Cranial Oncology

Question 1

In the UK, which one of the following state- ments regarding driving restrictions due to neurological disorders is LEAST accurate?
a. Driving can be reconsidered 6 months after craniotomy for a benign meningi- oma if there is no seizure history
b. Driving can be considered after 12 months for most craniotomies
c. Driving can be considered whenever there is no residual impairment likely to affect driv- ing after trans-sphenoidal pituitary surgery
d. Driving can be considered after 6 months for after craniotomy for a benign brain- stem tumor if asymptomatic
e. Driving can be considered 3 years after craniotomy for high-grade glioma if safe to do so and no evidence of tumor progression

Answer 1

e. Driving can be considered 3 years after craniotomy for high-grade glioma if safe to do so and no evidence of tumor progression

• First seizure: 6 months off driving if the license holder has undergone assessment by an appropriate specialist and no relevant abnormality has been identified on investiga- tion, for example, EEG and brain scan where indicated. For patients with established epi- lepsy they must be fit free for 12 months before being able to drive
• Stroke or TIA: 1 month off driving, multi- ple TIAs over a short period of time: 3 months off driving
• Craniotomy for low-grade tumor: 1 year off driving (if the tumor is a benign meningi- oma and there is no seizure history, license can be reconsidered 6 months after surgery if remains seizure free)
• Craniotomy for high-grade tumor: 2 years off driving, and no evidence of tumor pro- gression before
  Pituitary tumor surgery: driving can resume when safe after trans-sphenoidal surgery but if a craniotomy is required 6 months off driving
• Chronic neurological disorders (e.g. multi- ple sclerosis, motor neuron disease, Alzhei- mer’s) DVLA should be informed, complete application for driving license holders state of health
• Syncope: simple faint: no restriction, single episode, explained and treated: 4 weeks off, single episode, unexplained: 6 months off, two or more episodes: 12 months off.
• Stereotactic radiosurgery: Do not drive for 1 month after treatment
• Benign brainstem/posterior fossa tumor: can return to driving as soon as recovered from surgery but let DVLA know (you do not need to tell DVLA about acoustic neuromas unless you have dizziness).

Question 2

Which one of the following lists of primary brain tumors is in order of frequency (highest to lowest)?
a. Glioblastoma multiforme, meningioma, nerve sheath tumors, diffuse astrocytoma, pituitary tumors
b. Meningioma, glioblastoma multiforme, diffuse astrocytoma, pituitary tumors, nerve sheath tumors
c. Meningioma, glioblastoma multiforme, pituitary tumors, nerve sheath tumors, diffuse astrocytoma
d. Meningioma, pituitary tumors, glioblas- toma multiforme, nerve sheath tumors, diffuse astrocytoma
e. Pituitary tumors, meningioma, glioblas- toma multiforme, nerve sheath tumors, diffuse astrocytoma

Answer 2

d. Meningioma, pituitary tumors, glioblas- toma multiforme, nerve sheath tumors, diffuse astrocytoma

The commonest intracranial tumors are brain metastases (just over 50%). Incidence of primary brain tumors is approximately 20-30 per 100,000 in adults and 5 per 100,000 children. Approxi- mately one third of primary brain tumors in adults are malignant whereas they account for two thirds in childhood. Frequency of WHO subgroups and specific tumors is given:

Question 3

Which one of the following statements regarding brain metastases in adults is LEAST accurate?
a. Brain metastases are over twice as com- mon in small cell lung cancer than non- small cell lung cancer
b. Distribution of brain metastases in the CNS is proportional to amount of arterial blood supplied
c. Colorectal cancer has a higher propensity for brain metastases than breast cancer
d. Melanoma is the third most commonly
diagnosed type of brain metastases
e. Prostate cancer is the most frequent can- cer of males but has a low propensity to
metastasize to the brain

Answer 3

c. Colorectal cancer has a higher propensity for brain metastases than breast cancer

Colorectal cancer has a higher propensity for brain metastases than breast cancer The majority of brain metastases diagnosed origi- nate from lung, breast, melanoma, renal and colo- rectal primary tumors—reflecting how common those primary cancers are, but not necessarily their respective propensity for metastasizing to the brain. Propensity for spread to brain parenchyma is high in melanoma, small cell lung cancer, cho- riocarcinoma, and other germ cell tumors; inter- mediate in breast cancer, non-small cell lung cancer (adenocarcinoma > squamous cell), and renal cell carcinoma; low in prostate, colorectal, ovarian carcinoma, thyroid cancer and sarcomas. Metastases spread via the circulation and seed at the gray-white matter junction, and particularly watershed areas (most obviously PCA vs. MCA border) in a distribution proportional to amount of arterial blood supplied: 80% occur in cerebral hemispheres, 15% in posterior fossa and 5% in the brainstem. The frequency of metastases found at autopsy is much higher than that detected during the illness.

Question 4

A 67-year-old patient presents with left hemisensory change. Postcontrast MRI is shown below, and diffusion weighted imag- ing shows the lesion to be dark on DWI and bright on ADC map. Which one of the following options is most appropriate next?
a. Urgent image-guided drainage of lesion
b. CT of chest, abdomen and pelvis with contrast
c. Imaging surveillance
d. Intravenous antibiotics
e. Lumbar puncture

