My task today is primarily to talk about malignant brain tumors. However, I think they can only be truly understood by at least a reference to the lower grade tumors.
This is a distribution of brain tumor types from the Central Brain Tumor Registry of the United States for a 5 year period. We are not going to talk about any of the more minor tumor types in any detail today, but just note that this is for primary tumors of the brain only, not metastatic tumors. Focus on the glioblastoma, astrocytoma combined figures of 30% and the meningioma figure of 30%. We will discuss the difference between intra-axial tumors, those within the brain substance, and extra-axial tumors – meningiomas, that grow adjacent to the brain substance, may displace the brain, but rarely grow into the brain substance. The outcome of these patients is very different as well as the initial approach to management because a slow growing meningioma can attain quite a large size slowly and can be approached much more leisurely than a primary brain tumor of comparable size.
This distinction may seem quite easy on the surface. Either a tumor is outside of the brain or it isn’t. In reality, however, we often have heated arguments in the NeuroRadiology conference because if a tumor is iso-intense to brain it can often be very difficult to be clear about the location, particularly if the meningioma, for instance, pushes so far into the brain that the brain molds around the lesion and, on certain slices can really appear to be within the brain substance.
This slide discusses intra-axial brain tumors----- or primary brain tumor types. Notice that the final diagnosis for tissue type is, in some ways, related to tumor location. Some of these tumors are flagged * as benign and others ** as malignant. You will note that, if you make the assumption that a primary brain tumor is malignant, you will be right most of the time. Also note that the size of the lesion is important. I once had a patient referred to me with a “small” 3 centimeter tumor that turned out to be in the pituitary gland. A tumor this size in the brainstem, pituitary gland or cerebellum is obviously much “bigger” in reality because of the brain tissue that can be displaced in those areas and the density of cellular connections, as well as the confining brain and dura surrounding those areas.
This shows 5 year survival based on tumor type. Astrocytomas, the most common type of brain tumor, is graded I through IV. Note that even with the lower grade tumors 5 year survival is 30% with only 5% of patients surviving 5 years with glioblastoma. With our newer treatments this is improving somewhat, but clearly not at the pace that we would hope.
This is a simple review of why space occupying lesions in the brain are difficult. It can really be summed up by a single word…the skull which prevents expansion, allowing some brain shift but then alarming clinical decline once that small degree of brain shift is exceeded. Although HA is listed as part of the symptom complex of increased intra-cranial pressure, the most common presenting symptoms of a brain tumor are personality change and seizures. Nighttime headache remains a “red flag” for the diagnosis of a brain tumor, but personality change and seizures are key.
This shows the infiltrating nature of brain tumors. Though you will note that the cellular density of the tumor is 1:1 within the tumor and 1:10 2 cm away from visible tumor, there are tumor cells even distant, across the corpus callosum in the other side of the brain albeit with a density of 1:1000. This is why radiation therapists add a 2 cm margin around the tumor when they give partial brain radiotherapy to our patients and allows you to predict pattern of hair loss for your patients.
We are now going to discuss some specific clinical situations to show the clinical and radiographic differences. These patients often have a few years of just treatment for their seizures before there is a period of more rapid clinical decline when the tumor “de-differentiates” into a more malignant tumor type.
Figure 1. MRI Scans of the Brain Obtained at the Time of Diagnosis and after Treatment. A fluid-attenuated inversion recovery (FLAIR) image (Panel A) shows a heterogeneous, infiltrative mass in the right frontal lobe involving both gray and white matter. The bulk of the lesion has signal characteristics of solid tissue -- bright on the T2-weighted and FLAIR sequences, and isointense to slightly hypointense to the gray matter on the T1-weighted sequences (Panel B). There is a small cystic component just behind and lateral to the center of the lesion that is bright on T2-weighted and dark on FLAIR and T1-weighted sequences (arrow, Panel A). Mass effect on the adjacent ventricle and minimal midline shift are evident. A FLAIR image (Panel C) obtained after the surgical debulking shows the residual tumor (bright signal). Another FLAIR image (Panel D) after four cycles of procarbazine, lomustine, and vincristine combination chemotherapy shows only a small residual focus of bright signal. This region did not enhance with gadolinium contrast medium, and magnetic resonance spectroscopy showed no evidence of tumor.
The above information is based, in part, on the fact that the contrast enhanced scan, which I did not show you, showed no evidence of enhancement and therefore, likely lower grade.
