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Brain Tumor Education Resource

Brain tumor series #2: GLIOMA

This series covers:

• Glioblastoma multiforme (GBM; WHO Grade 4 on 4 fibrillary astrocytoma)
• Awake craniotomy for recurrent frontal oligoastrocytoma
• Frontal oligodendroglioma
• Ependymoma
• Pilocytic astrocytoma
• Brainstem glioma
• Gliomatosis cerebri

For each of these cases, the following format is used:

• Brain tumor background: An introduction to the type of brain tumor being case-presented.
• Brain tumor clinical presentation: What were the brain tumor 's symptoms and signs?
• Brain tumor diagnostic workup: What investigations were used to diagnose the brain tumor?
• Brain tumor treatment paradigm: What were the options and proposed treatment for the brain tumor?
• Brain tumor operative procedure and approach: What specific approach did the surgeon use for the brain tumor?
• Brain tumor technical nuances and potential surgical pitfalls: What were important considerations for the brain tumor surgery?
• Where available, brain tumor pre- and post- and/or intra-operative radiological images will be shown for the following brain tumor case examples.

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Introduction to gliomas

Gliomas are tumors that arise in the central nervous system (CNS; i.e., brain and spinal cord) from supporting cells known as glial cells. There are many types of glial cells in the CNS. These include astrocytes (which give rise to a type fo tumor referred to as an astrocytoma), oligodendrocytes (which give rise to the tumor referred to as an oligodendroglioma), and ependymal cells (cells that tend to line the ventricles of the brain, and which give rise to a type of tumor called an ependymoma). Sometimes, mixed-cell gliomas arise, such an oligoastrocytoma, which is a tumor comprised of principally two cell types, i.e., astrocytes and oligodendrocytes.

Why do "primary" brain tumors arise (a primary brain tumor is one originating from a cell within the CNS itself)? Some primary brain tumors (in fact the minority) arise in association with a genetic abnormality or genetic/inherited/familial syndrome (examples of such syndromes include neurofibromatosis or NF1 and NF2, Von Hippel Lindau or VHL, and tuberous sclerosis or TS), or in association with previous significant radiation exposure. The overwhelming majority of primary brain tumors, however, arise from (at this time) an unknown cause. Something (be it environmental, or some yet-indentified genetic aberration, or a truly "random" or "sporadic" event at a subcellular or "molecular" level) causes a brain cell to become abnormal and genetically "mutate" in such as way that it continues to divide and divide and divide....forming a clump or mass of cells referred to as a brain tumor. It has been reported that electromagnetic or radiofrequency radiation from mobile and cordless phone may be a significant risk factor for developing a particular type of malignant brain tumor known as an astrocytoma, the most common type of "glioma" ( see elsewhere for details). The rate at which the glial cell mass continues to divide and grow and its associated microscopic signature [e.g., how much it invades the brain, or whether or not is associated with brain tissue death (necrosis) and blood vessel changes (endothelial proliferation) -- all of which are bad microscopic or histopathologic "signs"] determine the "grade" of the tumor.