Answer 4

b. CT of chest, abdomen and pelvis with contrast

MRI shows a peripherally enhancing, centrally necrotic lesion in the right thalamus, with DWI pattern consistent with a relatively unrestricted diffusion in the center of the mass hence this is most likely a metastasis (given previous history of breast cancer) or a primary tumor. As such, ini- tial management in a patient should consist of a search for the primary tumor based on a full clin- ical examination and staging CT of the body, fol- lowed by discussion in the primary tumor site multidisciplinary meeting to decide on options for tissue diagnosis and further management, as well as the neuro-oncology MDT. The primary neoplasms that most commonly metastasize to the brain are carcinoma of the lung, breast, malig- nant melanoma, renal cell carcinoma, and GI can- cers (e.g. colorectal). Generally, metastases appear as multiple rounded lesions with a ten- dency to seed peripherally in the cerebral sub- stance, at the gray/white matter junction. They can, however, occur anywhere in the cerebrum, brainstem or cerebellum, and can also spread to the meninges. Metastases are characterized by edema in the surrounding white matter which is often disproportionate to the size of the tumor itself. On T2 images, the neoplastic nodule may blend with the surrounding edema, giving a picture of widespread vasogenic edema and obscuring the diagnosis. Most metastases enhance strongly with IV contrast medium, either uniformly, or ring-like if the metastasis has outgrown its blood supply. Most metastases from lung and breast are similar in density to normal brain parenchyma on CT, but some types are spontaneously dense, particu- larly deposits from malignant melanoma. Hemor- rhage occurs in about 10% of metastases, resulting in high signal on T1 images and high or low signal on T2 images. Similar signal characteristics can also occur in non-hemorrhagic metastases from melanoma, due to the paramagnetic properties of melanin. Small metastases and those that are not made conspicuous by surrounding edema are often only detected on contrast-enhanced studies. Increasing the contrast dose or relaxivity of gado- linium compounds can improve the sensitivity for detection of metastases on MRI.

Question 5

A 55-year-old right handed male presents with headache and cognitive slowing. There is no significant past medical history. MRI is shown. Which one of the following manage- ment strategies is most appropriate?
a. Surveillance imaging
b. Awake craniotomy with goal of maximal
safe resection
c. Cerebral angiogram
d. Gross total resection under general
anesthetic e. Stereotactic
classification
biopsy
for molecular

Answer 5

b. Awake craniotomy with goal of maximal
safe resection

Glioblastoma (WHO grade IV) is the commonest primary intracranial neoplasm in adults (fourth commonest intracranial tumor after metastases, meningioma and pituitary tumors). About 90% of glioblastomas arise de novo (primary glioblas- toma) and 10% are from malignant transforma- tion of lower-grade astrocytomas (secondary glioblastoma). The two groups have different genetic characteristics: primary glioblastomas, which occurs in a slightly older age group, show EGFR overexpression and secondary glioblasto- mas show IDH mutations like the lower-grade gliomas from which they arise. Methylation of the DNA repair gene MGMT is associated with a better response to temozolomide and better prognosis in glioblastomas. The MRI appear- ances of glioblastomas are heterogeneous, show- ing a mixture of solid tumor portions, central necrosis and surrounding edema. The solid por- tion is usually T1 hypointense, but T2/FLAIR
hyperintensity is to a lesser degree than areas of central necrosis and surrounding edema, which are similar to CSF. The solid portion of the glio- blastomas may show complete or partial or enhancement with contrast. The standard treat- ment for glioblastoma (GBM) consists of surgery (with a variable extent of resection depending on tumor location and the patient’s clinical status), followed by a combination of radiotherapy and chemotherapy with temozolomide.

Question 6

A 44-year-old patient with a known history of relapsing remitting multiple sclerosis presents with worsening memory. MRI is shown below. MRI spectroscopy shows reduced NAA and myoinositol, increased choline and lipid, lactate peaks. Perfusion weighted MR shows markedly elevated cerebral blood flow in the rim of the necrotic mass. Which one of the following best explains his new deterioration?
a. Tumefactive multiple sclerosis
b. Glioblastoma
c. Lymphoma
d. Oligodendroglioma
e. Choroid plexus carcinoma

Answer 6

b. Glioblastoma

Tumefactive multiple sclerosis, high-grade gli- oma (GBM), PCNSL and occasionally an abscess can appear similar on imaging. Tumefactive MS refers to patients with known MS developing large tumefactive demyelinating plaques (as opposed to patients presenting with tumefactive demyelinating lesions who rarely go on to develop MS).

Question 7

Which one of the following factors is most important in improving length of survival in gliomas?
a. 1p19q codeletion
b. ATRX mutation
c. TERT mutation
d. EGFR mutation
e. IDH1/2 mutations

Answer 7

b. ATRX mutation

Question 8

Median survival advantage in glioblastoma multiforme patients undergoing 5-ALA fluorescence assisted tumor resection versus conventional surgery in the randomized controlled trial by Stummer and colleagues (2006) was which one of the following?
a. No advantage
b. 1 month advantage
c. 3 month advantage
d. 5 month advantage
e. 7 month advantage

Answer 8

d. 5 month advantage

Question 9

Two-year survival in glioblastoma multi- forme patients receiving post-surgery temo- zolomide and radiotherapy verus in the randomized controlled trial by Stupp and colleagues (2005) is which one of the following?
a. 16.5%
b. 26.5%
c. 36.5%
d. 46.5%
e. 56.5%

Answer 9

b. 26.5%

Question 10

Which one of the following statements regarding radiological phenomena follow- ing modern treatment of high-grade glio- mas is most accurate?
a. Tumor recurrence has a lower FDG PET uptake than radiation necrosis
b. Radiation necrosis typically occurs 2-3 months after radiotherapy
c. Pseudoprogression is associated with anti-VEGF pharmacotherapy
d. Pseudoresponse typically occurs 6-12 months after temozolomide chemora- diotherapy
e. Recurrent tumors usually show a lower ADC than radiation necrosis on diffusion weighted MRI

Answer 10

e. Recurrent tumors usually show a lower ADC than radiation necrosis on diffusion weighted MRI

