What is DIPG

DIPG is short for “diffuse intrinsic pontine glioma”, a rare fast-growing tumor that forms in cells called glial cells in a part of the brain stem called the pons. The pons controls vital life functions including balance, breathing, bladder control, heart rate, and blood pressure. Nerves that control vision, hearing, speech, swallowing, and movement also pass through this part of the brain. DIPG tends to be a high-grade tumor and is the most aggressive primary pediatric brain tumor with <10% of children surviving 2 years ¹⁾. Diffuse intrinsic pontine gliomas or DIPG tend to spread to nearby tissue and other parts of the brain stem with little notable mass effect ²⁾ and are hard to treat and have a poor prognosis (outcome).

DIPG is a diffuse tumor, meaning that the tumor is not well-defined or contained. The tumor extends finger-like projections into healthy tissue. Because of the location in the brainstem and spread out nature of the tumor, surgery cannot safely remove DIPG.

DIPG is almost exclusively seen in children, with a median age at diagnosis of 6 to 7 years ³⁾. Approximately 300 to 400 pediatric brain stem tumors are diagnosed each year in the United States. DIPG accounts for approximately 75% to 80% of pediatric brain stem tumors ⁴⁾. There are about 200-300 new cases of DIPG every year in the United States. Most children with DIPG are diagnosed between the ages of 5 and 10 years. DIPG is rare in adults.

Radiation therapy delivered over a 6-week period remains the mainstay of DIPG treatment ⁵⁾, but there is a great clinical need for improvements and advancements in treatment strategies ⁶⁾. Although radiation temporarily improves symptoms in most patients, it is not a cure. Upfront radiation appears to only provide transient relief of symptoms while offering minimal survival advantage ⁷⁾. Studies examining the role of alternative fractionation regimens and/or addition of radiosensitizers have failed to demonstrate a survival benefit ⁸⁾.

In the recently revised World Health Organization (WHO) classification of central nervous system (CNS) tumors, the majority of DIPG has neuropathologically been reclassified within a novel tumor entity: diffuse midline glioma, H3-K27 mutant (DMG H3-K27M). This entity is defined as an infiltrative high-grade glioma, located in the brain midline, i.e. usually brainstem, spinal cord, cerebellum or thalamus, with astrocytic differentiation and K27M mutation in either H3F3A or HIST1H3B/C ⁹⁾. Up to 85% of the DIPGs harbor this mutation ¹⁰⁾. Wild-type H3-K27 DIPGs have not yet been separately classified within the revised WHO classification, but show similar survival as H3-K27M DIPGs ¹¹⁾.

Figure 1. Brain anatomy

DIPG causes

Researchers do not yet know what causes DIPG. However, researchers are learning more about gene changes associated with these tumors. Having certain genetic disorders, including neurofibromatosis type 1 (NF1), may increase the risk of a brainstem glioma. There is no evidence that indicates DIPG is caused by environmental factors (exposure to chemicals or radiation).

Diffuse intrinsic pontine glioma symptoms

DIPG tumors grow quickly, and symptoms usually develop in a short period of time (often about 1 month before diagnosis). There is a rapid onset and fast progression of problems. Children with DIPG may present with the following classic triad of cerebellar signs, long tract signs, and cranial nerve palsies; however, children may present with only one or two of these symptoms at diagnosis:

1. Cranial neuropathies, particularly abducens paresis. Facial weakness or drooping or abnormal eye movement due to problems with nerves that control the muscles and sensation of the head, face, and eyes (cranial nerve disorders or neuropathies)
   • Cranial nerves are 12 pairs of nerves that arise in the brain. Cranial nerves 5, 6 and 7, which arise in the pons, can be affected in DIPG. Specific problems can be related to each of these nerves:
     • Cranial Nerve 5: Loss of sensation or numbness over the face and parts of the mouth.
     • Cranial Nerve 6: Abnormal eye movements such as not being able to look to the side or crossing of the eye so that it is pulled in towards the nose.
     • Cranial Nerve 7: Weakness over the face, particularly over the mouth and the eyelids.
     • Problems with cranial nerves 6 and 7 are most common in DIPG. Sometimes other cranial nerves can be injured. If the tumor spreads to an area above the pons (midbrain), patients can develop additional problems with eye movements. If the tumor spreads to area below the pons (medulla), problems with swallowing, and changes in voice can occur.
2. Weakness in the arms and legs, jerking movements, and abnormal reflexes (long tract signs).
3. Problems with balance and coordination (ataxia)

Signs and symptoms of DIPG may include:

• Loss of balance or problems walking
• Eye problems such as blurred vision, double vision, drooping eyelids, uncontrolled eye movements, not being able to fully close the eye, eyes don’t look the same direction together or appear crossed (strabismus)
• Facial weakness or drooping, usually on one side
• Drooling or problems swallowing
• Weakness in the legs and arms, usually on one side
• Irregular or jerking movements
• Abnormal reflexes
• In very young children, a failure to thrive

Less common symptoms may include:

• Nausea and vomiting
• Headache, especially in the morning and often gets better after vomiting
• Behavioral changes, school problems, irritability, or night laughter

Obstructive hydrocephalus caused by expansion of the pons can also be a presenting symptom. Nonspecific symptoms may also occur, including behavioral changes and decreased school performance.