The most common type of glioma is the astrocytoma. In the U.S., about 12,000-13,000 new astrocytomas are diagnosed every year. There are different "grades" of gliomas. For example, for astrocytomas, the World Health Organization (WHO) has designated 4 grades, i.e., grades 1-4. Grade 1 is regarded as being relatively benign and carrying the best prognosis, while grade 4 is regarded as being the most malignant and carrying the worst prognosis. The lowest grade (WHO grade I) astrocytoma includes pilocytic astrocytoma (PCA), pleomorphic xanthoastrocytoma (PXA) and subependymal giant cell astrocytoma (SEGA); these tend to occur in the childhood population and are regarded mainly as "benign" in that they are potentially "curable" (but not always). The next grade (WHO grade II) astrocytoma is frequently labelled as a "low grade glioma" or low grade astrocytoma. Although they tend to grow very slowly over many years, they can undergo change within them, and mutate or "dedifferentiate" into a higher grade (WHO grade III or IV) of astrocytoma, both of which are regarded as "incurable". WHO grade III astrocytomas are also known as anaplastic astrocytomas (AA). They tend to have more malignant features. A WHO grade IV astrocytoma is referred to as glioblastoma multiforme (GBM). This has the most malignant features, and unfortunately for most persons carries the worst prognosis. Gliomas can cause disability and death by invading or infiltrating through white matter tracts of the brain, or by growing to a size that causes compression or obstruction of surrounding structures and leads to the syndrome of "raised intracranial pressure". Although gliomas tend not to seed ("metastasize") from one location in the CNS to another separate or unconnected location, they sometimes can do so (even the lowest grade of astrocytoma referred to as a PCA has been reported to seed through the cerebrospinal fluid). On rare occasions, two or more (independent/separate) gliomas are found to be present at the same time in the CNS of a given patient, a diagnosis referred to as "multicentric glioma". Following treatment, gliomas (esp. astrocytomas grade II-IV) frequently recur, and the vast majority of these recurrences are at the same location as the original tumor. Finally, surgical debulking of a tumor (implying incomplete resection) is frequent in the case of astrocytomas. The rationale for debulking is to alleviate dangerous "mass effect" and to reduce the "tumor-burden", the latter logically making postoperative chemotherapy and radiation therapy more effective (akin to their being "less tumor mass to penetrate and kill"). The mass "doubling time" of an untreated glioblastoma multiforme has been estimated to be a mere one month. This is indeed startling.

A summary of astrocytomas occurring in adults is included here for completeness. Note that any given tumor will follow its own rules but some averages are given below.

WHO GRADE	NAME OF TUMOR (see above)	FREQUENCY	PEAK AGE GROUP	CURABLE?	FIRST-LINE TREATMENT	OTHER TREATMENTS	CURRENT AVERAGE SURVIVAL*
I	PCA	5%	(Usually in kids)	Yes, usually	Surgery	--	Potential "cure"
II	"Low grade"	15-20%	30s	+/-	Surgery	Radiation, chemotherapy	Several or possibly many years
III	"Anaplastic"	25-30%	40s	No	Surgery	Radiation + chemotherapy	2-3 years
IV	"GBM"	45-50%	50-60s	No	Surgery or nothing	Radiation + chemotherapy	12-15 months (<20% make three years even with aggressive multi-modality treatment)

* Importantly, "survival" varies from individual to individual and is based on many different factors, not just the type of tumor -- i.e., Not all tumors that are thought to be curable result in cures, and not all incurable tumors result in death from that tumor. For astrocytoma grades II-IV, other factors include the patient's age and neurological condition at the time of diagnosis, overall psychological or motivational "strength", the location of the tumor (which determines surgical access and the amount of surrounding tissue or "margin" that can be safely resected), the type(s) of treatment used and the role of "salvage surgery". Also note that different neurosurgeons have varying degrees of "aggressiveness" towards the management of WHO grade II-IV astrocytomas.

Brain Tumor section; Case 5 - Glioblastoma multiforme (GBM; WHO Grade 4 on 4 fibrillary astrocytoma)

Background: The glioblastoma multiforme (GBM) is the highest grade of astrocytoma, carrying the worst prognosis. Under the microscope, this tumor shows features of advanced malignancy including hypercellularity with mitoses (evidence for high cell-division rates), necrosis (tissue death), nuclear atypia and cellular pleomorphism (very different cellular and nuclear shapes), brain infiltration (invasion), blood vessel changes (endothelial proliferation), and a bizarre cell-alignment feature known as pseudopalisading. Treatment, if offered, is usually surgery, followed by whole-brain (or wide-field) radiation therapy and chemotherapy (e.g., using Temozolamide). Repeat surgery (owing to the expected regrowth of the tumor) is referred to as salvage surgery, and may certainly be appropriate for some patients, especially younger patients. The cells of a GBM certainly spread out well beyond their perceived location based on MRI imaging, and may cross the midline ("butterfly glioma") at various locations including the corpus callosum. At the time of GBM diagnosis, in addition to the age of the patient, his or her neurofunctional status (as measured by the Karnofsky score, a numerical measure of a patient's ability to carry out a set of "activities of daily living" or ADLs) can have a significant impact on survival. A younger age and a higher Karnofsky score (e.g., Karnofsky score >= 80) are better for survival, and may be used in determining whether or not surgery is feasible for a given patient.

