Diagnostic and Prognostic Markers in Glioblastoma

Transcript:Susan C. Pannullo, MD: The patient who has a glioblastoma will often present with neurologic symptoms, as one would expect. These can include headache, progressive neurologic deficit, and seizures. With the progressive neurologic deficit, it’s important to remember that sometimes the patient will show up with something that appears sudden. For example, in the emergency room, a patient may come in with what seems like the sudden onset of symptoms—paralysis on one side of the body, for example. And when seen, it’s important to get a good history from the patient to make it clear that this is, in fact, progression. Retrospectively, perhaps the patient is noticed to have some mild weakness a few weeks before, and then this has progressed to the point where something became so apparent as to prompt an appearance in an emergency setting.

For patients who come in with seizures, it’s often a much more clear onset of symptoms. The patient may have been normal up to the point where they have the seizure, and then they come in with a sudden occurrence of shaking of the body, loss of consciousness, or something that appears, clinically, to be a seizure—that may be one way of presentation. The headache is often an early morning headache, improving during the course of the day, and it has varying qualities. It has to be recalled that it’s very rare for a patient who has a headache to harbor something like a glioblastoma. But that’s certainly in the differential diagnosis of somebody with a headache. They may have a space-occupying lesion like a brain tumor, like a glioblastoma. But those are the major ways in which a patient with a glioblastoma may present.

Once the patient is recognized to have one of these neurologic symptoms, then usually some sort of imaging occurs. A CAT scan is often performed which may reveal a mass. A CAT scan with contrast is much more sensitive than a noncontrast CAT scan. And an MRI scan is much more sensitive than a CAT scan at picking up smaller lesions. Usually on a CAT scan or an MRI, a glioblastoma will enhance, and this is believed to be due to a breakdown of the blood-brain barrier that allows for the leakage of the contrast agent that’s administered as part of the scan.

Once an MRI has revealed that there is a lesion, some additional imaging is often done to help further characterize what’s seen on an MRI. So MR spectroscopy, or magnetic resonance spectroscopy, is one technique. Positron emission tomography can be useful. But ultimately, it comes down to making a diagnosis using a histologic examination of what’s inside of the head. In order to do that, some sort of surgery needs to be done, and this can range from a needle biopsy to an open biopsy to an open surgery, with the goal of resecting or removing as much of the tumor as feasible.

Many years ago, because of a fatalistic attitude toward glioblastoma, a tumor that was suspected to be a glioblastoma on a scan was often interrogated only with a needle biopsy. And the limitations of the needle biopsy and sometimes sampling errors could cause the tumor to be undergraded and not to be recognized as a glioblastoma, therefore not permitting the patient to get adequate treatment.

Currently, almost in all cases, an open biopsy is preferred unless the tumor is unavailable in terms of safety for open biopsy—the goal being to get adequate tissue to make the diagnosis and then send the tumor for special studies that are often used in helping make decisions down the line. With surgery, the tumor is taken out and given to the pathologist, and that is the way the diagnosis is ultimately made.

Steven A. Toms, MD: After surgery, the tissue goes off to the pathologist for histopathologic diagnosis. Typically, the pathologist is going to look at the tissue, find that necrosis—the endothelial proliferation—and say that this is a glioblastoma. However, there’s one specific subtype that can look like that, that has a better prognostic group and actually won’t end up with a final diagnosis of glioblastoma. And that is a group called the anaplastic oligodendroglioma.

The cells tend to have a little different appearance; they look somewhat like a fried egg under the microscope to the pathologist—and they do a molecular test for oligodendroglioma, looking for 1p and 19q deletions. If the specimen has those deletions and that fried egg—cell type, it’s called an anaplastic oligodendroglioma. It’s treated in much the same way as the glioblastoma, although there are some different chemotherapies that are offered for that and they have a much better prognosis.

One of the other prognostic variables that tends to be looked at for glioblastoma is the methylation status of MGMT. If the MGMT is methylated, that tends to indicate that the patient will respond to temozolomide and puts them in a better prognostic group. But the most important prognostic factor of the last few years has been the IDH1 mutation—the isocyanate dehydrogenase. IDH1 mutations tend to be in younger patients. This is the old classification of the secondary glioblastoma often arising from a lower-grade glioma. And these patients tend to do much better than their counterparts who are IDH1 wild-type.

These patients with the IDH1 wild-type tend to be older patients who have the de novo, or newly arising glioblastoma, and often also have epidermal growth factor receptor mutations with them. The epidermal growth factor receptor mutations, with some of the therapies that are coming out these days, are starting to allow a bit of molecular classification, as there are a couple of vaccines and a couple of therapies out there right now that specifically attack epidermal growth factor receptor mutations—especially one that has a truncated expression on the surfaces of the cell called the EGFRvIII mutation, which occurs in about 60% or 70% of de novo glioblastomas.

Transcript Edited for Clarity