Radiation necrosis is a late complication of radio- therapy or gamma knife surgery, and can present as an enhancing mass lesion 6-12 months after radiotherapy, difficult to distinguish from recur- rent tumor on conventional imaging. FDG- PET, PWI and DWI may help to distinguish between radiation necrosis and tumor recurrence. In radiation necrosis the enhancing lesion has a low glucose metabolism (FDG uptake) and low rCBV, both of which tend to be high in tumor recurrence. On DCE perfusion imaging, recur- rent tumors show a much higher maximum slope of enhancement than radiation necrosis. ADC measurements of the enhancing components in recurrent tumor are significantly lower than in radiation necrosis, mirroring the higher cellular density in recurrent neoplasms. The assessment of tumor response and progression in GBM had traditionally been based on measurements of enhancing tumor portions known as Macdonald criteria. With the advent of combined chemora- diation as standard therapy and antiangiogenic drugs as second-line treatment, new phenomena such a pseudoprogression and pseudoresponse have to be taken into account and have made an assessment solely based on assessment of enhanc- ing tumor portion unreliable. Pseudoprogression (therapy induced necrosis) is due to an inflamma- tory reaction, which results in a temporary increase of contrast enhancement and edema in 20% of patient, usually within 12weeks of temozolomide chemoradiotherapy, and subsides subsequently without additional treatment. Pseu- doprogression is more frequently observed in patients with methylation of the DNA repair gene MGMT, and is associated with a better prognosis (longer overall survival). Advanced MR imaging such as DSC and DCE perfusion imaging shows promise in differentiating these two conditions from true tumor progression. Pseudoresponse is characterized by a decrease of enhancement and edema following the administration of antiangio- genic drugs without improved survival. In pseu- doresponse the tumor progresses by infiltrative patterns without neoangiogenesis, resulting in an increase of non-enhancing T2/FLAIR hyper- intense tumor portions

Question 11

Which one of the following statements regarding advanced imaging in gliomas is LEAST accurate?
a. Anaplastic astrocytoma
b. Oligodendrogliomas commonly show
calcification (central, peripheral or
ribbon like)
c. FDG-PET imaging of WHO grade III
gliomas shows an uptake greater than white matter but lower than gray matter, whereas grade II gliomas have an uptake similar to white matter
d. MR perfusion imaging shows elevated regional cerebral blood flow in grade III oligodendrogliomas compared to grade II oligodendrogliomas
e. Glioblastomas show reduced NAA and myoinositol peaks and increased choline, lipid and lactate peaks on MR spec- troscopy

Answer 11

d. MR perfusion imaging shows elevated regional cerebral blood flow in grade III oligodendrogliomas compared to grade II oligodendrogliomas

With recent advances in our understanding of prognostic and predictive factors of gliomas and within current paradigms of care, glioma grade and molecular genetic features frequently guide our management approach. In general, high- grade gliomas are treated aggressively with up- front surgical resection followed by radiotherapy with or without chemotherapy. In contrast, the
management of LGG is often more conservative, even with an initial period of close observation, with serial imaging being considered in some cases. Common molecular and genetic features that are considered in the overall management approach for gliomas include 1p/19q deletion sta- tus and isocitrate dehydrogenase (IDH) mutation status. With advances in MRI and positron emis- sion tomography (PET) imaging, there have been developments to better characterize tumors non- invasively with respect to grade, known molecu- lar, and genetic factors such as 1p/19q deletion status and additional physiological features including tumor vascularity and metabolism. In the future, the use of multiparametric/multimod- ality imaging more routinely may make preoper- ative distinction between grade II and grade III gliomas more sensitive.

Question 12

Which one of the following PET tracers is LEAST appropriate for detection of de novo low-grade glioma?
a. 18F-FET
b. 18F-FDG
c. 18F-DOPA
d. 11C-MET
e. 18F-DOPA

Answer 12

b. 18F-FDG

F-FDG PET was the first tracer used for assess- ment of brain tumors; however, it has a low tumor-to-background ratio in brain, limiting its utility. 18F-FDG uptake correlates with tumor grade, with high-grade gliomas (grades III and IV) showing higher uptake than low-grade glio- mas. Therefore, in spite of its limitations, 18F-FDG PET-CT is used for imaging of high-grade glioma. Amino acid PET radio- tracers including 18F-FDOPA display superior contrast to 18F-FDG because of low uptake of amino acids in normal brain tissue. They have particularly special value in the detection of low-grade gliomas. However, 18F-FDOPA tumor uptake cannot provide reasonable predic- tions about tumor grade and proliferation in recurrent tumors that have undergone treat- ments. Also, their difficult synthesis or need for an on-site cyclotron limits their widespread use. The present case shows the utility of 18F- FDOPA PET-CT in detection of a recurrent high-grade AA that was missed by 18F-FDG PET-CT. It highlights that 18F-FDG PET- CT can be falsely negative, even in high-grade recurrent gliomas and, therefore, in cases with strong clinical suspicion 18F-FDOPA PET-CT
can be an alternative imaging modality to rule out recurrence even when 18F-FDG PET-CT is negative. In general, practical and experimen- tal roles of PET imaging in glioma management include: (1) Grading tumors and estimating prognosis; (2) Localizing the optimum biopsy site, (3) Defining target volumes for radiother- apy (RT), (4) Assessing response to therapy, and (5) Detecting tumor recurrence and distin- guishing it from radionecrosis.

Question 13

A 34-year-old male presents with seizures. He has no significant past medical history. MRI is shown (FLAIR) and T1 postcontrast imaging does not show any enhancement. Which one of the following management strategies is most appropriate?
a. Imaging surveillance until starts to show focal enhancement
b. Gamma knife surgery
c. Methotrexate chemotherapy
d. Dexamethasone
e. Maximal safe resection

Answer 13

e. Maximal safe resection

Diffused astrocytomas are WHO grade II (low- grade) gliomas. Infiltrating low-grade tumors which occur typically in the cerebral hemispheres of young adults, involving cortex and white mat- ter with less well-defined borders than pilocytic astrocytomas. They frequently show IDH1 and IDH2 mutations, which have a favorable impact on overall survival. WHO grade II astrocytomas appear iso- or hypodense on CT and show areas of calcification in up to 20%. MRI is better in defining the extent of the low-grade gliomas. They are hyperintense on T2 images and FLAIR images and hypo/isointense on T1 images and show no contrast enhancement as opposed to pilocytic (WHO grade I) and anaplastic (WHO grade III) astrocytomas. All diffuse astrocytomas (as well as other low-grade gliomas such as grade II oligodendrogliomas and oligoastrocytoma have) will inevitably transform into a higher
high-grade glioma usually within 3-10 years. As such, from a surgical management perspective they are considered collectively. Current stan- dard of care for low-grade gliomas is maximal safe anatomical resection based on tumor borders as seen on FLAIR MRI, with or without early radio- therapy to the tumor bed (especially if residual) or late radiotherapy at the time of tumor progres- sion on imaging. More recently, some have argued that since tumor cells are likely to have spread significantly further along white matter than visualized on FLAIR MRI the limit of tumor resection should instead be based on functional limits identified by continuous intraoperative functional mapping/testing during surgery. Adju- vant treatment with stereotactic radiosurgery is under investigation.

