High-grade glioma in children

Summarize

Central Nervous System (CNS) tumors are Brain tumors are the second most common tumor in children (20% of all pediatric cancers). There are two main types of cells that make up the CNS: neurons and glial cells. Neurons are responsible for information processing, while glial cells form the support and nourishing network for neurons. Gliomas are CNS tumors that originate in glial cells, and approximately 2/3 of all childhood brain tumors are gliomas.

Glial cells can be further subdivided into different types, including oligodendrocytes, which cover the axons of neurons with myelin sheaths, and astrocytes, which have many functions. Gliomas develop from the abnormal growth of glial cells that support neurons in the brain, i.e., tumors of glial cells, especially astrocytes and oligodendrocytes.

Approximately 60% of brain tumors in children occur in the sub-tentorial region (the posterior cranial fossa). The infratentorial portion is primarily the lower part of the brain near the middle of the back of the head and includes the cerebellum and the brainstem, whose main function is to control movement and balance. The brainstem is the middle part of the brain that connects the brain to the spinal cord. The brainstem controls breathing as well as eye movements and transmits information about sensations and involuntary muscle movements. The epencephalon is the main part of the brain above the cerebellum and is the largest part of the central nervous system. The brain controls thinking, emotions, problem solving, learning, speaking, reading, writing, and voluntary movement. Gliomas can be seen anywhere in the brain or spinal cord.

Epidemiological

The incidence of high-grade gliomas in children is significantly lower than in adults, with fewer than 400 children newly diagnosed with high-grade gliomas each year in the United States.

Overall, the incidence of brain tumors is 4.84 cases per 100,000 children per year. Although the incidence of pediatric brain tumors has increased over the past few years, it is likely that there has not been an actual increase, and the increase in the number of diagnosed brain tumors may be due to an improved level of diagnosis.

Etiolog & Risk factors

In most cases, we don't know why children develop brain tumors. We do know that there are a number of syndromes or genetic mutations that increase a child's risk of developing a glioma. These syndromes include Li-Fraumeni syndrome, Turcot syndrome, neurofibromatosis, and tuberous sclerosis. Sometimes, children who have been treated for other types of cancer may develop secondary brain tumors.

Classification & Stage

Gliomas can be classified into four grades based on the grading system most commonly used by the World Health Organization (WHO). WHO grade I and II gliomas are considered low-grade, and although these tumors are not considered benign, they are slow-growing and do not usually spread to other tissues or organs. WHO grades III and IV are high-grade gliomas that are more malignant.

Although the histopathology of high-grade gliomas in children is very similar to that of adults, their biology is very different. The World Health Organization's criteria were revised in 2016, and many gliomas are now classified by their names and descriptions of their molecular or genetic features.

● mesenchymal astrocytoma

This is a high-grade (WHO grade III) glioma. It is called mesenchymal because the tumor cells do not have the structure of normal brain glioma cells. These tumors can grow anywhere in the CNS tumor. These tumors grow faster than low-grade gliomas and are more likely to come back even after treatment. They usually do not spread to nerve tissue outside the site of origin.

● Glioblastoma multiforme

This is a high-grade (WHO grade IV) glioma. These tumors can occur anywhere in the brain or spinal cord. Although the tumors may start in one part of the brain, they sometimes spread to other areas of the central nervous system. These tumors are more aggressive, which means they grow faster than low-grade gliomas, and they may come back even after treatment.

● Diffuse midline glioma

H3K27M mutant (formerly known as diffuse pontine glioma). This is a highly malignant glioma found in the brainstem. These tumors account for 10% of all brain tumors in children. Children with these tumors usually have significant neurological dysfunction leading to their brain tumor diagnosis.

The staging of brain tumors depends on the type of tumor. Staging will depend on whether the tumor is located only at the primary site or whether it has spread to other parts of the CNS. Gliomas do not usually spread to other parts of the CNS and usually they only metastasize in localized areas.

Clinical manifestations

When brain tumors grow, they press on normal parts of the brain and cause dysfunction. Signs and symptoms of brain tumors depend on where the tumor is located in the brain. Gliomas can occur anywhere in the central nervous system. However, neither parents nor doctors can know exactly what type of brain tumor is causing these problems from the symptoms.

The most common symptoms are headache and vomiting. Headaches that occur in the morning or that improve with vomiting can be caused by a brain tumor. Severe and frequent vomiting that is not caused by a gastrointestinal disorder is also a reason to suspect a brain tumor.