Why does DIPG cause weight gain and face swelling?

This is a common question. However, most often, this is not due to the tumor itself. Weight gain, face swelling, and puffiness are mainly due to high doses of corticosteroid medications given to help manage symptoms of DIPG. Brain tumors can cause fluid and pressure to build up. This pressure (hydrocephalus) causes symptoms such as headaches, nausea, weakness, and problems walking. Steroid medicines like dexamethasone decrease brain swelling and pressure. But they also have side effects, especially when given in high doses or for a long time.

Corticosteroids can increase appetite and cause patients to eat more and gain weight. They can make it hard for the body to get rid of fluids, causing swelling. The body may also store fat differently, leading to puffy cheeks or “moon face.” Rapid weight gain sometimes causes stretch marks on the skin. The change in appearance due to corticosteroids can be very distressing to patients and families. Other side effects of steroid treatment include mood swings, irritability, and muscle weakness. Despite the side effects, these medicines are an important part of supportive care and quality of life for many brain tumor patients. Families should talk to their care team about side effects and goals of care.

Diffuse intrinsic pontine glioma diagnosis

Of pediatric brain tumors, about 10-20% are found in the brainstem. When a tumor develops in the brainstem, it is usually DIPG. However, about 20% of brainstem tumors are low-grade astrocytomas and are not considered DIPG.

Doctors test for DIPG in several ways. These tests include:

• A physical exam and medical history help doctors learn about the type and time course of symptoms, general health, past illness, and risk factors.
• A neurological exam measures different aspects of brain function including memory, vision, hearing, muscle strength, balance, coordination, and reflexes.
• Imaging tests are used to help identify the tumor, see how big the tumor is, and find out what brain areas may be affected. Magnetic resonance imaging (MRI) is the main imaging technique that is used to diagnose DIPG.

Doctors look for key features of the tumor on the MRI to diagnose DIPG:

1. The tumor is located in the pons.
2. It usually involves and expands most of the pons (intrinsic).
3. The tumor does not have well-defined borders. It infiltrates healthy tissue (diffuse).

The diagnosis is typically made using a combination of clinical signs and symptoms of short latency (<3-6 months) and characteristic radiographic findings, either on magnetic resonance imaging (MRI) or computed tomography (CT scan). Findings on MRI include an intrinsic, centrally located tumor involving >50% to 66% of the pons ¹²⁾ with hypointensity on T1 images ¹³⁾, hyperintensity on T2 images ¹⁴⁾ with indistinct tumor margins and engulfment of the basilar artery and absence of cystic or exophytic components ¹⁵⁾.

Role of biopsy in DIPG diagnosis

A biopsy is sometimes used to diagnose DIPG. Historically, biopsy has not been routinely performed as the standard of care unless a tissue analysis is required to identify a potential pharmacologic target. Although biopsy has not been shown to alter treatment outcomes,10 recent advances in stereotactic neurosurgery have enabled surgeons to obtain reliable tissue for histologic and genomic analyses with morbidity of <4% ¹⁶⁾. Complete surgical resection of DIPG is hindered by the location and infiltrative nature of the tumor ¹⁷⁾. However, it is becoming more common. Reasons for not doing a biopsy include:

• DIPG frequently has specific features on both MRI and clinical evaluation, so it can often be diagnosed without any additional tests.
• There is risk of causing harm by doing a biopsy because of the location of the tumor.
• A biopsy may not change treatment plans or influence outcomes.

With better surgical techniques and advances in the understanding of the biology of DIPG, the recommendation for a biopsy has become more common. After a biopsy, a pathologist will look at the tissue sample under a microscope to identify the specific type and grade of tumor. The tumor will also be tested for genetic changes or markers. Understanding tumor histology and molecular features may one day offer better treatments for DIPG such as targeted therapy and immunotherapy.

