3rd article

Question 1

A 54-year-old man was admitted to this hospital because of

Answer 1

visual-field loss and a mass in the brain.

Question 2

The patient had been well until 3 weeks before admission, when loss of vision in the right eye, associated with

Answer 2

diplopia, developed while he was jogging; it resolved spontaneously after several minutes.

Question 3

Four days before admission, the symptoms recurred transiently, and he

Answer 3

bumped into a tree while running.

Question 4

On the morning of admission,

Answer 4

dizziness and loss of vision in the right lower visual field in both eyes developed, which did not resolve and resulted in difficulty driving.

Question 5

He went to the emergency department at another hospital. On examination,

Answer 5

nystagmus was present in both eyes on left and right gaze.

Question 6

The vital signs and the remainder of the examination were

Answer 6

normal, as were the results of laboratory tests, including a complete blood count; blood levels of electrolytes, calcium, and glucose; and tests of coagulation and renal and hepatic function.

Question 7

Magnetic resonance imaging (MRI) of the brain, after the administration of gadolinium, revealed

Answer 7

two adjacent masses (2 cm by 2 cm and 1 cm by 1.5 cm) in the left occipital and posterior parietal regions.

Question 8

Mass effect on the

Answer 8

left occipital horn was associated with abnormal T2-weighted and fluid-attenuated inversion recovery (FLAIR) signal hyperintensity extending through the splenium of the corpus callosum.

Question 9

The patient was admitted to the hospital, and

Answer 9

1. acetylsalicylic acid,
2. dexamethasone, and
3. phenytoin were administered.

Question 10

Later that day, he was transferred to this hospital. The patient reported

Answer 10

1. difficulty seeing objects in the right lower visual field and
2. dizziness.

Question 11

He reported no

Answer 11

headache, nausea, vomiting, numbness, weakness, bowel or bladder dysfunction, or seizures.

Question 12

He had a history of

Answer 12

1. gastroesophageal reflux disease and

2. Helicobacter pylori infection and had recently had hematuria.

Question 13

A computed tomographic (CT) scan of the abdomen obtained 3 months before admission showed

Answer 13

prostatic enlargement and was otherwise normal. y.

Question 14

He had had

Answer 14

inguinal herniorrhaphies in the past.

Question 15

He took

Answer 15

esomeprazole and had no known allergies.

Question 16

He drank

Answer 16

alcohol in moderation, had never smoked, and had no recent exposure to ill persons, tuberculosis, or asbestos.

Question 17

An uncle had had an inoperable

Answer 17

primary brain tumor; the patient’s siblings and children were health

Question 18

On examination, there was

Answer 18

1. bilateral right inferior quadrantanopia;

2. the vital signs, oxygen saturation, and remainder of the general and neurologic examination were normal.

Question 19

The administration of dexamethasone was continued, and

Answer 19

omeprazole was added.

Question 20

the pt had high blood

Answer 20

high blood glucose and high lactate dehydrogenase

1. The blood glucose level was 199 mg per deciliter (11.0 mmol per liter) (reference range, 70 to 110 mg per deciliter [3.9 to 6.1 mmol per liter]), and the
2. lactate dehydrogenase level 217 U per liter (reference range, 110 to 210).

Question 21

The complete blood count and blood levels of electrolytes, protein, albumin, globulin, calcium, phosphorus, magnesium, carcinoembryonic antigen, prostatespecific antigen, CA 19-9, and nonmaternal alphafetoprotein were

Answer 21

normal, as were tests of coagulation and renal function and a urinalysis.

Question 22

A chest radiograph was normal. On the second day, an MRI scan of the brain, obtained after the administration of gadolinium, showed

Answer 22

two heterogeneously enhancing, well-circumscribed lesions in the left occipital lobe (2.2 cm by 1.8 cm and 1.1 cm by 1.4 cm).

Question 23

Within the enhancing portions of the lesions, there was

Answer 23

restricted diffusion.

