Childhood brainstem glioma

Summarize

The term "brainstem glioma" reflects two characteristics of this tumor: first, its location, which usually means that it originates in the brainstem (including the midbrain, pons, and medulla oblongata); and second, that it originates from glial cells.

Childhood brainstem gliomas are divided into two main groups: focal brainstem gliomas (FBSG) and diffuse intrinsic pontine gliomas (DIPG), which are highly malignant brain tumors.

Approximately 10% to 20% of CNS tumors presenting in children are brainstem glial tumors. Of these, FBSGs account for about 20% of childhood brainstem gliomas, usually occurring outside of the pontine brain (which is part of the brainstem), and the majority of the pathologic types are either hairy cell astrocytomas (WHO grade I) or fibrous astrocytomas (WHO grade II). In contrast, the majority (80%) of other pediatric brainstem tumors are DIPGs, with the pathologic type being malignant gliomas of WHO grade II to IV. DIPGs in children under the age of 3 years are likely to have a better prognosis than DIPGs in children 3 years of age and older.

The etiology of childhood brainstem gliomas is still unclear, and relevant studies in recent years have shown that mutations in genes such as H3F3A, HISTlH3B/C, IDHl, TP53, PPMlD, ACVRl, and BRAF may be associated with the development of brainstem tumors. In addition to this, some pediatric brainstem glioma patients are associated with neurofibromatosis type 1 (NF1).

Epidemiological

There are approximately 300-400 new pediatric brainstem tumors in the United States each year, and the incidence of pediatric brainstem gliomas is 0.60/100,000 per year. Approximately 10% to 20% of CNS tumors presenting in children are brainstem glial tumors; of these, DIPG accounts for approximately 75-80% of pediatric brainstem tumors. Most pediatric DIPGs are diagnosed between the ages of 5 and 10 years; FBSGs have a lower incidence.

At present, China lacks a large-scale systematic epidemiological survey of brainstem tumors. Academician Wang Zhong et al. have counted 311 patients with brainstem tumors surgically treated at Beijing Tiantan Hospital of Capital Medical University from 1980 to 2001, which accounted for 50.8% of the surgical treatment of brainstem occupying lesions during the same period, and 3.6% of intracranial gliomas during the same period.

Etiolog & Risk factors

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Classification & Stage

Currently, there are six main pathologic classifications of brainstem gliomas in children, which are:

(1) Hairy cell astrocytoma (WHO grade I)

(2) Astrocytoma (WHO grade II)

(3) Oligodendroglial astrocytoma (WHO grade II)

(4) Mesenchymal astrocytoma (WHO grade III)

(5) Mesenchymal Oligodendroglial Astrocytoma (WHO grade III)

(6) Glioblastoma (WHO grade IV)

In addition, combining the age of onset, molecular genetic features, and prognosis of brainstem gliomas, brainstem gliomas can be divided into the four molecular subtypes described below:

(1) H3F3A K27M (encoding histone H3.3) mutant

H3F3A K27M is the highest-frequency mutation identified in brainstem gliomas, and this type of tumor is insensitive to radiotherapy, prone to metastatic recurrence, and has a poor prognosis.

(2) HISTlH3B/C K27M (encoding histone H3.1) mutant

It is common in DIPG patients younger than 5 years of age and has a better prognosis compared to the H3F3A K27M mutant type, which is often accompanied by the ACVRl mutation.

(3) IDHl mutant type

It is seen only in adults, predominantly non-DIPG, with a median age at diagnosis of 43 years and a favorable prognosis.

(4) Other types

A small number of patients do not have IDHl/2, H3.3/3.1 mutations and are double-negative. The pathogenesis of this group of patients requires further study.

Clinical manifestations

Due to the rapid progression of diffuse endogenous pontine gliomas (DIPG), children usually have symptoms for a month or less before diagnosis. Symptoms typically deteriorate rapidly, which is associated with rapid tumor growth, resulting in compression or dysfunction of the pontine brain and nearby anatomical structures.