Clinical presentation: This 58 year old female presented with headache. Her physical examination was entirely normal, including her mental status. She had a Karnofsky score of 100.

Diagnostic workup: A head CT was ordered by her local doctor. This showed a large area of hypodensity at the junction of her temporal and occipital lobes on the right side. There was no hydrocephalus. A brain MRI with and without contrast showed the lesion (abormality) to have "fluffy" contrast-enhancement along its walls, with central nerosis, and some degree of "mass effect", all of which were consistent with a high-grade primary brain tumor. The differential diagnosis based on the imaging included metastasis ( see metastasis section) and brain abscess (brain infection), but based on the patient's history the lesion was most likely a glioma (GBM in this case).

Treatment paradigm: Based on the patient's age and Karnofsky score, and the fact that the lesion was in the nondominant side of the brain and readily accessible, open surgery (craniotomy) was offered to the patient as the first-line treatment. It was explained to the patient that this kind of tumor was most likely a GBM (but this depended in the end on the pathologic diagnosis based on the forthcoming operative specimen). If indeed a GBM, it was neither completely resectable nor typically curable. Further, if it was a GBM, the patient would most likely benefit (in terms of survival time) from postoperative whole-brain (or wide-field) irradiation and chemotherapy. The option of salvage surgery was also discussed if the tumor recurred, as expected for a GBM.

Operative procedure/operative approach: A right parietotemporal craniotomy was carried out using stereotactic-MRI guidance. The contrast-enhancing area of the tumor with a slight margin was resected (as confirmed by the immediate postoperative imaging) without perceived complication. The pathologic diagnosis was GBM, as expected.

Technical nuances and potential surgical pitfalls: Stereotactic guidance should be used, especially as certain tumor-brain interfaces can be difficult to discern by eye. The author favors a rationally aggressive approach, including salvage surgery when appropriate. In nondominant brain, and for lobar GBMs, a generous margin or lobectomy should be considered where feasible. Note that surgery for GBM can be carried out for those located in deep nuclei (basal ganglia, thalamus) and brainstem. That is, these more challenging locations do not necessarily represent a contraindication to surgery, although the complication potential is higher.

Imaging:

Image 5.1 (above). Temporo-occipital glioblastoma multiforme (GBM). Preoperative multiplanar enhanced MRI images. This highest-grade astrocytoma is encircled. Enhancement (bright parts of the tumor near its outer margin or along internal walls or septations) appears nodular or "fluffy". Note the central necrosis (darker regions within the tumor mass).

Image 5.2 (above). Temporo-occipital glioblastoma multiforme (GBM). Postoperative multiplanar enhanced MRI images. The contrast-enhancing and centrally necrotic areas of the tumor have been resected (operative cavity now shown by dashed circles). Abnormal (neoplastic) cells of this kind of tumor exist well beyond what is seen by imaging, a fact that makes these tumors recurrent, malignant, and typically incurable.

 

Brain Tumor section; Case 6 - Awake craniotomy / Awake brain surgery for recurrent frontal oligoastrocytoma (also see link for "Awake craniotomy" below)

Background: An oligoastrocytoma is a "mixed glioma", namely, a tumor comprised of abnormal astrocytes and abnormal oligodendrocytes. There may be a predominance of either type, e.g., "astrocyte-predominant oligoastrocytoma". The pathologic "grade" of the tumor (which will determine how benignly or aggressively the tumor will behave) is likely to be dependent on the degree of astrocytic involvement in the tumor. That is to say, the more the astrocytic involvement, the more aggressively the mixed tumor is likely to behave (as a rule of thumb at least). This is because astrocytomas in general tend to behave more aggressively than oligodendrogliomas. Oligoastrocytomas should be expected to recur and a treatment plan should always include a salvage option if appropriate.