Other symptoms of brain tumors include changes in vision, such as double vision or blurred vision, and hearing or speech difficulties. Children with brain tumors may become less stable or have difficulty balancing when walking. This is especially common in patients with astrocytomas, as they usually occur in the subcurtain area. In addition, children may become clumsy or have difficulty holding objects or writing. And children may feel sleepier than usual. If a child has a brain tumor, their behavior may also change. In some cases, the first sign of a brain tumor can be a seizure. In infants, if a brain tumor is present, sometimes the head can become significantly larger. Children with high-grade gliomas tend to develop symptoms in a shorter period of time because these tumors grow faster.

Clinical Department

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Examination & Diagnosis

1. Medical history and examination

The first step in diagnosing a brain tumor is an evaluation by a doctor. The doctor will ask many questions about the changes in the child and all the signs and symptoms mentioned above. They will ask if other members of the family have brain tumors or any other cancers, as some types of cancer tend to run in families. A complete physical examination, including a thorough neurological exam, will also be performed. A neurological exam evaluates the functioning of the brain and spinal cord to look for any abnormalities. The neurological exam will include a check of the child's mental state, coordination, senses and reactions. If the child is old enough to walk, the child will also be checked for normal walking.

2. Imaging

The two main screening methods are computed tomography (CT) scanning and magnetic resonance imaging (MRI).

A CT scan uses x-rays to take a series of pictures of the brain from different angles and takes a short time to scan. Sometimes a contrast dye can be injected into a vein before the CT scan to enhance the imaging. If the CT scan suspects a brain tumor, the patient will undergo a further MRI.

An MRI scan can take detailed pictures of the brain from many angles at different levels. A gadolinium-containing enhancer injected into a vein before the MRI will help to show the boundaries of the tumor more clearly.MRI scans can take a long time, and children need to be completely quiet during the scan, so sometimes medication is needed to put them to sleep so they don't move during the MRI scan.

Brain tumors can look different from normal brain tissue on a CT scan or MRI, and an experienced doctor or some reading skills can find out a lot based on how bright or dark it looks on a diagnostic picture. Depending on the type of tumor, an additional MRI scan of the spinal cord is sometimes needed to look for spread (metastasis) of the tumor to other areas.

High-grade gliomas, such as mesenchymal astrocytoma and glioblastoma multiforme, usually have poorly defined borders and an uneven appearance (parts of the tumor look different from other parts). There may also be swelling around the tumor, and the normal brain may be displaced by the compression of the tumor tissue. Diffuse pontine gliomas usually make the brainstem look larger because they occur in the brainstem.

3. Biopsies

The best way to make a final diagnosis of a brain tumor type is to look at the tumor cells under a microscope to evaluate the cancer. In order to do this, a small piece of tumor tissue is surgically removed from the lesion. This is called a biopsy. The pathologist will look at the tumor cells under a microscope to diagnose the pathological type of tumor.

4. Lumbar puncture

Children with high-grade gliomas may need a lumbar puncture (spinal tap) to determine if the tumor has spread into the spinal fluid.

Clinical Management

The main treatments for high-grade gliomas include surgical removal of the tumor, radiation therapy, and chemotherapy. As with most other brain tumors, attempts at curative treatment for high-grade gliomas begin with surgical removal. Ideally, the goal of surgery is to achieve a total resection, which means that the surgeon has removed all visible tumor and there is no visible tumor remaining on a post-surgical scan.

In addition, studies have shown that surgery alone is not enough to solve the problem, and most patients need chemotherapy and/or radiation therapy for further treatment. Sometimes brain tumors are located in certain parts of the brain where having surgery can lead to additional problems. This is the case in most optic nerve gliomas and brain stem gliomas. In these cases, the child should not undergo surgery and can be directed to radiation and/or chemotherapy.

1. Surgery

The mainstay of treatment for high-grade gliomas is to remove as much of the tumor tissue as possible while staying safe. Newer techniques such as intraoperative MRI can allow surgeons to obtain a more complete resection

The neurosurgeon will use a CT or MRI scan to determine the surgical plan.

● Total Resection (TR) is when the entire tumor is removed during surgery and no residual tumor is seen during surgery or on MRI.

● Gross total resection (GTR) is the surgical removal of more than 90% of the tumor.

● Subtotal Resection (STR) except is the removal of 51-90% of the tumor during surgery.

● Partial Resection (PR) is the removal of 10-50% of the tumor during surgery.