This is a good time to remind you of the motor homunculus. This is based on a coronal image showing the leg region hanging down between the hemispheres, the hand and face closely aligned and the trunk with very little representation. This is important to keep in mind when speaking with patients, as I try to review their scans with them, review the tumor location and, in this way, predict for them is their seizures are going to be twitching of the right side of the mouth or tingling of the left foot. I had a recent patient with a left parietal tumor whose seizures involved just elevation of his right arm. This kept happened to him in the line at Starbucks and everyone just thought he was eager to order his coffee.
Typical patient with a low grade tumor…thinking again about the motor homunculus and motor pathways, it is clear why his seizures presented with twitching of the right arm and face.
Characteristics of a large, lower grade tumor.
This shows very little contrast enhancement and, therefore, not likely to be higher grade.
Sagittal view. Likely primary tumor based on location and appearace.
Low grade gliomas are one of the most controversial tumor types in all of neuro-oncology. Different than tumor types in other parts of the body, there is no evidence that treatment impacts survival. It clearly impacts “neurologic progression-free survival” a somewhat tortured concept we up with to explain the benefits of treatment to patients.
Anti-convulsants only for those patients with demonstrated seizures (meta-analysis to follow). You may have noticed that we try now to switch from the old P-450 enzyme inducing anticonvulsants such as phenytoin and carbamazepine to newer agents such as keppra. There have been studies that show that chemotherapy is 25% less effective if patients are taking liver enzyme inducing anti-convulsants. With the advent of IV keppra now we are convincing the neurosurgeons to use iv keppra instead of phenytoin and routinely change all of our patients over. This might be a good time to mention anti-convulsant serum levels. We check them on a stable dose to ensure it is in the mid-therapeutic range, if someone has signs of toxicity or with a breakthrough seizure to determine complaince. Once the dose is set, however, we do not measure levels and then change the dose because some patients require only low levels to be therapeutic and you don’t want to give them drug related toxicity. Dexamethasone is only indicated if you really feel the patient has clinically worrisome increases in intracranial pressure and it is to be avoided in certain other situations which we will discuss later. Knowing the location and size of the tumor then helps you know how to educate the patient about symptoms to report immediately.
This was a very good review of all of the existing literature about the use of prophylactic anticonvulsants by the American Academy of Neurology. They were able to find all of the evidence-based papers in this regard and published this meta-analysis in 2000 in the journal Neurology. So anticonvulsants should not be started routinely, patients should be educated about seizures and about status epilepticus. Also, there is a small but definite risk of Stevens-Johnson syndrome in brain tumor patients who have cranial radiotherapy. Severe skin reactions in all of the irradiated head fields which actually led to functional blindness in one of my patients. Avoid phenytoin!
In contra-distinction to the malignant tumors of adults, this is a “benign” and curable variant. The JPA or juvenile pilocytc astrocytoma of childhood. As long as this child gets complete surgical removal of this tumor, nodule and cyst, the hydrocephalus will resolve. You can see, however, the worrisome midline shift and acute hydrocephalus changes here.
Here is another type of “benign” tumor of the young.
Demonstrates the importance of tumor typing, and illustrates how often we are now using genetic markers, not just histology.
Figure 4. Loss of Heterozygosity. An autoradiograph shows allelic loss at a polymorphic locus on the short arm of chromosome 1 (D1S199) when tumor (T) and blood (N) DNA are compared. Note the loss of the upper allele (arrow) in the tumor DNA.
Mib-1 or ki-67 immunostain is the new “mitotic index” 5% is the usual somewhat arbitrary dividing line between benign and malignant.
Two pathways to GBM. (Left panel) Astrocytoma, WHO grade II from a young woman whose tumor recurred 5 yr later as GBM (not shown). Note the mild increase in cellularity, with scattered neoplastic astrocytes having elongated hyperchromatic nuclei (arrows). (Right panel) GBM in an elderly man with a short clinical history. Note the dense cellularity, necrosis (N) with palisading nuclei (P) and microvascular proliferation (MVP)—the histological hallmarks of GBM.
Two pathways to GBM. GBM can develop over 5–10 yr from a low-grade astrocytoma (secondary GBM), or it can be the initial pathology at diagnosis (primary GBM). The clinical features of GBM are the same regardless of clinical route.
Depression!! There is a difference between the bradykinesia of depression and the “flat frontal affect” of a brain tumor patient.
Constipation and nausea and some mild fatigue.