Image 6.1 (above). Recurrent left frontal oligoastrocytoma. Left MRI image sagittal T1-unenhanced; right MRI image axial FLAIR. After an initial resection elsewhere 2 years earlier, the follow-up MRI imaging showed a large, left frontal recurrence (dashed circle) with some cross-over into the right hemisphere (see right image, above). Considerable edema and infiltration noted (hence its incurability). This seizure-generating lesion came close to the motor and speech areas.

Image 6.2 (above). Recurrent left frontal oligoastrocytoma. The intraoperative image from the second-stage surgery shows the recently placed EEG electrodes. As shown, a black suture/thread has been placed around the cortical margins of the tumor based on the preceding brain-mapping studies. The posterior straight-paddle array (white dashed circle) is actually over the patient's "motor strip" (which controls movement of the opposite side of the body). The patient was awake and comfortable for this surgery.

Image 6.3 (above). Recurrent left frontal oligoastrocytoma. The postoperative contrast sagittal MRI image shows considerable debulking of the tumor (previoous tumor-bed encircled), with a thin layer of (bright) enhancement representing blood products and hemostatic fabric in the resection cavity's floor. All of the tumor was not able to be resected owing to its intrinsic infiltrative properties and crossover into the right frontal lobe from the left or dominant hemisphere (as seen in Image 6.1).

 

Image 6.4 (above). Recurrent left frontal oligoastrocytoma. MRI diffusion weighted imaging (DWI) sequences; preoperative (left dashed circle) and postoperative (right dashed circle) images shown. The tumor has been extensively debulked without perceived morbidity in this young, high-functioning patient.

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MORE ABOUT AWAKE CRANIOTOMY/AWAKE BRAIN SURGERY:

• What is an "awake craniotomy"/"awake brain surgery"? An "awake craniotomy" is a neurosurgical procedure that involves using specialised equipment to make a bony opening (craniotomy) in a part of the skull of a patient who is awake during some part of the operation. The part for which they are awake is usually the "critical part" involving removal of the brain tumour itself, or during the surgical obliteration or disconnection of a brain vascular malformation (e.g., AV malformation, AV fistula, or cavernous malformation/cavernoma). Therefore, the procedure is also referred to as "awake brain surgery". Currently, it is a procedure carried out comfortably by only some neurosurgeons worldwide.
• Why is an "awake craniotomy"/"awake brain surgery" carried out? Awake craniotomy is carried out or recommended to be carried out only in SOME neurosurgical patients. Its purpose (i.e., the purpose of the patient being awake during the critical part of the operation) is to make the operation safer (i.e., reduce the likelihood of a neurological impairment or "deficit" in that particular patient). CERTAIN or "SELECT" PATIENTS with brain tumours or vascular malformations involving highly eloquent (i.e., highly functionally important) parts of the brain may benefit from an awake craniotomy because the neurosurgeon can be assured of the neurological progress of the patient in real-time. Of course, the majority of patients with brain tumours or vascular malformations may not need awake surgery because their tumours or vascular malformations may not involve any highly eloquent parts of their brains. It's in the select few that being awake during the critical part of the operation can make a very positive difference to the outcome, as the neurosurgeon can be more aggressive with the condition (such as a brain cancer) knowing that the patient is awake and responsive and neurologically intact as the tumour removal or resection proceeds while the patient is simultaneously functionally tested by other members of the team. This is the key advantange of awake brain surgery.
• Is "awake craniotomy"/"awake brain surgery" right for me? Awake craniotomy/awake brain surgery may be very appropriate for you if:

1. You can tolerate the concept of undergoing some part of the neurosurgical procedure in a fully awake state; and
2. You have a condition such as a brain tumour or vascular malformation that is located in or very close to a highly functionally important or eloquent part of your brain; and
3. Your neurosurgical team is experienced and comfortable with such an approach, and the neurosurgeon and anaesthesiologist explain the expected procedure to you in appropriate detail prior to the day of the operation.