Question 24

Extensive signal abnormality on T2-weighted and FLAIR images was seen

Answer 24

in the surrounding white matter of

1. the left occipital lobe,
2. extending into the posterior left temporal lobe and
3. the splenium of the corpus callosum.

Question 25

The next day, an MRI scan of the abdomen and pelvis after the administration of gadolinium, a CT scan of the chest, and a bone scan showed

Answer 25

no evidence of cancer.

Question 26

The patient was discharged on the fourth hospital day, taking

Answer 26

1. omeprazole and

2. dexamethasone.

Question 27

Three days later, the patient was

Answer 27

readmitted, and a diagnostic procedure was performed.

Question 28

MRI examination reveals

Answer 28

two masses in the left occipital lobe that are enhanced on images obtained after the administration of gadolinium (Fig. 1A).

Question 29

There is abnormal T2-weighted signal in the

Answer 29

left occipital lobe surrounding the foci of enhancement and extending across the splenium of the corpus callosum (Fig. 1B), a feature consistent with edema.

Question 30

Additional imaging studies showed

Answer 30

no evidence of highly restrictive diffusion that would be typical for an infarct; instead they showed increased diffusion of water, a finding consistent with edema.

Question 31

Susceptibility-weighted MRI scans showed that the masses had small regions of very short T2-weighted signal that were consistent with

Answer 31

1. microhemorrhages or

2. calcifications (Fig. 1C).

Question 32

Dr. Batchelor: I cared for this patient and am aware of the diagnosis. This 54-year-old man presented with

Answer 32

1. episodic,

2. reversible neurologic deficits, followed by persistent bilateral right inferior quadrantanopia.

Question 33

Cranial MRI showed contrast enhancing masses in the

Answer 33

left occipital lobe, and

Question 34

additional imaging showed

Answer 34

no evidence of lesions outside the brain.

Question 35

A tumor was the leading diagnostic possibility, and a

Answer 35

primary brain tumor was more likely than a metastatic tumor.

Question 36

Other neurologic diseases were in the differential diagnosis. On cranial MRI,

Answer 36

a cerebral abscess may have an appearance similar to that of a tumor;

Question 37

cerebral abscess was ruled out

Answer 37

however, this patient had no systemic symptoms, no fever, and no recent craniofacial infections or procedures that might have conferred the risk of an abscess. subsequent infarct.

Question 38

Acute disseminated encephalomyelitis may present as a

Answer 38

contrast-enhancing mass lesion; however, the absence of more severe neurologic deficits would be somewhat atypical.

Question 39

His transient neurologic symptoms raised the possibility of

Answer 39

transient ischemic attacks, with a subsequent infarct.

Question 40

Although infarcts may be contrast enhancing, the appearance of two discrete,

Answer 40

contrast-enhancing mass lesions is more typical of tumor than of cerebral infarcts.

Question 41

Moreover, there was

Answer 41

no restricted diffusion on the initial cranial MRI scan to suggest acute infarction.

Question 42

The leading diagnosis in this case was therefore a

Answer 42

primary malignant tumor of the brain parenchyma.

Question 43

The appearance on imaging and the patient’s age make

Answer 43

glioblastoma the most likely diagnosis.

Question 44

Resection of a suspected malignant brain tumor confers several benefits. A resection specimen provides representative tumor tissue for

Answer 44

pathological diagnosis, including molecular genetic tests.

Question 45

A debulking resection may also reduce

Answer 45

1. mass effect and
2. intracranial pressure, leading to clinical improvement and decreasing the need for medications such as glucocorticoids to reduce intracerebral edema.

Question 46

A prospective, randomized trial showed that, in a subset of patients with

Answer 46

1. glioblastoma,

2. gross total resection conferred a survival benefit as compared with subtotal resection.1

Question 47

Therefore, craniotomy for

Answer 47

both diagnosis and resection of the mass was recommended and performed.

Question 48

Malignant primary brain tumor, most likely

Answer 48

glioblastoma.

Question 49

Examination of the specimen of the tumor in the left

Answer 49

occipital lobe showed a

1. densely cellular glial tumor with
2. mitoses,
3. microvascular (so-called endothelial) proliferation, and 4. necrosis (Fig. 1D), features diagnostic of glioblastoma (World Health Organization [WHO] grade IV of IV).

