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Diffuse Intrinsic Pontine Glioma (DIPG)

Other names for Diffuse Intrinsic Pontine Glioma (DIPG) include: Diffuse midline glioma, H3 K27M-mutant, Brain stem glioma, Pontine glioma, Diffuse (infiltrating) astrocytoma

What is DIPG?

Diffuse intrinsic pontine glioma, or DIPG, is an aggressive brain tumor that begins in the brainstem in an area called the pons. The pons is responsible for 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 region of the brain.

Illustration showing the cerebellum, pons and medulla structures of the brain within a child's head

DIPG is located in the pons area of the brain, usually involves and expands most of pons, and does not have well-defined borders.

Brainstem tumors account for 10-20% of pediatric brain tumors. Of brainstem tumors, most (80%) are DIPG. Low grade astrocytomas account for 20% of brainstem tumors. In the United States, there are about 200-300 new cases of DIPG every year. This tumor most often occurs in children ages 5-10 years old, but it can sometimes occur in younger children and adolescents. DIPG is rarely seen in adults.

DIPG arises from glial cells, which make up the supportive tissue of the brain. It is a diffuse tumor, meaning that the tumor is not well-contained. The tumor extends finger-like projections into healthy tissue. Because of the location and infiltrative nature of the tumor, surgery cannot be performed to safely remove DIPG tumors.

DIPG is very hard to treat. Most children do not survive more than 2 years after diagnosis. Currently, the primary treatment for DIPG is radiation therapy. However, while this temporarily improves symptoms in most patients, this is not a curative treatment. Families may consider clinical trials which test new treatments to see if outcomes can be improved.

Signs and Symptoms of DIPG

These tumors grow quickly, and symptoms usually develop in a short period of time (median of 1 month). There is a rapid onset and fast progression of problems. Symptoms of DIPG may include:

  • Loss of balance or problems walking
  • Eye problems such as blurred vision, double vision, drooping eyelids, uncontrolled eye movements, strabismus
  • Facial weakness or drooping, usually on one side
  • Problems swallowing or drooling
  • Weakness in the legs and arms, usually on one side
  • Irregular or jerking movements
  • Abnormal reflexes
  • In very young children, a failure to thrive

More rarely symptoms may include:

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

DIPG triad of symptoms

DIPG may present with a characteristic “Triad” of symptoms that includes problems with balance ("ataxia"), problems with nerves that control the muscles and sensation of the head, face, and eyes ("cranial neuropathies"), and problems with strength in the arms and legs, including jerking movements and heightened reflexes ("long tract signs"). While these three signs are present at diagnosis of DIPG in only about one-third of patients, most patients develop at least one of these three signs.

Problems related to cranial nerves

Cranial nerves are a set of 12 paired nerves that arise in the brain. Cranial nerves 5, 6 and 7, which arise in the pons, can be affected in DIPG. Problems in cranial nerve 5 can result in loss of sensation or numbness over the face and parts of the mouth. Problems in cranial nerve 6 can result in abnormal eye movements, where the eye is unable to move laterally and may be pulled in towards the nose. Problems in cranial nerve 7 can result in weakness over the face, particularly over the mouth and closing the eyelids. Problems with cranial nerve 6 are most common in DIPG.

Diagnosis of DIPG 

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

  • A health history and physical exam helps doctors learn about symptoms, general health, past illness, and risk factors.
    • There is currently no known cause of 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.
  • 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).

Role of Biopsy in DIPG Diagnosis:

biopsy is not usually recommended to diagnose DIPG in the United States. Reasons for not doing a biopsy include:

  • DIPG has characteristic features on both MRI and clinical evaluation, so it can often be diagnosed without any additional tests.
  • Because of the location of the tumor, there is risk of causing harm by doing a biopsy.
  • At this time, a biopsy does not usually change treatment plans or influence outcomes.

However, with recent advances in the understanding of the biology of DIPG  and molecularly targeted therapy, the use of a biopsy and histologic diagnosis in DIPG is currently being explored in select centers in the US. If a biopsy is performed, a pathologist will look at the tissue sample under a microscope to identify the specific type and grade of tumor, and an analysis of the genetic changes of the tumor may be done.

Staging and Grading of DIPG

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

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

Based on studies done at autopsy or on biopsies obtained at diagnosis, DIPG tumors are usually high grade.  However, more rarely DIPG may appear as a low grade tumor (grade II).

Recent studies have found a specific mutation, or change in the DNA within DIPG tumors, in the majority of patients with DIPG. This mutation is referred to as H3 K27M. The knowledge that this mutation is found in tumors with infiltrative growth and locations deep within the middle aspect in the brain and spine has resulted in a newly defined pathologic type called diffuse midline glioma, H3 K27M-mutant. Thus, it is thought that the majority of DIPG are diffuse midline glioma, H3-K27M-mutant, even in the absence of biopsy. An important aspect of these aggressive tumors is that tumor grade is thought not to influence long-term prognosis. Tumors that have an H3 K27M mutation are expected to have a poor outcome regardless if the tumor appears less or more aggressive under the microscope.