• Are there any disadvantages of "awake craniotomy"/"awake brain surgery"? There are no significant downsides to this approach if all of the three criteria mentioned above are met.
• Will I be in any pain during "awake craniotomy"/"awake brain surgery"? In the hands of an experienced neurosurgical team, you will not be in any pain during awake brain surgery. Why? Because appropriate local anaesthetic nerve blocks are administered around the scalp while you are asleep and prior to the commencement of surgery and before any incision is made, to allow those tissues to go numb for the duration of the procedure. Such nerve blocks can last up to 8 or so hours, while Dr Khurana carries out his awake craniotomies on average in less than 4 hours from incision to closure. Further, the anaesthesiologist adminsters certain medications in precise amounts to allow the patient to be asleep during some of the noncritical parts of the procedure, and awake for the critical parts, or as desired. Finally, the brain itself feels no pain (the brain's leathery covering known as the "dura" does sense pain, and therefore this covering layer is numbed well by the neurosurgeon using directly applied local anaesthetic solution before it is incised/opened).
• Does The Canberra Hospital Offer an Awake Craniotomy Service/Awake Brain Surgery Program? Yes. Dr Khurana, a staff specialist neurosurgeon at The Canberra Hospital, is one of the few neurosurgeons in the Southern Hemisphere to comfortably offer awake neurosurgery as an option to some of his patients with "eloquent" brain tumours or vascular malformations. His experience was derived from training in this approach under the tutelage of Dr Fred Meyer, Chairman of the Dept. of Neurosurgery at the Mayo Clinic in Rochester, Minnesota USA, during the course of Dr Khurana's nine years at the Mayo. Awake neurosurgery has already been successfully carried out at The Canberra Hospital by Dr Khurana and the anaesthesiologist Dr David Duke and their dedicated team members (see images of the Awake Craniotomy Program / Awake Brain Surgery Service of The Canberra Hospital by CLICKING HERE - our Australasian partner site, www.brain-surgery.net.au]

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Brain Tumor section; Case 7 - Frontal oligodendroglioma

Background: Oligodendrogliomas are gliomas that arise from oligodendrocytes. Oligodendrocytes are cells which normally lay down the myelin sheath (a fat- or lipid-rich coat that is spun around each conducting portion of a nerve cell or neuron referred to as its axon) in the CNS. Such sheaths allow axons to conduct faster and constitute much of the "white matter" of the brain. Oligodendrogliomas represent about one-quarter to one-third of all gliomas, and tend to occur most commonly in young-to-middle age adults. They most frequently present with seizures and they usually occur at the junction between the gray- and white-matter ("gray-white interface"). Frequently, on a CT scan, some degree of calcification (bright speckling) is seen in these tumors, but they seldom enhance with intravenous contrast. About one-third of these tumors have another cell type involved in the tumor, such as astrocytes or ependymal cells, and therefore often present as a "mixed" tumor. Oligodendrogliomas (or oligos for short) are classified as low-grade (grades I & II) or high-grade (grades III & IV or "anaplastic") depending on their microscopic features (many of which parallel the kinds of microscopic features noted for astrocytomas, with the key exception being that the predominant cell type in an oligodendroglioma is, as expected, an oligodendrocyte). One interesting feature about oligodendrogliomas worth noting is a certain part of its genetic signature (based on studying the specimen derived from surgery). If the oligodendroglioma's genetic makeup involves a "1p 19q deletion", then such a tumor has a higher chance of being more susceptible to chemotherapy, and the patient may have a longer tumor-free survival period. That is, a 1p 19q loss is a favorable prognostic indicator for most oligodendrogliomas.

In terms of treating oligodendrogliomas, the usual first-line treatment is surgery. Chemotherapy has also been found to be useful. Radiation therapy is frequently reserved for patients with recurrent high-grade oligodendrogliomas, particularly if salvage surgery is not carried out for whatever reason. Pure oligodendrogliomas have a better prognosis than mixed oligoastrocytomas (and a mixed oligoastrocytoma usually has a better prognosis than a pure astrocytoma). A very calcified oligodendroglioma may have a better prognosis than a non-calcified oligodendroglioma, but this remains to be proven. An oligodendroglioma located in a region where more radical resection can be carried out (i.e., where a wider surgical margin around the tumor can be safely obtained) should be expected to be associated with longer disease-free survival.