Question 14

A 27-year-old presents with a generalized tonic-clonic seizure. On examination there is no residual neurological deficit or speech dis- turbance. Some spots of calcification are seen on CT therefore MRI is performed. Which one of the following statements regarding this type of tumor is LEAST accurate?
a. Functional mapping is a perquisite for resection
b. MRS findings may include increased 2-hydroxyglutarate
c. Prognosis is related to extent of resection
d. The majority of patients with dominant hemisphere lesions of this type present
with seizures
e. Tumor margins are usually seen best onT1+gad MRI sequences

Answer 14

e. Tumor margins are usually seen best onT1+gad MRI sequences

Oligodendrogliomas account for 10-15% of all gliomas and occur predominantly in adults. They are diffusely infiltrating neoplasms, which are found almost exclusively in the cerebral hemi- spheres, most commonly in the frontal or temporo-frontal region, and typically involving subcortical white matter and cortex. The WHO classification distinguishes between WHO grade II (well-differentiated low-grade) and WHO grade III (anaplastic high-grade) oligodendro- gliomas. The former are slowly growing tumors with rounded homogeneous nuclei; the latter have increased tumor cell density, mitotic activ- ity, microvascular proliferation and necrosis. Both low- and high-grade oligodendral tumors express proangiogenic mitogens and may contain regions of increased vascular density with finely branching capillaries that have a “chicken wire” appearance. This contributes to their appearance on contrast-enhanced MRI and MR perfusion. Up to 90% of oligodendrogliomas contain visible calcification on CT, which can be central, periph- eral or ribbon-like. On MRI, intratumoral calci- fication appears typically T2 hypo- and T1 hyperintense and causes marked signal loss on T2* or SWI images. Contrast enhancement is variable and often heterogeneous. Unlike in astrocytomas, contrast enhancement is not a reli- able indicator of tumor grade in oligodendroglio- mas: it occurs in about 20% of WHO grade II tumors and in over 70% of WHO grade III oligo- dendrogliomas. Low-grade oligodendrogliomas may also have an elevated rCBV on PWI. Despite commonly being located in functional “eloquent”
areas of cortex and corresponding white matter, their slow growth and tumor-induced plasticity means that seizures rather than functional deficits are by far the most common presenting features. As with astrocytomas, standard of care is maximal safe resection to the FLAIR border, often requir- ing awake intraoperative functional mapping for eloquent area tumors due to distortion of cortical functional maps by the tumor.

Question 15

Which one of the following statements regarding surgical management of low grade glioma (LGG) is LEAST accurate?
a. Gross total resection involves taking the tumor until its border as visualized on T2/FLAIR MRI sequences
b. Craniotomy under GA with functional mapping is the standard of care for low- grade gliomas in eloquent cortex
c. Biopsy of low-grade gliomas are prone to histological undergrading as they may miss anaplastic foci
d. Extent of resection correlated with survival
e. PET imaging can facilitate biopsy targets in low-grade glioma

Answer 15

b. Craniotomy under GA with functional mapping is the standard of care for low- grade gliomas in eloquent cortex

The primary goal in the initial treatment of LGG is maximum safe resection in the majority of patients. The goal of achieving more extensive resection (over biopsy alone) is often favored because, in retrospective analyses, it is associated with prolonged survival, greater seizure control and reduced risk of transformation to a higher grade. However, surgical treatment of suspected LGGs poses a special challenge for the neurosur- geon for the following reasons: (1) Gross total resection is difficult as their diffusely infiltrative growth pattern means that intraoperative identi- fication of the exact tumor border in an LGG is frequently not possible with certainty, hence image guidance based on tumor limits on FLAIR MRI is key. (2) Histopathological undergrading is common with biopsy as LGG generally exhibits focal areas of malignant transformation (anaplas- tic foci) therefore the surgical goal is to perform precise tissue sampling from a potential anaplastic focus to avoid this and reduce subsequent treat- ment failure. (3) “Eloquent” tumor localization and infiltrative growth pattern means that awake surgery and/or functional mapping are generally employed to avoid new postoperative neurologi- cal deficits. (4) precise localization of the tumor and its relation to cortical surface anatomy and vasculature in the preoperative planning phase as well as during the operative approach is required to avoid morbidity (e.g. insular gliomas).

Question 16

Which one of the following statements regarding brain mapping is LEAST accurate?
a. Connectome refers to the organization of the CNS into parallel networks, which are dynamic, interactive and able to compen- sate for each other
b. Hodotopy suggests individual functions of the brain are supported by extensive circuits comprising both the cortical nodes and connections between them created by asso- ciating bundles of white matter
c. Cortical map reorganization for a given function can occur as long as the subcor- tical white matter tracts subserving it are preserved
d. Brodmann areas represent a connectionist model of brain function
e. Neuroplasticity is seen in slow growing low-grade gliomas more than in acute insults such as stroke