The definition of the extent of resection may vary slightly in some studies. GTR (global to the naked eye) is defined as total tumor resection with no increase in imaging; STR (sub-total resection) is defined as 90% or more of the tumor being resected; and 50-90% of the extent of resection is referred to as partial resection. The degree and extent of resection for an individual needs to be confirmed after careful communication with the doctor.

One of the difficulties in achieving total resection, especially for glioblastomas, is that microscopic tumor cells that are not visible to the MRI or neurosurgeon may extend beyond the obvious tumor boundaries. This is because these tumors are infiltrative, meaning they tend to invade normal brain structures. Some tumor cells may have migrated to the other side of the brain, far from the tumor seen on preoperative scans and during surgery. If surgical removal is not feasible in some cases, the surgeon may only obtain a biopsy to confirm the diagnosis. In these patients, the tumor cannot be safely removed completely.

Due to the aggressive nature of the tumor, children with high-grade gliomas require additional therapy after surgery. This additional therapy is to treat the tumor cells that remain after surgery that are not visible to the naked eye. Most children will have high-dose radiation therapy to the tumor site after surgery. This radiation therapy is usually given over a 6-week period and is combined with weekly chemotherapy. After radiotherapy is completed, children often receive further maintenance chemotherapy.

2. Radiotherapy

Radiation therapy uses X-rays or high-energy particles directed at the tumor to kill tumor cells. The dose of radiation depends on the type of tumor, the location of the tumor, and the age of the child.

Two types of radiation therapy can usually be used: photon radiotherapy and proton radiotherapy. Photon radiotherapy, the traditional form of radiotherapy, uses x-rays that are directed at the tumor, shone into the body, through the tumor, and then left through the other side of the body. This means that tissue on both sides of the tumor is radiated in addition to the tumor itself. This is not the case with proton therapy, where protons enter the body and reach their peak dose at the tumor site. This means that they generally do not over-radiate the normal tissue on either side of the tumor, and when radiation is administered to important parts of the body (such as the brain), proton therapy is precise and the benefits that come from it may be higher.

Radiation can have side effects, especially long-term damage to the development of very young children. The younger the child, the more careful one should be in choosing whether to have radiation or not, and many doctors usually choose to delay it as long as possible to give them a chance to grow and develop as much as possible before receiving radiation.

3. Chemotherapy

Chemotherapy can be given orally, intravenously, intramuscularly, or by sheath injection. After surgery, children with high-grade gliomas often receive chemotherapy in addition to radiation therapy. In addition to this, chemotherapy can be given before surgery, and some children may receive chemotherapy before surgery to shrink the tumor so that it can be more completely removed by surgery.

The main chemotherapeutic agents currently used to treat high-grade gliomas are vincristine, carboplatin, temozolomide, lomustine, vorinostat, bevacizumab, and irinotecan.

The role of chemotherapy in the treatment of high-grade gliomas has been controversial, but it is still frequently used because of the high rate of surgical failure in the treatment of high-grade gliomas in combination with radiation therapy. There have been a number of studies focusing on the role of chemotherapy in the treatment of high-grade gliomas, and in general, chemotherapy may provide some benefit for some patients. There are also a number of chemotherapies that are offered in the context of clinical trials.

Radiotherapy can cause irreversible damage to children, especially young ones, because of the undifferentiated damage to surrounding cells, so it is sometimes necessary to delay the use of radiotherapy, when children are aggressively treated with chemotherapeutic drugs, with a view to holding them over until they are old enough to undergo radiotherapy. While this technique has been shown to be somewhat effective for some brain tumors, it is less effective for children with high-grade gliomas. Adults with high-grade gliomas are usually treated with radiation and temozolomide, but the utility of this approach is controversial in the pediatric neuro-oncology community.

One difficulty with chemotherapy is how to ensure that the drug actually reaches the tumor area, since the blood-brain barrier tends to limit the transport of drugs from other parts of the body to the central nervous system.

Prognosis

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Follow-up & Review

After children are treated for high-grade gliomas, they need to be followed closely to monitor the recurrence of the cancer, to help them manage the side effects of treatment, and to help them transition to long-term survival. Because the presentation of high-grade gliomas is highly variable among children, monitoring and follow-up will need to be individualized. Initially, follow-up visits will be fairly frequent. Over time, these follow-up visits will become less frequent. The child's primary care team will develop an individualized follow-up plan for each child, which will require the cooperation of both the parents and the child.

Routine

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Cutting-edge Therapeutic & Clinical Research

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References

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