Staging and Grading of DIPG

There is no standard staging system for DIPG. Treatment recommendations are based on two main factors:

1. Whether DIPG is found only in the brainstem or if it has spread to other distant areas in the brain or spinal cord (metastatic disease)
2. Whether DIPG is newly diagnosed or has come back after initial treatment (recurrent disease)

Gliomas are grouped by how they look under the microscope. The more abnormal cells look, the higher the assigned grade. Grade I and II tumors are considered low grade gliomas. The cells look more like normal cells and grow more slowly. Grade III and IV tumors are considered high grade gliomas. They are aggressive and grow quickly and can spread throughout the brain. DIPG tumors are usually high grade. More rarely DIPG may appear as a low grade tumor (grade II).

H3 K27M Mutation in DIPG

A specific mutation, or change in the DNA, is found in most (about 80%) DIPG tumors. This mutation is known as H3 K27M. It is found in tumors located deep within the middle part of the brain and spine that show diffuse or infiltrative growth. This finding has led to a new diagnosis based on pathology called diffuse midline glioma, H3 K27M-mutant. These tumors most often occur in the pons, but they may also be found in the thalamus, spinal cord, and other sites in the midline of the brain.

Even without a biopsy, it is thought that most DIPG tumors have the H3 K27M mutation. These are aggressive tumors. Tumors that have an H3 K27M mutation usually have a poor outcome no matter the grade or how they appear under the microscope.

DIPG treatment

DIPG is a very aggressive cancer. There is no cure at this time. The current standard of care is based on radiation therapy. Much of DIPG patient care is focused on controlling symptoms and supporting quality of life as much as possible. Corticosteroid medications such as dexamethasone (Decadron) can help reduce some of the symptoms caused by the tumor by decreasing the swelling associated with the tumor. They are usually used at diagnosis and at tumor progression to help manage neurologic symptoms. Corticosteroid medications 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.

A number of clinical trials are exploring therapies that may improve outcomes for patients with DIPG. Many patients with DIPG receive care through a clinical trial. Clinical trials are available for patients at the time of diagnosis, after completion of radiation therapy but before progression, or after tumor progression.

Radiation therapy

Radiation therapy is the main treatment for DIPG. In most cases, radiation provides a temporary response to slow or shrink the tumor. However, radiation therapy does not provide a long-term cure. It may provide a temporary easing of symptoms lasting an average of 6 months and may extend life by an average of 3 months.

At most treatment centers in the US, the standard recommendation is local radiation therapy with a dose range of 54-60 Gy for a period of 6 to 7 weeks. Newer studies suggest that hypofractionated radiation therapy may offer similar benefits with less burden on the patient and family. This hypofractionated approach gives larger doses of radiation over a shorter time (usually 3 weeks).

Radiation upfront is usually helpful in stalling disease progression for a time. Recent studies have shown that repeat radiation to the DIPG tumor can be done safely; however, when the disease recurs, the tumor has become more resistant to radiation, and the benefits of radiation are more limited. When radiation is given a second time, it is usually done over 2 to 3 weeks.

There is often a time after initial radiation therapy where the tumor shrinks temporarily. Symptoms improve, and patients are able to go home to their usual activities. This is sometimes known as the “honeymoon period.” This phase is hard to predict. Some children are almost back to normal during this time. Some children do not improve at all. Families may use the time to be together or do something special as a family.

Chemotherapy

Chemotherapy may be used in addition to radiation therapy to see if better outcomes can be achieved. However, chemotherapy has not been found to increase length of life or overall survival in DIPG. As a result, chemotherapy is generally not offered as part of standard care for DIPG.

With new insights into the underlying genetic changes in DIPG, more tumor-specific treatment protocols are being tested through clinical trials. These include different combinations of drugs and new methods of administration.

The blood-brain barrier can limit the effectiveness of chemotherapy for some brain tumors. This protective barrier acts to prevent substances in the blood from getting into the brain. This can limit how much medicine reaches a brain tumor. New drug delivery techniques are being explored to overcome this problem. One of these methods is Convection-Enhanced Delivery (CED). It involves placing a catheter into the region of the DIPG tumor by precise surgery. This allows the drug to reach the tumor directly in a more controlled way.

Surgery

Surgery is not used to treat DIPG due to the location of the tumor. The pons, the region of the brain where the tumor occurs, is responsible for vital life functions. Therefore, the tumor cannot be removed by surgery.

Surgery may be used to help treat hydrocephalus. As the pons expands due to tumor, it can block cerebrospinal fluid surrounding the brain and spinal cord. This can cause increased pressure on the brain. Some children with hydrocephalus due to DIPG may have a shunt placed to drain fluid from the brain.

In some cases, surgery may be used to remove parts of the bone at the base of the skull (decompression) to relieve pressure on the brainstem and spinal cord.