Answer 16

d. Brodmann areas represent a connectionist model of brain function

The locationist view that each region of the brain corresponds to a given function (e.g. Brodmann areas) producing a topographical map has been used for over a century, and implies that brain injury in an “eloquent” area will result in a massive and permanent neurolog- ical deficit. However, it is unable to explain the many observations of recovery after brain dam- age, even in eloquent regions as well as fMRI and intraoperative mapping evidence of pre- and postoperative cortical topographic map reorganization in diffuse low-grade glioma patients with “eloquent” lesions. More recently, the idea of a brain connectome where the CNS is organized into parallel networks, which are dynamic, interactive and able to compensate for each other (at least to a certain extent) has gained favor. This is underpinned by the hodo- topic principle where functions of the brain are supported by extensive circuits comprising both the cortical nodes (topos) and connections between them created by associating bundles of white matter (hodos). Neurological function arises from the synchronization between differ- ent nodes, working in phase during a given task, and the same node may take part in several func- tions depending on the other cortical areas with which it is temporarily connected at any one time. Functional maps may be reorganized within remote networks over time, making neu- roplasticity mechanisms possible. Modest redis- tribution of neurosynaptic networks occurs in acute injuries (e.g. stroke) explaining the limited recovery, whereas massive redistribution of function can occur in chronic slowly progressive injuries (e.g. DLGG) so that an “eloquent” loca- tion generally does not result in functional def- icit. Cortical map reorganization mechanisms involve recruitment of areas around the lesion and/or within the hemisphere remote to the gli- oma and/or contralateral to the lesion. However, the plasticity index is high for cortical reorganiza- tion but very limited for subcortical connectivity hence it is crucial to preserve functionally impor- tant subcortical white matter (determined by intraoperative white matter functional mapping), allowing post injury/operative cortical map reorga- nization and avoidance of permanent neurological deficit. In this way, supratotal resection of diffuse low-grade gliomas (i.e. to the functional limit defined by intraoperative white matter mapping, rather than to the tumor limit defined by FLAIR MRI) has been supported by some. While this approach may tackle microscopic tumor spread, all cases must be done awake with functional mapping, requires a large craniotomy, and is seen as too aggressive by many at present.

Question 17

Which one of the following chemotherapy options is most likely to be utilized in the context of anaplastic oligodendroglioma?
a. Anti-VEGF
b. Cyclophosphamide
c. Etoposide
d. PCV
e. Temozolomide

Answer 17

d. PCV

LGG management involves surgery, radiother- apy, chemotherapy, or a combination of these modalities. Surgery is first-line therapy whose chief role is to provide tissue to confirm the diag- nosis. The next most common step in manage- ment is radiotherapy: either early radiotherapy
(within a few weeks of surgery) or delayed radio- therapy (at time of clinical or imaging progres- sion). Controversy exists on its optimal timing, particularly due to the long term neurocognitive side effects in LGG patients who are mostly young adults. Early adverse effects of radiation include headache, dizziness, ear inflammation, nausea, vomiting, seizure, altered level of con- sciousness, alopecia, dermatitis, urinary inconti- nence, and personality change. Late clinical consequences of brain irradiation include leu- koencephalopathy, neurocognitive decline, reduced quality of life, and tissue necrosis that may mimic tumor progression. The toxic effects of radiotherapy must be carefully weighed against the benefits for tumor control, including an improvement of seizures. SRS can produce long-term control with an acceptable toxicity profile, and is generally reserved for inoperable tumors in close proximity to critical structures. Similarly, chemotherapy has potential either as a concurrent treatment or substitute for radio- therapy and can also improve seizure control. Studies have focused primarily on a three-drug reg- imen of procarbazine, lomustine, and vincristine (PCV) or single agent temozolomide (temozolo- mide response may be predicted by IDH1/2 muta- tion). Ongoing randomized controlled trials are evaluating whether temozolomide can substitute for radiotherapy, or whether concurrent temozolo- mide and radiotherapy is superior to radiotherapy alone for postoperative tumor control.

Question 18

Which one of the following statements regarding O(6)-Methylguanine-DNA Methyl Transferase (MGMT) promoter methylation status is LEAST accurate?
a. MGMT is a DNA repair enzyme that reverts the naturally occurring mutagenic O6-methylguanine back to guanine, pre- venting errors during DNA replication
b. Functional MGMT increases the effec- tiveness of cancer chemotherapy
c. Hypermethylation of the MGMT pro- moter results in less DNA repair activity of MGMT
d. Temozolomide chemotherapy is more effective in glioblastoma multiforme cells with a hypermethylated MGMT promoter
e. MGMT promoter-unmethylated tumors have no survival benefit from temozolo- mide chemotherapy

Answer 18

b. Functional MGMT increases the effec- tiveness of cancer chemotherapy

The O(6)-Methylguanine-DNA Methyl Trans- ferase (MGMT) is a DNA repair enzyme that reverts the naturally occurring mutagenic O6- methylguanine back to guanine. This prevents errors during DNA replication. In the context of chemotherapy with alkylating agents (e.g. temozo- lomide) it removes a cytotoxic lesion, thus coun- teracting the chemotherapeutic effects of the drug. Aberrant, cancer related methylation of the MGMT promoter region leads to its silencing, a reduction of the MGMT enzyme expression and subsequently to less repair activity of DNA dam- age, including that induced by temozolomide (TMZ). MGMT promoter methylation in GBM is a prognostic and predictive biomarker indicating response to chemoradiation. It has no diagnostic value. This was demonstrated in the EORTC NCIC registration trial for TMZ in newly diag- nosed GBM where patients with MGMT pro- moter methylated tumors derived most benefit when treated with TMZ. Patients with tumors with methylated MGMT promoter had a survival benefit when treated with TMZ and radiotherapy, compared with those who received radiotherapy
only, whereas absence of MGMT promoter meth- ylation resulted in a smaller and statistically insig- nificant difference in survival between the treatment groups. Further studies showed that patients with MGMT promoter-unmethylated tumors had no survival benefit from chemother- apy, regardless of whether given at diagnosis together with RT or as a salvage treatment. Pro- spective randomized trials (NOA-08), the Nordic trial and RTOG 0525 concluded that MGMT promoter methylation is a useful predictive bio- marker to stratify elderly (>70 years of age; the Stupp protocol was studied in GBM patients under 70) GBM patients for RT versus alkylating agent chemotherapy and should be tested for

Question 19

Which one of the following statements regarding telomerase reverse transcriptase (TERT) promotor mutations in gliomas is LEAST accurate?
a. Overexpression of TERT in cells results in an increase in the number of times a cell can successfully divide
b. TERT normally prevents telomerase repair ensuring that cells become replica- tively senescent
c. TERT promoter mutations were also strongly associated with 1p/19q codele- tion and co-occur with IDH1/2 in oligodendrogliomas
d. TERT and IDH1/2 mutations are largely mutually exclusive in GBM and astrocytomas
e. GliomaswithTERTpromotermutations but no IDH1/2 mutation have been shown to have poor overall survival

