Surgical Options with DIPG

The problem with operating on diffuse intrinsic pontine gliomas (DIPGs) is captured immediately by the name itself—they are diffuse, they are intrinsic, and they are in the pons. Tumors elsewhere in the brain tend to grow as a lump that pushes aside more normal brain tissue, but DIPGs do not. Lumps of DIPG cells are generally not large individual masses that a surgeon can try to take out. Instead, the cells making up the tumor project diffusely in fingers that sit widely among other areas of normal brain tissue.

With DIPGs, it isn’t possible to separate normal from abnormal tissue when the surgeon looks at it. Thus, an attempt to remove large pieces of tissue to try to control the tumor (and improve the child’s outcome by getting enough of the tumor out) is not possible. Instead, attempts to remove abnormal tissue result in pieces of normal brain tissue being removed. Removal of normal tissue can also happen during surgery on other parts of the brain, but in other parts of the brain the nearby normal tissue usually doesn’t have as important a function as pons tissue.

The Pons

The pons is a small area of the brain about 3.5 cm. long and 2.5 cm. wide. In it are the brain centers that control sleeping and waking, eye movements, facial movement, and hearing. The major pathways for movement of the arms and legs, and for most of the body’s sensations, pass through it in a complex manner. The cerebellum which sits behind the pons sends fibers from one side of the brain to the other through the pons. The cerebellum controls smooth muscular movements and balance, and some of the balance centers of the brain are located in the pons. Additional centers controlling balance are located in the medulla. Thus, the pons is a critical structure that highly influences the entire body’s ability to function properly. When the pons is damaged, it can have an extremely wide impact on the body’s ability to sustain itself. Any surgeon should be extremely cautious when attempting an operation in this region. Taking small amounts of tissue may be possible without inflicting serious neurologic damage, but taking large amounts of tissue simply is not.

History of DIPG Diagnosis and Imaging

Surgeons’ current thinking about DIPG tumors is based on the tumors’ history. In the past, surgeons would generally try to remove brain tumors. But that was, and is still, rarely possible in the pons. With tumors in other areas of the body, surgeon’s usually try to take a small amount of tissue with a “needle biopsy” to gain a better understanding about the tumor before considering a larger operation. Biopsies, however, were rarely done on brain tumors, because biopsies were much more difficult in the brain than elsewhere in the body. The reason for the difficulty was that it used to be very difficult to know exactly where in the skull, and therefore where in the brain, a needle should go to make a diagnosis. While surgeons used a variety of external landmarks for placing needles in the brain, this technique—called stereotactic biopsy—was not good enough for widespread use. Forty years ago, that began to change. New computerized brain imaging technology suddenly made it possible to see anatomic details in a remarkable way. The technique of stereotactic biopsy became feasible, and surgeons began to use it.

Meanwhile, brain imaging itself became much more precise. In particular, MRI revolutionized surgeons’ ability to understand and visualize the location of tumors, particularly in the posterior fossa—the back of the brain where the pons is located. MRI and stereotactic technology were now linked in a constructive way, and surgeons began to try stereotactic biopsy in the pons.

Clinical Study Recommendations for Standard of Care

Pediatric oncologists have long worked collaboratively to try and develop the best new treatments for tumors, in the most efficient way. One such collaborative study, organized through the Children’s Cancer Group (the CCG study 9928), looked at patients with diffuse pontine gliomas and proposed new treatments. This study, published in 1993, concluded that when an MRI shows specific characteristic features of changes in the pons, it was sufficient evidence to make a DIPG diagnosis without a biopsy. It also turned out that when a biopsy was taken, the result of the pathology was not helpful in planning a particular treatment strategy and did not appear to alter a child’s subsequent outcome. Therefore, the recommendation became that no biopsy should be undertaken in cases that appear to be typical pontine gliomas.

At that time, the risk for harm from a biopsy was not yet well known, because the technology for stereotactic biopsy was still relatively new. But because the benefit from biopsy is so small, the risks were too large for it to be undertaken. Based on this historical data, the accepted standard of care has become that no biopsy need be done for DIPGs.

When the neurosurgeon, oncologist, and radiologist agree that a tumor does not appear to be a typical DIPG it is considered appropriate to proceed with a biopsy. Since the publication of the CCG study, many more publications have documented the safety of stereotactic biopsy in the posterior fossa with relatively little inflicted harm. Thus, the decision to do a biopsy is based on whether the tumor appears enough atypical that a different diagnosis could be considered. In addition, some tumors—in the opinion of the surgeon, oncologist, and radiologist—remain so unusual that an open operation (removal of a flap of the skull and entering the brain tissue with instruments larger than a needle) is more appropriate.