Children with DIPG often present with the classic triad of symptoms (cranial neuropathy, long fasciculations and ataxia). Children with DIPG may also present with only one or two of the triad of symptoms. The neurological manifestations vary as the tumor grows or invades different areas.

Diplopia is often the first symptom and is caused by problems with the function of the VIth pair of cranial nerves in the pons, a condition called abduction palsy.

Facial paralysis, on the other hand, is a manifestation of damage to the facial nerve in pair VII.

During the neurological examination, the doctor usually performs a Pap test, in which the child is laid flat with the lower limbs straightened, and the doctor will hold the ankle in one hand, and with the other hand, he or she will use a blunt needle or bamboo skewer to scratch along the lateral edge of the sole of the foot, from back to front, to the root of the little toe, and then turn to the inner side.

A normal person presents with the toes flexed toward the metatarsal plane, which is a negative Bartholomew's sign, or a positive Bartholomew's sign if they present with the bunion flexed dorsally and the remaining four toes spread out in a fan-like pattern. A positive Bartholomew's sign is caused by damage to the long motor bundles that run from the brain through the pons to the spinal cord.

In addition, cerebellar function may be affected by ataxia, dysarthria, or dysphonia. In less than 10% of children with DIPG, obstructive hydrocephalus due to pontine dilatation also leads to symptoms of increased intracranial pressure, such as headache, nausea, or fatigue. In addition, children may also exhibit non-specific symptoms, such as behavioral changes and decreased academic performance. Focal brainstem gliomas (FBSG), on the other hand, present with a variety of signs and symptoms depending on the location in the brainstem.

Taken together, the common clinical manifestations of childhood brainstem gliomas are as follows:

● Inability to move one side of the face or body

● Loss of balance, difficulty walking

● Vision and hearing problems

● Morning headaches or headaches that are significantly relieved by vomiting

● nausea and vomiting

● unusually tired

● Significantly more or less activity than usual

● Behavior change

● learning difficulty

Clinical Department

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Examination & Diagnosis

The diagnosis of brainstem tumors in children requires a combination of the doctor's observation of the child's clinical presentation and magnetic resonance imaging (MRI). However, when the diagnosis cannot be confirmed using these imaging diagnostics, or if the tumor is not diffuse or endogenous, a biopsy or surgical removal of the tumor is usually performed. The histological diagnosis after biopsy or surgery is a careful study of the excised tissues in order for the doctor to do pathologic staging to determine the characteristics, type, and extent of the tumor, to determine how to treat it, and to make a prognosis of the effect of the treatment.

The tumors are growing inside the skull and craniotomy is a very scary procedure indeed for most parents, so new methods such as stereotactic biopsy may become available in the future, which may make biopsy safer.

In addition to this, children with neurofibromatosis type 1 (NF1) are at greater risk of developing brainstem tumors, they may present with a long history of the disease, and the diagnosis can be confirmed by screening for NF1.

Therefore, routine testing for BRAF V600E, BRAF-KIAAl549 fusion mutation and IDHl/2, H3 K27M, PPMlD, TP53, ACVRl mutation and MGMT promoter methylation is recommended for pediatric brainstem gliomas. The above molecular pathology results can help guide treatment and determine prognosis.

Clinical Management

Treatments for brainstem gliomas have not progressed in any particular way over the years. To date, no particularly good new treatments have been identified, and the routine use of radiation therapy alone is the standard treatment, which generally stabilizes or improves the disease.

1. Radiotherapy

Focal radiotherapy is the mainstay of treatment for brainstem gliomas, improving or stabilizing the patient's condition. The dose range for conventional radiotherapy is 54-60 Gy, or up to 72 Gy if hyperfractionation is used.

There is no evidence that radiotherapy doses greater than 72 Gy result in greater efficacy in pediatric patients with brainstem gliomas.

The efficacy of radiotherapy depends on tumor location, histological type, and response to early treatment, in addition to the radiation dose. Survival after radiotherapy has been reported to be better in patients with exophytic tumors than in those without an exophytic predisposition.