Answer 19

b. TERT normally prevents telomerase repair ensuring that cells become replica- tively senescent

Telomere (repetitive nucleotide sequences at the ends of chromosomes) length shortens with each cell division, normally leading to replicative senes- cence and thus a limit to the number of times a cell can divide. Cancer cells bypass this limit in various ways, including an increased ability to maintain telomere length. The enzyme telomerase reverse transcriptase (TERT) plays a critical role in extending the telomeres in normal cells and muta- tions in the TERT promoter, resulting in overex- pression of TERT is a feature of most human cancers including gliomas. It has been suggested that tumors derived from cell populations with low self-renewal capacity generally rely on alter- ations that restore/gain telomerase activity, while epigenetic mechanisms maintain/prevent loss of telomerase activity in tumor types derived from self-renewing stem cells. In contrast, ATRX or DAXX mutations have been shown to underlie a telomere maintenance mechanism not involving telomerase (“alternative lengthening of telo- meres;” ALT). TERT is essential in maintaining telomere length and its activity is pathologically increased in a number of human cancers, includ- ing GBM. Analysis of TERT promoter mutations in 1515 CNS tumors showed 327 mutations, pre- dominantly in adult patients, with a strong associ- ation with older age. Mutations were seen in gliosarcomas (81%), oligodendrogliomas (78%), oligoastrocytomas (58%) and primary GBMs (54%). TERT promoter mutations were also strongly associated with 1p/19q codeletion and inversely associated with loss of ATRX expression and IDH1/IDH2 mutations. In general, TERT and IDH mutations are largely mutually exclusive
in GBM and astrocytomas but co-occur in most oligodendrogliomas. In a study of 400 gliomas patients with TERT promoter mutations alone (i.e. no IDH mutation) had the poorest overall sur- vival (median 11.3 months), patients with tumors without TERT or IDH1/2 mutations had a slightly better survival (median 16.6 months), whereas patients with IDH-only mutant GBM had the best survival (median 42.3 months). Although an earlier study with 358 patients found no significant difference in overall survival between TERT mutant and TERT wild-type (IDH wt) GBM, the role of TERT mutations may in the future provide a tool to identify non- IDH1/2 mutant GBMs and suggests that com- bined IDH1/2 and TERT promoter genotyping will be useful for patient management.

Question 20

Which one of the following statements regarding isocitrate dehydrogenase 1 or 2 (IDH1/2) gene mutations in gliomas is LEAST accurate?
a. The most common mutation ($90%) in glial brain tumors causes a substitution of the amino acid Arginine to Histidine at codon 132 of the IDH1 gene
b. IDH1 and 2 are homologous enzymes decarboxylate isocitrate to α-ketoglutarate (αKG)
c. IDH1/2 mutations result in accumulation of 2-hydroxyglutarate to high levels in glioma tissues possibly promoting onco- genic transformation through epigenetic mechanisms
d. Mutant IDH is the molecular basis of the CpG island methylator phenotype (CIMP) in gliomas, leading to global dys- regulation of gene expression
e. IDH1/2 mutations co-segregate with 1p/ 19q codeletion in oligodendrogliomas
f. IDH1/2 mutation is associated with an
improved prognosis in grade II astrocytomas

Answer 20

f. IDH1/2 mutation is associated with an
improved prognosis in grade II astrocytomas

Pathogenic mutations in the isocitrate dehydroge- nase genes 1 (IDH1; chromosome 2q) or 2 (IDH2; chromosome 15q) were discovered in next- generation sequencing studies of 22 GBM, includ- ing in secondary GBM. Likely to be a tumor initi- ating or driver mutation in astrocytomas and oligodendrogliomas, even in the presence of a pre- existing mutation of the tumor suppressor p53 (TP53) gene. The most common mutation ($ 90%) in glial brain tumors causes a substitution of the amino acid Arginine to Histidine at codon 132 of the IDH1 gene (IDH1 R132H); alterna- tively, a mutually exclusive mutation in codon 172 of the mitochondrial IDH2 gene can occur. These homologous enzymes decarboxylate isocitrate to α- ketoglutarate (αKG) and this “neomorphic” muta- tion renders the IDH enzyme to reduce αKG into 2-hydroxyglutarate (2-HG) in an NADPH depen- dent manner. Accumulation of 2-HG to high levels in glioma tissues may cause epigenetic alterations in both, DNA and histones, altering gene expression and promoting oncogenic transformation. Reorga- nization of the methylome due to mutant IDH is the molecular basis of the CpG island methylator phenotype (CIMP) in gliomas, leading to global dysregulation of gene expression.
IDH1 mutations occur early, with a high fre- quency, in WHO grade II and III astrocytic and oligodendroglial tumors and in secondary GBMs, which develop from astrocytomas. IDH mutations in gliomas are early events in their pathogenesis, and are associated with several clinically relevant parameters including patient age, histopatho- logical diagnosis, combined 1p/19q deletion (co-segregate in oligodendrogliomas), TP53 mutation, MGMT promoter hypermethylation and patient survival. Diagnostically it serves 2 roles when used with ATRX and 1p19q status: (1) differentiate grade II/III oligodendrogliomas from other lesions with potentially similar histo- logical appearance or “oligodendroglial-like differentiation” (e.g. primary GBM, clear cell ependymomas, neurocytomas or pilocytic astrocy- tomas), and (2) high-grade astrocytomas or oligo- dendrogliomas from “primary GBMs with oligodendroglial differentiation.” The association between IDH1/2 mutation and a favorable prog- nosis is better established in high-grade gliomas. The majority of studies reporting mutant IDH1 as a favorable factor in WHO grade II tumors often include oligodendroglial tumors (which will also have 1p19q loss hence better chemotherapy response) and studies comprising low-grade astro- cytomas only showed no prognostic value of mutant IDH1/2. The NOA4 trial identified that MGMT promoter methylation is prognostic for patients with IDH1/2-mutant WHO grade III gliomas, but in patients with IDH-wild-type tumors it was predictive for benefit from alkylating chemotherapy.