Stereotactic Biopsy

A stereotactic biopsy is based on obtaining a computerized image on which a target (tumor) can be identified; that image can be an MRI or CT scan. Technology is then used to calculate the position of the target in relation to the scan. Several different technologies are available to do that, some using a rigid frame that is attached to the head before the scan, and others that can map the surface of the face and use that as the basis for determining the tumor’s position. With the head in a fixed position and the trajectory calculated, a very small hole is made in the skull to allow the needle to pass to the target and obtain the tissue. The tissue is then removed and prepared so as to identify the pathology; other studies may also be done. Stereotactic biopsy has the advantage of a very small incision, a small hole in the bone, and less risk than a larger open operation.

Most studies of stereotactic biopsy have shown relatively little damage as a result and a very low rate of death from the procedure (less than 1%).

Deciding When to Operate

The decision whether or not to operate must be based on the imaging features of the tumor and on whether the treatment is appropriate for the individual child.

The DIPG’s location presents a problem (in addition to that of the tumor itself). The brain produces cerebrospinal fluid (CSF), which circulates through a series of spaces in the brain called the ventricles, which include:

• Lateral ventricles: One lateral ventricle is found in each cerebral hemisphere, and each lateral ventricle communicates through a small channel (called the foramen of Monro) to the third ventricle.
• Third ventricle: The third ventricle sits on the midline at the base of the brain and ends in a channel, called the aqueduct of Silvius that goes to the fourth ventricle.
• Fourth ventricle: The fourth ventricle sits behind the pons and medulla, in front of the cerebellum.

 CSF goes downstream from the lateral ventricles to the third and fourth, then leaves the fourth ventricle through channels that connect to the space around the brain (the subarachnoid space) where CSF is absorbed into the bloodstream. Because DIPGs sit adjacent to this fluid pathway, as they grow they may at times block the flow of CSF. This blockage causes fluid pressure in the brain to go up and the fluid spaces to enlarge—a condition called hydrocephalus. When the fluid pressure builds up, it can cause headaches, vomiting, mental changes, and even coma. Thus, sometimes children with DIPGs need procedures to control the fluid pressure.

Treating Hydrocephalus

The most common and well-established procedure to treat hydrocephalus is the ventriculoperitoneal shunt (VP shunt). A tube is placed from the outer surface of the head through the skull and brain into a lateral ventricle. The shunt is connected to a device—the valve—which determines how much pressure must build up before CSF starts to flow, and makes sure CSF only flows out of the ventricle and not back in. The valve sits under the skin and connects to a tube that leads to a place in the body where the CSF can be absorbed back into the blood stream (where it would have gone from the brain directly, if it could). The most common end point of shunts is the peritoneal cavity—the belly—but other times shunts go to the chest, through blood vessels to the heart, or even to the gall bladder. Effective shunts have been around for about 50 years, and they save and improve the lives of tens of thousands of kids each year.

Shunts, however, have their own problems. They are foreign to the body, so the body may react to them and block off their flow. They are also mechanical systems that can break or malfunction. The most common way they become a problem is when they become infected. Infections happen between 5 to 14 percent of the times they are implanted. (Neurosurgeons are very focused on how to reduce the rate of these infections.) When a shunt is infected, it has to be removed, and—after a period of time—replaced with a clean system.

Because of the problems with shunts, another way to drain fluid from the ventricles is the endoscopic third ventriculostomy (ETV), which creates an alternative pathway from the third or fourth ventricle when the normal pathway is blocked. Whether the ETV is an option depends on the particular anatomy of a child with hydrocephalus due to a DIPG. This is a matter only the surgeon can assess. (The pons sits behind the area where CSF goes after an ETV. If a DIPG can block the CSF pathway behind it, it can block the pathway in front as well.)

Biopsy of More Routine Tumors: Why or Why Not?

A fundamental ethical dilemma raised by the current standard of care is that when the tumor looks typical on MRI, the recommendation (based on research completed 20 years ago) is that no biopsy should be done. The potential risk for the individual child, as interpreted at that time, could not be balanced by the potential benefit. Since then, two things have changed:

1. Many more patients have undergone safe biopsy of brainstem masses than had done so when that observation was made;
2. The ability to study tumors has been vastly advanced by genomic analysis.

DIPG tumors will not be understood as other pediatric brain tumors are, unless more tissue is obtained for study by contemporary techniques. The cancer community will have to decide the most appropriate course of action with DIPG tumors.

Federal Guidelines for Clinical Research

Federal guidelines for conducting research, particularly in children, stipulate that there must be the potential for benefit for the individual child if he or she is to undergo a procedure with more than a minimal amount of risk. What will be the benefit to undergoing a procedure; will the procedure allow us to better understand the nature of the tumor; and will it benefit a particular child? How should we measure benefit? If the child and his or her family decide that to help advance knowledge is a very significant benefit to that child, is that substantial enough to offset the notion that because “the child’s survival won’t change,” there is no potential benefit? This is the overarching question that has no easy answers.