Radiotherapy should be given to any patient with significant and worsening neurologic symptoms. Radiotherapy should be given to all patients with clearly progressive tumors, except for some adult patients with parietal or cervical medullary lesions or who have only mild symptoms for a long period of time who can be followed up periodically without radiotherapy.

2. Chemotherapy

Adjuvant chemotherapy is not used in children because its efficacy has not been proven. Neoadjuvant chemotherapy has been shown to improve survival in children with diffuse gliomas of the brainstem, but its efficacy in adults is also unproven, so adjuvant chemotherapy after radiation therapy cannot be recommended at this time. In addition, the effectiveness of combination radiotherapy (usually temozolomide) has not been thoroughly evaluated. Although the effectiveness of chemotherapy at relapse is uncertain, it may benefit some patients.

Chemotherapeutic agents routinely used to treat brainstem gliomas generally include temozolomide and carboplatin/vincristine. Antiangiogenic agents that have been successfully used to treat supratentorial glioblastoma include thalidomide and bevacizumab, the latter of which is a VEGF receptor inhibitor that was approved in May 2009 as a single-agent treatment for recurrent glioblastoma. In addition, targeted agents against EGFR (e.g., erlotinib) are currently effective in the treatment of supratentorial glioblastoma. If chemotherapy combined with or concurrent with radiation therapy is needed for pediatric brainstem glioma patients, it should first be considered in a clinical trial.

3. Surgical excision

Otherwise, surgical resection may be done in conjunction with radiation therapy, chemotherapy, or both. Typically, surgical resection is not used to treat diffuse pontine glioma (DIPG) or tectal glioma.

Surgery may be considered for patients with the following conditions:

● Tumors of the cervical medullary-medullary junction

● Tumor of the dorsal exophyte of the brainstem protruding into the fourth ventricle

● cystic tumor

● Tumors with well-defined margins and occupying effect after enhancement

● Benign tumors (e.g., those with slow clinical progression)

Prognosis

The median survival of children with diffuse pontine gliomas (DIPG) is generally less than 1 year, i.e., half of the children survive less than 1 year. In contrast, focal brainstem gliomas (FBSG) (e.g., hairy cell astrocytomas) have a better prognosis, with a 5-year overall survival rate of more than 90%. Other factors that influence prognosis include histologic classification, age of onset, and molecular genetic features. The higher the histologic WHO classification, the worse the prognosis for the average patient. children under 3 years of age with a diagnosis of DIPG have a better prognosis. children with NF1-related brainstem tumors may have a better prognosis than other children.

Follow-up & Review

Surgery, radiation, and chemotherapy are all aimed at stabilizing the tumor from growing, so the role of follow-up is to observe the changes in the tumor, which is very important.

After treatment of brainstem tumors in children, standard follow-up often includes periodic clinical assessments and MRIs.The duration of MRI follow-up varies from patient to patient. It depends largely on the presence of residual imaging abnormalities and the histologic type of the brainstem tumor.

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Routine

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Cutting-edge Therapeutic & Clinical Research

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References

1. https://www.cancer.gov/types/brain/hp/child-glioma-treatment-pdq
        2. https://www.cancer.gov/types/brain/patient/child-glioma- treatment-pdq
        3. https://www.childhoodbraintumor.org/medical-information/diagnostics-and-epidemiology/item/272-dipg-2014
        4. Green AL, Kieran MW. Pediatric brainstem gliomas: new understanding leads to potential new treatments for two very different tumors. Curr Oncol Rep. 2015 Mar;17( 3):436. doi: 10.1007/s11912-014-0436-7
        5. https://emedicine.medscape.com/article/1156030-treatment
        6. "Chinese Expert Consensus on Comprehensive Diagnosis and Treatment of Brainstem Gliomas" Chinese Journal of Neurosurgery March 2017, Vol. 33, No. 3, pp. 217-229