Question 21

A 30-year-old man with AIDS develops headaches and left hemiparesis and is found to have a right frontal white matter homogeneously enhancing lesion. The lesion shows increased uptake on Thallium SPECT

Supratentorial lesions:
a. Anaplastic oligodendroglioma
b. Central neurocytoma
c. Diffuse astrocytoma
d. DNET
e. Germinoma
f. Glioblastoma multiforme
g. Metastatic melanoma
h. Non-germinomatous germ cell tumor
i. Oligodendroglioma
j. Pineoblastoma
k. Primary CNS lymphoma
l. Subependymal giant cell astrocytoma

Answer 21

k. Primary CNS lymphoma

Question 22

A 13-year-old presents with diabetes insipidus

Supratentorial lesions:
a. Anaplastic oligodendroglioma
b. Central neurocytoma
c. Diffuse astrocytoma
d. DNET
e. Germinoma
f. Glioblastoma multiforme
g. Metastatic melanoma
h. Non-germinomatous germ cell tumor
i. Oligodendroglioma
j. Pineoblastoma
k. Primary CNS lymphoma
l. Subependymal giant cell astrocytoma

Answer 22

e. Germinoma

Question 23

A17-year-oldpresentswithParinaudsyn- drome. Blood tests show a markedly raised HCG, but normal AFP

Supratentorial lesions:
a. Anaplastic oligodendroglioma
b. Central neurocytoma
c. Diffuse astrocytoma
d. DNET
e. Germinoma
f. Glioblastoma multiforme
g. Metastatic melanoma
h. Non-germinomatous germ cell tumor
i. Oligodendroglioma
j. Pineoblastoma
k. Primary CNS lymphoma
l. Subependymal giant cell astrocytoma

Answer 23

h. Non-germinomatous germ cell tumor

Question 24

Commonest posterior fossa primary brain tumor in adults

Posterior fossa lesions:
a. Brainstem glioma
b. Choroid plexus papilloma
c. Dysplastic cerebellar gangliocytoma d. Ependymoma
e. Epidermoid
f. Hemangioblastoma
g. Medulloblastoma h. Meningioma
i. Pilocytic astrocytoma
j. Vestibular schwannoma

Answer 24

f. Hemangioblastoma

Question 25

Commonest posterior fossa primary brain tumor in children

Posterior fossa lesions:
a. Brainstem glioma
b. Choroid plexus papilloma
c. Dysplastic cerebellar gangliocytoma d. Ependymoma
e. Epidermoid
f. Hemangioblastoma
g. Medulloblastoma h. Meningioma
i. Pilocytic astrocytoma
j. Vestibular schwannoma

Answer 25

i. Pilocytic astrocytoma

Question 26

Associated with mutation in PTEN tumor suppressor gene

Posterior fossa lesions:
a. Brainstem glioma
b. Choroid plexus papilloma
c. Dysplastic cerebellar gangliocytoma
d. Ependymoma
e. Epidermoid
f. Hemangioblastoma
g. Medulloblastoma h. Meningioma
i. Pilocytic astrocytoma
j. Vestibular schwannoma

Answer 26

c. Dysplastic cerebellar gangliocytoma

Question 27

A mutation which gives patients with IDH wild type, ATRX mutant (negative) astro- cytoma a similar prognosis to glioblastoma multiforme

Molecular classification of brain tumors:
a. TERT
b. TP53
c. IDH1/2 mutation
d. MGMT promoter methylation
e. 1p19q co-deletion
f. EGFRvIII ‘
g. Histone H3
h. ATRX
i. BRAF
j. 10q loss

Answer 27

g. Histone H3

Question 28

Highly prevalent in all gliomas except primary glioblastoma multiforme

Molecular classification of brain tumors: a. TERT
b. TP53
c. IDH1/2 mutation
d. MGMT promoter methylation
e. 1p19q co-deletion
f. EGFRvIII ‘
g. Histone H3
h. ATRX
i. BRAF
j. 10q loss

Answer 28

c. IDH1/2 mutation

Question 29

Improves prognosis in oligodendroglio- mas, irrespective of IDH1/2 status

Molecular classification of brain tumors: a. TERT
b. TP53
c. IDH1/2 mutation
d. MGMT promoter methylation
e. 1p19q co-deletion
f. EGFRvIII ‘
g. Histone H3
h. ATRX
i. BRAF
j. 10q loss

Answer 29

e. 1p19q co-deletion

Question 30

Target for glioblastoma vaccine trials

Molecular classification of brain tumors: a. TERT
b. TP53
c. IDH1/2 mutation
d. MGMT promoter methylation
e. 1p19q co-deletion
f. EGFRvIII
g. Histone H3
h. ATRX
i. BRAF
j. 10q loss

Answer 30

f. EGFRvIII

Question 31

Predictive of benefit from temozolomide
in primary GBM

Molecular classification of brain tumors: a. TERT
b. TP53
c. IDH1/2 mutation
d. MGMT promoter methylation
e. 1p19q co-deletion
f. EGFRvIII ‘
g. Histone H3
h. ATRX
i. BRAF
j. 10q loss

Answer 31

d. MGMT promoter methylation

BRAF gene mutations are diagnostically useful in differentiating low-grade glial and glioneuronal (pilocytic astrocytoma, PXA, ganglioglioma, SEGA) from diffuse astrocytomas, but not prog- nostically relevant. The table below reflects com- monest patterns of molecular status according to histological grades

Question 32

Which one of the following statements regarding management of brain metastases is LEAST accurate?
a. Chemotherapy/biologics should be con- sidered alone when asymptomatic brain metastasis is found on screening before planned systemic therapy
b. Whole brain radiotherapy should be con- sidered in the setting of multiple brain metastasis (4-10) especially if primary tumor is known to be radiotherapy sensitive
c. SRS could be considered in multiple brain metastases (4-10) when the primary tumor is known to be radiotherapy resistant
d. Surgical resection should be considered in the setting of a dominant hemisphere metastasis in a critical location
e. SRS could be considered in oligometas- tases if they are greater than 4 cm in diameter

