstem is a great challenge for many neurosurgeons and complete resection can be achieved in only a small number of selected patients 4).
Classification
Intrinsic brainstem tumors are classified based on their location, histology, and the age of the patient. Here's an overview of the primary classifications:
1. Location-Based Classification Midbrain Tumors: Tumors located in the upper part of the brainstem. Pons Tumors: Tumors situated in the middle portion of the brainstem. Medullary Tumors: Tumors found in the lower part of the brainstem.
2. Histological Classification Glial Tumors: Astrocytomas: Common in both children and adults; can be low-grade (pilocytic astrocytoma) or high-grade (anaplastic astrocytoma or glioblastoma). Ependymomas: Tumors arising from ependymal cells; can occur in the fourth ventricle area. Non-Glial Tumors: Brainstem Germ Cell Tumors: These include germinomas and other germ cell tumors, typically found in children and adolescents. Choroid Plexus Tumors: Although more commonly found in the lateral ventricles, they can also occur in the brainstem.
3. Age-Based Classification Pediatric Brainstem Tumors: Commonly includes pontine gliomas, especially diffuse intrinsic pontine gliomas (DIPG). Adult Brainstem Tumors: Less common than in children and typically includes high-grade gliomas and metastases.
4. Molecular and Genetic Classification Recent advances in molecular genetics have led to classifications based on genetic alterations (e.g., IDH mutations, histone mutations) that influence prognosis and treatment.
Common Types of Intrinsic Brainstem Tumors
Diffuse Intrinsic Pontine Glioma (DIPG): A highly aggressive tumor located in the pons, primarily affecting children.
Pilocytic Astrocytoma: A slow-growing tumor often found in the brainstem, especially in younger patients.
Ependymoma: May arise in the fourth ventricle or brainstem and can vary in aggressiveness.
Anaplastic Astrocytoma: A more aggressive form of astrocytoma that can occur in the brainstem, typically seen in adults.
Brainstem glioma
Treatment
Intrinsic brainstem tumor treatment.
A report summarizes the first author's experience with radical excision of intrinsic non-exophytic brain-stem gliomas in 34 pediatric patients. On retrospective analysis, these tumors may be classified into three subgroups: focal, diffuse, and cervicomedullary. A focal neoplasm is a circumscribed mass less than 2 cm in diameter and without associated edema. Tumors of a larger size or in which the “focal” neoplasm is associated with a large area of apparent edema are classified as diffuse. Cervicomedullary neoplasms occur at the junction of the medulla and spinal cord and involve both of the structures but do not extend rostrally into the pons. A radical tumor excision was carried out in all patients, and the only mortality and morbidity occurred in children harboring diffuse gliomas. All of the diffuse gliomas were malignant (grade III or IV astrocytomas), whereas three of the four focal astrocytomas and all of the cervicomedullary tumors were grade II astrocytomas. No patient with a diffuse astrocytoma was benefitted by surgery, while two of the focal astrocytomas and all of the cervicomedullary neoplasms either became stable or improved postoperatively. It is concluded that, although surgery may be accomplished within the substance of the brain stem with low morbidity and mortality rates, it is not indicated for malignant astrocytomas as it has no impact on the biology of the neoplasm. Therefore, while primary radical excision is recommended for cervicomedullary neoplasms, which are often benign, the more traditional radiation therapy and/or chemotherapy remain appropriate for tumors above the medulla 5).
Outcome
The outcome of intrinsic brainstem tumors can vary widely based on several factors, including the type of tumor, its location within the brainstem, the age of the patient, and the overall health of the individual. Unfortunately, many intrinsic brainstem tumors are associated with a generally poor prognosis. The brainstem is a critical region of the brain responsible for regulating essential functions such as breathing, heart rate, and basic reflexes. Tumors in this area can be challenging to treat due to their location and the potential impact on vital functions.
Children with WHO grade 3-4, Ki-67 LI ≥ 20%, TP53 mutation, H3K27M mutation, DIPG, and hydrocephalus had significantly decreased overall survival (OS).
A high rate of resection has been obtained in non-DIPG, and surgical intervention is remarkably safe and efficient for children with brainstem tumors. WHO grade 3-4, H3K27M mutation and hydrocephalus indicate poor prognosis in children with brainstem tumors 6).
Case series
50 children with brainstem tumors who underwent surgical treatment, including frameless- or frame-based stereotactic biopsy and resection, were included and followed up for clinical and biological analysis. Factors of outcomes were assessed by univariate and multivariate analysis.
27 cases (54.0%) underwent resection in all children with brainstem tumors. The rate of resection reached as high as 81.8% in children with non-diffuse intrinsic pontine glioma (DIPG), while in children with DIPG, biopsy was performed in the majority, and resection was obtained in the minority with focal necrosis. A rare complication was found following the surgery. Multivariate analysis considered World Health Organization (WHO) grade 3-4, with hazard ratio (HR)=4.48, 95% confidence interval (CI) of 2.84-8.69, p=0.001, H3K27M mutation (HR=2.50, 95% CI 1.73-5.69, p=0.015), and hydrocephalus (HR=2.17, 95% CI 1.08-5.32, p=0.014) as independent adverse prognostic factors. For Kaplan-Meier analysis, children with WHO grade 3-4, Ki-67 LI ≥ 20%, TP53 mutation, H3K27M mutation, DIPG, and hydrocephalus had significantly decreased overall survival (OS).
A high rate of resection has been obtained in non-DIPG, and surgical intervention is remarkably safe and efficient for children with brainstem tumors. WHO grade 3-4, H3K27M mutation and hydrocephalus indicate poor prognosis in children with brainstem tumors 7)
All patients admitted for a brainstem tumor at the Pediatric Neurosurgical Unit at Hôpital Femme Mère Enfant hospital between January 1997 and December 2019 were considered. Patients data were obtained through a retrospective review of the medical records; follow-up was from the last outpatient consultation.
One hundred and twelve patients were included. Eighty-five patients (75.9%) had open surgery or stereotactic biopsy. Thirty-five patients were treated for hydrocephalus. Sixty-six received an adjuvant treatment. Several protocols were adopted according to the SFOP and SIOP during this period. The overall survival rate was 45% with a median follow-up of five years (range 1-18 years). However, the survival rate was very different between the diffuse intrinsic pontine gliomas (DIPG) and the other tumor types. If we exclude the DIPG (59 patients), of which only 1 was alive at 3 years, the survival rate was 90.6% (only 5 deaths over 53 patients) with a median follow-up of 5 years.
The series confirms that benign tumors of the brainstem have a good survival when treated with surgical removal ± adjuvant therapy. Diffuse pontine gliomas continue to have a dismal prognosis. Individualized treatment based on molecular fingerprints may help to select the best adjuvant therapy and hence potentially improve survival 8).