Prognosis for DIPG 

Unfortunately, there is no cure for DIPG at this time. Long term survival is very rare, with less than 10% of children surviving more than 2 years after diagnosis. There may be a somewhat more favorable prognosis for 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 have a more favorable outcome. However, long-term survival in DIPG is typically thought to be associated with atypical features or misdiagnosis. 

In a recent review of patients in an international DIPG registry, the median overall survival was 11 months, and the time to tumor progression from diagnosis was 7 months. Once the tumor had come back after initial treatment, the median time to death was a little over 2 months. Approximately 20% of patients with DIPG have spread of disease to the meninges or cerebrospinal fluid (CSF) at diagnosis. This spread of disease is called leptomeningeal metastases. Spread of disease to other areas of the brain and spinal cord may occur as the disease progresses. About 20% of patients have spread to distant brain and or spine regions at tumor progression. Even without spread of disease, DIPG is typically incurable.

Treatment of DIPG

DIPG is a very aggressive cancer, and current standard of care is limited to radiation therapy.

A number of clinical trials are ongoing to explore therapies that may improve outcomes for patients with DIPG.

  1. Radiation therapy is the main standard of care 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 6-12 months and may extend life by an average of three months.

    At most treatment centers in the US, the standard recommendation is conventionally fractionated local field radiotherapy with dose range of 54-60 Gy for a period of 6 weeks. Newer studies suggest that hypofractionated therapy (larger doses over a shorter period of 3 weeks) may offer similar overall survival with reduced burden on the patient and family.

    Radiation upfront is usually helpful in stalling disease progression. However, when the disease recurs, the tumor has become resistant to radiation and there is little benefit (and risk of harm) from further radiation. Therefore, further radiation is typically not offered after disease progression.

  2. Chemotherapy may be used in addition to radiation therapy to see if better outcomes can be achieved. However, no consistent improvements in length of life or overall survival have been shown with chemotherapy. As a result, chemotherapy is not offered in conjunction with radiation therapy as a standard of care treatment.

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

    Clinical trials are available for patients with DIPG at the time of diagnosis, after completion of radiation therapy but before progression, or after tumor progression.

  3. 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 surgically.

    In some cases, a biopsy may be performed to diagnose DIPG. However, a biopsy is not usually recommended in DIPG.

    Sometimes surgery is required to treat hydrocephalus. As the pons expands due to tumor, it can block the fluid surrounding the brain and spinal cord, causing increased pressure on the brain. Surgery may be needed to relieve compression of other parts of the brainstem and spinal cord from the tumor by removing parts of the bone at the base of the skull (decompression).

    Importantly, new drug delivery techniques are being explored to overcome potential limitations in drug delivery by the blood brain barrier. These techniques, including Convection-Enhanced Delivery (CED), involve placing a catheter into the region of the DIPG tumor by stereotactic surgery.

  4. 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 that are particularly active in DIPG
    • Proteins that repair DNA damage that might be altered in DIPG and make them more resistant to radiation and chemotherapy
    • Proteins that regulate gene expression and are thought to be altered as a result of the specific mutation, H3 K27M

    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 and the delivery of a vaccine that may target DIPG tumor cells with a specific type of H3 K27M mutation.

Supportive Care for Children with DIPG 

DIPG is progressive, and symptoms worsen over time. Families should talk to their care team about what problems to expect and ways to help manage them. Medicines can help control pain, nausea and vomiting, and other symptoms. Steroid medications are usually used at diagnosis and at tumor progression to help reduce the severity of neurologic symptoms.

Common symptoms of late stage DIPG include:

  • Loss of mobility and motor control, often leading to inability to walk
  • Progressive weakness and paralysis, often on one side of the body
  • Difficulty swallowing, with problems related to aspiration pneumonia and nutrition
  • Problems breathing
  • Speech and communication problems
  • Anxiety and/or agitation
  • Sleep disturbances
  • Vision problems
  • Headache
  • Nausea and vomiting
  • Constipation
  • Urinary retention
  • Fatigue
  • Seizures
  • Problems with heart rate and blood pressure
  • Loss of consciousness
  • Weight gain and facial swelling as a result of long-term corticosteroid use

Given the poor prognosis of DIPG, discussion around goals of therapy and end of life care is critically important. These conversations should begin early in the care process, and goals of care may evolve over the course of the disease and treatment in alignment with the changing needs of the patient and family. Incorporating palliative care or quality of life services can help patients and families manage symptoms, promote quality of life, and navigate care decisions. 

Reviewed: June 2018