Diagnosis and early treatment
of brain tumors
Lynne Taylor, MD
Tufts Medical Center
Space occupying lesions
• Skull prevents expansion and forces “brain
shift” with increasing pressure
• Increasing pressure especially a problem with
rapidly growing tumors
• Signs of increased intra-cranial pressure
(ICP): HA, N/V, double vision
Low grade astrocytomas
• 15% of intra-cranial tumors in adults
• Diffuse, slow growing
• “Benign” but lack a capsule and infiltrate
surrounding brain tissue
• Potential for change into a more aggressive
type of tumor
• Younger patients 20-40 years of age
• Typically present with seizures only or with
“accidental” discovery of tumor on a scan
performed for headache or trauma
• Generally neurological examination is normal
at the Time of Diagnosi
s of the Brain Obtained
Eskandar, E. N. et al. N Engl J Med 2004;351:1875-1882
s and after Treatment
• Young, previously healthy patient with a new
onset of seizures. The clinical presentation
and overall appearance of the lesion are
consistent with a primary brain tumor, most
likely astrocytoma or oligodendroglioma.
Low grade glioma
• 35 year old male
with a 2 year history
of loss of initiative
• 2 month history of
increasing loss of
energy and HA
• Day of scan
right arm and face
Axial T-2 weighted image
• Diffuse lesion
• Same signal content
as spinal fluid
• No growth over the
corpus callosum to
the other side
Coronal Gd-enhanced scan
• Generally no
• Reflects lack of
break-down of the
• Radiographically very
little other than a low
grade glioma possible,
given location and
• Partial resection of the
• Radiation therapy can
• However, no evidence
that this will change
• 50% 5 year survival
even without treatment
• Neurologic and radiographic follow-up
• 3-6 month intervals
• Treatment only initiated with change in
symptoms or signs for the patient AND
change in radiographic studies
• Or, begun with growth noted on x-rays
• Anti-convulsants for seizures
• Keppra vs. Dilantin and Tegretol re:
subsequent change in chemotherapy
• Dexamethasone for increased intra-cranial
• Education re: symptoms to report immediately
Practice parameter: Anticonvulsant prophylaxis in patients
with newly diagnosed brain tumors
• 1. In patients with newly diagnosed brain tumors,
anticonvulsant medications are not effective in
preventing first seizures. Because of their lack
of efficacy and their potential side effects,
prophylactic anticonvulsants should not be used
routinely in patients with newly diagnosed brain
Rim of contrast enhancement
• Typically represents the break down of the
• Thought to be the actual tumor cells actively
expanding faster than the tumor blood supply
can keep up which produces dead or necrotic
tumor in the interior
Defining features GBM
• Necrosis (dead tissue which corresponds to
the dark area on the MRI scan within the rim
of white contrast enhancement)
• New tumor blood vessels
• Mitotic figures (dividing cells) or a high Ki-67
Prognostic factors GBM
• 1,578 pts on 3 consecutive RTOG
studies/defined six prognostic subsets
• Mental status
• Symptom duration
• Extent of surgical resection
• Neurologic deficit post-op (Karnofsky score)
• Accelerated approval in 1999 for the
treatment of RECURRENT AA in the USA but
both recurrent AA and GBM in Europe
• Rapidly adopted as first line therapy given
efficacy and low toxicity profile
• Drug company underestimated the power of a
low toxicity oral, highly bioavailable drug for
Temozolomide- a new standard of care
• Second generation imidazotetrazine
• Methylates specific DNA site, most critically
O6 position of guanine (AGT)
• Nucleotide mismatch leads to apoptosis
• Readily crosses the BBB, CSF concentrations
40% of plasma
• 100% bioavailable after oral dosing
• Mild and predictable toxicity
Figure 2 Kaplan–Meier estimates of progression-free survival in patients with
glioblastoma, according to treatment group
Mason WP and Cairncross JG (2005) Drug Insight: temozolomide as a treatment for malignant glioma—impact of a
recent trial Nat Clin Pract Neurol 1: 88–95 doi:10.1038/ncpneuro0045
Phase II Trial of Bevacizumab and Irinotecan in
Recurrent Malignant Glioma
JamesJ. Vredenburgh, Annick Desjardins, James E. Herndon II,
Jeannette M. Dowell, David A. Reardon, Jennifer A. Quinn,
Jeremy N. Rich, Sith Sathornsumetee, Sridharan Gururangan,
MelissaWagner, Darell D. Bigner, Allan H. Friedman,and Henry
Clin Cancer Res 2007;1253 13(4) February 15, 2007
6 month survival 72%
6 month PFS 38%