Answer 32

e. SRS could be considered in oligometas- tases if they are greater than 4 cm in diameter

Question 33

Which one of the following statements regarding average prognosis of patients pre- senting with Karnofsky of score less than 70 is most accurate?
a. A Karnofsky performance score less than 70 is associated with a median survival of 2 months
b. A Karnofsky performance score less than 70 is associated with a median survival of 4 months
c. A Karnofsky performance score less than 70 is associated with a median survival of 6 months
d. A Karnofsky performance score less than 70 is associated with a median survival of 8 months
e. A Karnofsky performance score less than 70 is associated with a median survival of 12 months

Answer 33

a. A Karnofsky performance score less than 70 is associated with a median survival of 2 months

The median survival of patients who receive sup- portive care with brain metastases and are treated only with corticosteroids is approximately 1- 2 months. The use of whole brain radiation therapy in large series increased the average survival to 3- 6 months, and larger gains were seen in carefully selected subsets. The key parameters that deter- mine survival after the diagnosis of brain metastases are performance status, the extent of extracranial disease, and age, as well as the primary diagnosis. Recursive partitioning analysis (RPA) system was based upon an analysis of prognostic factors in 1200 patients from three Radiation Therapy
Oncology Group (RTOG) brain metastases trials and resulted in three groups being identified:
Class 1 (20%)—Patients who had a Karnofsky performance score 70 or higher, were less than 65 years of age, and had a controlled primary tumor without extracranial metas- tases had a favorable prognosis (median sur- vival was 6-7 months).
Class 2 (65%)—Patients with a Karnofsky performance score 70 or higher, but with other unfavorable characteristics (e.g. uncon- trolled primary tumor, other extracranial metastases, age >65 years) had an intermedi- ate prognosis (median survival 4 months). From a further management point of view, they are treated as either RPA Class 1 or RPA Class 3, depending largely upon the likelihood of controlling systemic disease.
Class 3 (15%)—Patients with a Karnofsky performance score less than 70 have a poor prognosis (median survival of 2 months).

Question 34

Which one of the following statements regarding biopsy of brainstem lesions is LEAST accurate?
a. Contralateral extraventricular transfron- tal approach is suited to more lateral pon- tine lesions
b. Ipsilateraltransfrontalapproachmayhavea higher risk of intraventricular hemorrhage
c. Is more commonly used in adults com-
pared to children
d. Occipital transtentorial approach is routinely used
e. Suboccipital, transcerebellar approach is
associated with greater postoperative pain

Answer 34

d. Occipital transtentorial approach is routinely used

Lesions within the brainstem have long been considered challenging to diagnose and treat. Although brainstem tumors represent only about 2% of all intracranial tumors in adults as compared with about 10-15% in the pediatric population, radiologic diagnosis of brainstem lesions in adults is inaccurate 10-20% of the time whereas in chil- dren the majority are gliomas (diagnosable on MRI). In general, because most adult brainstem tumors are not amenable to surgical excision, ste- reotactic biopsy is important for obtaining a path- ologic diagnosis enabling replacement of empirical treatment modalities with more specific therapies, as well as determination of a more accurate prognosis. Equally, given the great diversity of brainstem lesions, patients most likely to benefit from stereotactic biopsy are those who are given a better prognosis based on biopsy results or who are spared a course of debilitating therapy. Such patients include those with radiation necro- sis, chemotherapy-sensitive metastasis, a lym- phoma, or an abscess rather than a malignant glioma. In terms of complications, 6.6% have tran- sient or mild symptoms and 1.8% have permanent deficits.

Question 35

Which one of the following indications for stereotactic biopsy of a brain lesion is LEAST appropriate?
a. Deep seated lesions
b. Infiltrative lesion
c. Lesions in eloquent cortex
d. Lesions not curable by surgical excision
(e.g. brainstem tumors)
e. Suspected frontal renal cell carcinoma brain metastasis

Answer 35

e. Suspected frontal renal cell carcinoma brain metastasis

The significant development of intracranial imaging over the past few decades has allowed
much earlier diagnosis of brain tumors. Although some tumors have a characteristic appearance on imaging, no imaging modality is yet able to pro- vide sufficient diagnostic information to direct subsequent aggressive therapy. The goal of biopsy is to provide a representative sample for pathologic diagnosis to guide subsequent treat- ment, which can include cytoreductive surgery, radiotherapy, or chemotherapy. The main stimu- lus for the adoption of stereotactic biopsy over an open operative procedure is to achieve a higher rate of diagnostic accuracy while minimizing potential adverse effects. Diagnostic accuracy is important for dictating appropriate adjuvant therapy. Particular characteristics of the tumor that favor the use of stereotactic biopsy over open biopsy include (1) lesions not requiring emergent surgery or that are not curable by surgical exci- sion, such as metastases or malignant intrinsic brain tumors; (2) deep-seated lesions or those occupying space in eloquent cortex or deep nuclei (i.e. basal ganglia, thalamus), where open resec- tion would lead to unacceptable morbidity/mor- tality; and (3) infiltrative lesions (i.e. gliomatosis cerebri) that do not have a clear brain-tumor mar- gin and are unlikely to be excised completely without significant loss of normal brain paren- chyma. Moreover, if the lesion’s appearance on imaging or the course of the disease suggests an alternative cause such as an infectious or demye- linating process rather than a neoplastic one, ste- reotactic biopsy is a more appropriate first step than a large open procedure. Relative contraindi- cations include vascular tumors (e.g. metastatic renal cell carcinoma, choriocarcinoma, or meta- static melanoma) where diagnosis and biopsy the primary neoplasm instead is generally recom- mended, close proximity to a major blood vessel/ sylvian fissure/cavernous sinus/brain-pial border all increase the risk of hemorrhage.