The brainstem is divided into three major areas—midbrain, pons and medulla—and different types of tumors can occur in any of these locations. A glioma is a tumor that arises from a cell in the brain called a glial cell. One type of glioma is called an astrocytoma, which is a tumor that arises from a specific type of glial cell called an astrocyte. The two major types of astrocytomas are pilocytic astrocytomas and diffuse, infiltrating astrocytomas. The term DIPG specifically refers to a diffuse, infiltrating astrocytoma that develops in the pons.
Who is Affected by DIPG?
Each year approximately 200 children in the United States are diagnosed with DIPG.The age range is broad, but the most common age at diagnosis is 7 to 9 years. All races and both sexes are equally affected.
Why Do Certain Children Get DIPG?
In short, doctors don’t know why. There are no known associations of DIPG with any environmental or infectious agents. Most researchers who study DIPG believe these brain tumors, similar to other tumors affecting children, arise when normal developmental and maturational processes go awry. In this case, developing brain cells accumulate alterations in their DNA that prevent them from properly maturing. These alterations allow the developing brain cells to continue growing, and this growth eventually becomes out of control, leading to cancer. During the process of uncontrolled growth, DIPG cells can gain DNA alterations that allow them to resist the effects of radiation and chemotherapy, making these cancer cells extremely difficult to kill.
Clinical signs of DIPG
The signs and symptoms of DIPG can start gradually. The pons contains nerve centers that control eye movements, facial movements, swallowing, and speech. As pontine glioma tumors grow, the cancer cells interfere with these centers, causing disruption of their functions. Sometimes parents notice odd eye movements, slurred speech, difficulty swallowing, and trouble maintaining balance, or drooping of one part of their child’s face. The pons also contains nerves that run from the brain to the rest of the body. Pontine tumors can press on and interfere with the function of these nerves, leading to weakness in an arm and/or a leg.
Tumors in the brainstem can also cause increased pressure within the skull. The swelling from the tumor can cause increased pressure directly, or it can block the flow of spinal fluid from the skull (where it is made) to the spinal cord (where it is absorbed). Increased pressure can cause patients to complain of persistent headaches and in some patients can lead to nausea and vomiting. These daily signs of increased pressure inside the skull will get worse over time, as the tumor grows.
DIPG Appearance on MRI
A magnetic resonance imaging (MRI) scan is the best non-invasive way to determine the size and properties of brain tumors. DIPGs have a characteristic appearance on an MRI, which other tumors that grow in the pons or other parts of the brainstem do not share. The boundaries of a DIPG are difficult to determine, because the tumor cells invade the surrounding tissue of the pons. A DIPG generally does not have portions of the tumor that push outside of the pons’ normal structure. In contrast, a pilocytic astrocytoma, another less-aggressive brainstem tumor, has a more focal appearance, is more likely to have a part that buds out of the normal structure of the brainstem, and will displace rather than invade surrounding brain tissue.
Because the MRI appearance of the two most common types of pediatric brainstem tumors, DIPGs and pilocytic astrocytomas, are so different, they can be accurately identified the vast majority of the time by MRI alone. In rare cases where the diagnosis is uncertain based on MRI results, neurosurgeons can perform biopsies to obtain small amounts of tissue for examination under a microscope by pathologists (doctors trained to identify the type of tumor by examining it under a microscope). The biopsy is performed very carefully, but because the pons contains many important neurologic centers, including those that control breathing and swallowing, there can be complications of biopsy, including additional neurologic impairment. For these reasons, biopsy is generally only performed in cases where the diagnosis is not clear from an MRI scan. In the future, some clinical trials may include a biopsy to find out more information about the tumor prior to starting therapy.
Pathologists grade a tumor based on its features. The characteristics that pathologists examine include cell growth, cell death, invasion of surrounding normal cells, and the architecture of the tumor itself—this refers to how mature or immature the cells look, among other factors.
Pathologists grade brainstem tumors on a 1 to 4 scale. The lower numbers generally indicate less-aggressive tumors, including pilocytic astrocytomas. The lowest grade consistent with a DIPG is a grade 2 tumor, but many DIPG tumors will be grade 3 or 4 (the most-aggressive, fastest-growing grades).
Clinical Course of DIPG
Once the diagnosis of a DIPG is suspected, anti-inflammatory steroids (such as dexamethasone) are usually started. The steroids can improve symptoms quickly by decreasing the swelling associated with the tumor. Steroids can cause side effects including increased moodiness, agitation, weight gain, increased appetite and high blood pressure and blood sugar. These last two side effects can be controlled with medication, if they become severe.
The only treatment that is routinely recommended for the treatment of all children with a DIPG is x-ray radiation therapy (XRT). XRT can be given either alone or with chemotherapy and usually takes 4 to 6 weeks to complete. Side effects during radiation can include mild nausea and fatigue.
Many chemotherapeutic drugs have been tried for DIPG, with studies looking at the use of chemotherapy before XRT, during XRT, immediately following XRT, and at the time of tumor progression. The results have been disappointing, with no drug(s) to date improving survival. While pediatric oncologists continue to develop new therapies for DIPG, the mainstay of current treatment remains XRT. There are ongoing clinical trials for DIPG, which allow new drugs to be tested in this disease. While there are always risks when enrolling in clinical trials, they are the best way to get your child the most promising new medications and to make sure the pediatric oncology community learns all it can about what therapies work best for DIPG.
Most DIPG tumors in the beginning respond to a combination of radiation and steroids. The child’s neurologic deficits will very often decrease and may disappear completely. Over the course of weeks to months, the steroids can be decreased and then stopped in many cases. The child can often return to school, take special trips, and almost return to normal life. During this time, the child has regular MRI scans to measure the regression of the tumor and monitor if the tumor is coming back.
In almost all cases, after about 6 to 12 months, the DIPG tumor starts to grow again. Sometimes the neurologic symptoms are the same as when the child was first diagnosed with DIPG. Sometimes new nerves and systems are affected. The child will often begin to show neurologic symptoms even if the MRI scan of the tumor appears largely unchanged.
Once the tumor has started to grow again, no further treatment has been shown to improve survival. When children start to have neurologic symptoms, they are often restarted on steroids. This treatment can sometimes improve symptoms for a short time. However, the tumor will continue to grow, and even if the steroid doses are increased, the child’s symptoms will continue to worsen. Eventually the tumor grows until it affects nerve centers that are important for swallowing, breathing, and controlling heartbeat.
If the tumor is blocking the flow of cerebrospinal fluid (CSF), some parents—in discussion with the doctors—may decide to have a neurosurgeon place a VP-shunt to help with pressure symptoms. A VP-shunt is a flexible plastic tube that bypasses the blockage in the brainstem and allows the CSF fluid to pass out of the skull. Neurosurgeons place the shunt into the fluid cistern in the brain, and then pass it out of the skull, under the skin, and to the abdomen, where the CSF is absorbed. This procedure can improve some of the headache and nausea symptoms of increased intracranial pressure, and it can extend the life of children with DIPG; it does not, however, change the ultimate outcome.
Only very few children are long-term survivors of DIPG. Because biopsies are not performed on these children with typical appearing DIPGs, it is unclear whether or not they actually had DIPG to start with, or in fact had a different tumor or condition that looked like a DIPG on the MRI. There is no one treatment that these children received that set them apart from the vast majority (more than 95 percent) of children who die from DIPG. Pediatric oncologists are actively looking for new treatments and are trying to learn more about DIPG. They hope that by learning more from tumor tissue taken at autopsy from children who die from DIPG they can help children who develop DIPG in the future.