Image 7.1 (above). Frontal oligodendroglioma. Preoperative MRI T1-contrast sagittal (left) and axial (right) images. The mass is located under the front (anterior) half of the corpus callosum (left dashed circle), and in the cavum septum pellucidum (right dashed circle). No significant enhancement is seen. Mild hydrocephalus is noted from CSF outflow obstruction at the level of the foramina of Monro.

Image 7.2 (above). Frontal oligodendroglioma. Preoperative MRI FLAIR axial (left) and postoperative MRI FLAIR axial (right) images. The mass has been gross-totally resected (compare contents of dashed circles). The hydrocephalus has resolved.

Brain Tumor section; Case 8 - Ependymoma

Background: An ependymoma arises from an ependymal cell that has mutated and begins to divide uncontrollably. Ependymal cells normally line the cerebrospinal fluid (CSF)-containing ventricles and spinal canal. Most patients presenting with brain ependymomas are in fact children; nearly all patients presenting with spinal cord ependymomas are adults. In the brain, one of the most common sites for an ependymoma to occur is in the fourth ventricle (posterior fossa). Unfortunately, ependymomas frequently seed the CSF with abnormal tumor cells, resulting in (metastatic) deposits elsewhere in the central nervous system. For this reason, any patient diagnosed with a brain ependymoma should also have the whole spine/spinal cord imaged, while patients presenting with spinal ependymomas should also have their brain imaged. In all cases, the imaging method of choice is MRI with and without contrast. Ependymomas may be low-grade (carrying a good prognosis) or high-grade (anaplastic; carrying a worse prognosis). Regrettably, children with brain ependymomas frequently have anaplastic lesions and therefore should, whenever feasible, be aggressively treated. The first-line treatment of choice for a brain ependymoma is surgery. Second line-treatment is radiation therapy. Ependymomas of the fourth ventricle are known to be quite radiosensitive. Chemotherapy for ependymomas has been generally reserved for difficult, recurrent tumors, and the role of chemotherapy in prolonging survival for patients with this type of tumor is debatable.

 

Brain Tumor section; Case 9 - Pilocytic astrocytoma

Brain Tumor section; Case 10 - Brainstem glioma

Background: A brainstem glioma in the truest and original sense is a low-grade astrocytoma (see above) that diffusely infiltrates and expands the brainstem, particularly the pons region. Most patients with this particular tumor are therefore not open surgical candidates, and typically not even candidates for stereotactic needle biopsy if the age-group and imaging features are consistent. They are, however, candidates for chemotherapy, radiation therapy, and CSF diversion procedures (e.g., ventriculoperitoneal or VP shunting).

Brain Tumor section; Case 11 - Gliomatosis cerebri

Background: Gliomatosis cerebri is a term used to describe an unusual circumstance where typically two or more lobes of a hemisphere, and possibly parts of the other hemisphere, are diffusely infiltrated by the same glioma. The glioma itself tends to be, for the most part at least, a low-grade glioma (equivalent to WHO grade II astrocytoma). However, some areas of dedifferentiation (see Case 5, above) may occur, resulting in foci of higher grade tumor within the "sea" of low-grade gliomatous change. Unfortunately surgical debulking is usually not a viable option owing to the extensive amount of brain tissue involved by this infiltrative tumor. Brain biopsy is frequently carried out to rule out some other CNS disease process such as CNS lymphoma, demyelination, and so forth. Treatment is largely a combination of chemotherapy and whole-brain (or wide-field) radiation therapy, and steroids are used to quell mass effect. A ventriculoperitoneal (VP) cerebrospinal fluid (CSF) shunt may be inserted palliatively to relieve the effects of raised intracranial pressure (ICP) from obstructive hydrocephalus.