Targeted therapy

Targeted therapies work by acting on, or targeting, specific features of the tumor such as genes and proteins. Some targeted therapies being studied as part of clinical trials in DIPG include targeting:

• Cell surface receptors thought to be enriched or active in DIPG
• Intracellular proteins that regulate cell growth and survival of tumor cells
• Proteins that repair DNA damage that might be altered in DIPG, making cancer cells more resistant to radiation and chemotherapy
• Proteins that regulate gene expression related to the specific mutation, H3 K27M

Immunotherapy

Immunotherapy is a type of treatment that uses the body’s own immune system to recognize and attack cancer cells. More recently, various types of immunotherapy are being explored in patients with DIPG. These include antibodies that may activate the patient’s immune system to fight against the DIPG tumor. Scientists are also studying whether a vaccine may be able to target DIPG tumor cells that have a specific type of H3 K27M mutation.

Supportive care for children with DIPG

DIPG is progressive, and symptoms get worse over time. Supportive care helps maintain quality of life as much as possible for as long as possible. Families should talk to their care team about what problems to expect and ways to help manage them.

Common symptoms of late stage DIPG

When DIPG comes back, symptoms can progress rapidly. However, symptoms and their course and severity can vary. Some signs and symptoms of late stage DIPG include:

• Loss of balance and motor control, often leading to inability to walk and the need for a wheelchair
• Progressive weakness and paralysis, often on one side of the body
• Difficulty swallowing, with problems related to aspiration pneumonia and not being able to eat normally and requiring a feeding tube
• Weight gain and face swelling or puffiness as a result of corticosteroid medications such as dexamethasone
• Problems speaking or communicating
• Anxiety, irritability, or agitation
• Depression and feelings of sadness
• Fatigue or drowsiness
• Sleep problems
• Changes in vision
• Headache
• Nausea and vomiting
• Constipation
• Decrease in urine, urinary retention
• Problems breathing
• Problems with heart rate and blood pressure
• Seizures
• Confusion, delirium
• Loss of consciousness

Medicines can help control pain, nausea and vomiting, anxiety and depression, and medical problems that develop as the tumor grows. Art therapy, music therapy, and other complementary therapies can also help patients and families manage symptoms.

Hydrocephalus causes symptoms such as headaches, nausea, weakness, and problems walking. Steroid medicines decrease brain swelling and pressure, but they also have side effects. Weight gain, face swelling, and puffiness are mainly due to high doses of corticosteroid medications to treat hydrocephalus.

DIPG prognosis

Unfortunately, there is no cure for DIPG at this time. Less than 10% of children survive more than 2 years after diagnosis. In a recent study ¹⁸⁾ of an international DIPG registry, the median overall survival was 11 months from diagnosis. The time to tumor progression was 7 months from diagnosis. Only 10% of patients lived more than 2 years with DIPG, and the survival rate was less than 2% at 5 years.

In most patients, radiation therapy helps to stop or slow the symptoms of DIPG. But this improvement is only temporary. Radiation may shrink the tumor, but it starts to grow again within months. Once DIPG comes back after initial treatment, the disease usually progresses quickly and does not respond to further treatment. Death often occurs within a few months.

DIPG can sometimes spread outside of the brainstem before treatment. About 20% of patients with DIPG have spread of disease to distant areas of the brain or spine or the meninges at diagnosis. This latter type of spread of disease is called leptomeningeal metastases. DIPG can also spread to other areas of the brain and spinal cord or the meninges as the disease progresses after treatment. About 20% of patients have spread to distant regions at tumor progression.

A somewhat better outcome may be seen in very young patients (3 years of age or younger) and patients with a longer duration of symptoms leading to diagnosis. Diffuse brainstem tumors in patients with neurofibromatosis type 1 (NF1) may also live longer with the disease. However, long-term survival in DIPG is generally thought to be associated with atypical features or misdiagnosis (the tumor was not actually DIPG).

DIPG survival

Despite advancements in radiation and systemic strategies as well as developments in oncologic research, survival outcomes for children with DIPG have not changed significantly over the past 20 years. Children suffering from diffuse intrinsic pontine glioma (DIPG) face a dismal prognosis with a median overall survival of approximately 11 months, and a 2 year survival rate of 10% ¹⁹⁾. The median overall survival for diffuse intrinsic pontine glioma patient population remains approximately 10 months ²⁰⁾. Due to the delicate location of the diffuse intrinsic pontine glioma tumor, surgical resection is not possible. To date, radiotherapy remains standard of care at diagnosis and confers a survival benefit of approximately 3 months ²¹⁾. Chemotherapy has not proven to be effective thus far ²²⁾.