Question 50

Methylation-specific polymerase chain reaction (PCR) to evaluate the methylation status of the

Answer 50

O6-methylguanine–DNA methyltransferase (MGMT) gene promoter, performed on DNA extracted from the formalin-fixed, paraffin-embedded block of tumor, showed methylated alleles.

Question 51

MGMT is a

Answer 51

DNA-repair protein;

Question 52

the methylation status of the MGMT promoter has

Answer 52

prognostic and potentially predictive significance in glioblastoma.

Question 53

Fluorescence in situ hybridization with the use of a probe to the epidermal growth factor receptor gene (EGFR) revealed

Answer 53

a normal number of EGFR signals.

Question 54

EGFR amplification is found in about

Answer 54

one third of glioblastomas and may have adverse prognostic relevance.

Question 55

The diagnosis was glioblastoma, WHO grade IV,

Answer 55

1. with methylation of the MGMT promoter and

2. without EGFR amplification.

Question 56

This patient has a newly diagnosed

Answer 56

glioblastoma that has been surgically resected.

Question 57

Examination of a specimen of the tumor shows MGMT methylation but

Answer 57

no EGFR amplification.

Question 58

Glioblastoma is a highly malignant tumor,

Answer 58

with a median survival of 9 to 14 months and 5-year survival in less than 10% of patients.

Question 59

Radiation was shown in the 1970s and 1980s to be superior to supportive care or chemotherapy alone in

Answer 59

prolonging survival and is a critical component of the management of glioblastoma.

Question 60

Radiation is delivered as

Answer 60

focal, fractionated, external-beam treatments.

Question 61

Temozolomide is an oral

Answer 61

methylating agent that improves progression-free and overall survival as compared with radiation alone.2 It is administered concurrently with radiation for 6 weeks (chemoradiation) and then without radiation for 6 months.

Question 62

(Temozolomide) This regimen is now considered the standard of care for patients with

Answer 62

newly diagnosed glioblastoma, regardless of the methylation status of MGMT.

Question 63

However, in patients with glioblastoma who are treated with this regimen,

Answer 63

the methylation status of the MGMT promoter has prognostic implications.

Question 64

In one study, patients with glioblastoma whose tumors were positive for MGMT methylation, as this patient’s was, had a median survival of 21.7 months and 2-year survival of

Answer 64

46%, as compared with patients whose tumors were negative for MGMT methylation, who had a median survival of 12.7 months and 2-year survival of 13.8%.3

Question 65

Since drugs that target the vascular endothelial growth factor (VEGF) signal-transduction pathway and consequently inhibit

Answer 65

angiogenesis have shown some benefit in patients with recurrent glioblastoma, this patient was enrolled in a phase 1 clinical trial in which vatalanib, an oral, pan-VEGF tyrosine kinase inhibitor, was added to concurrent radiation and temozolomide.
4

Question 66

The patient received this regimen with no adverse effects. Four weeks after completion of the 6-week course, a routine follow-up cranial MRI was performed, at which time, the patient was

Answer 66

asymptomatic, physically active, and managing all his activities of daily living.

Question 67

Dr. Sorensen: An MRI scan obtained 3 months after surgery showed irregular feathery enhancement around the surgical cavity, as well as mass effect as evidenced by compression of

Answer 67

the left lateral ventricle (Fig. 2A); both findings were new in comparison with immediate postoperative images. Extensive edema was evident on the T2-weighted FLAIR image (Fig. 2B).

Question 68

Diffusion weighted images showed

Answer 68

1. increased water mobility (i.e., increased diffusion of water), a feature consistent
2. with edema, and perfusion-weighted images showed no evidence of elevated cerebral blood volume or hypervascularity in the region.

Question 69

Positron-emission tomography after the administration of 18F-fluorodeoxyglucose revealed

Answer 69

no evidence of hypermetabolism in the region.
–> These imaging-based physiological and functional assays indicated that there was no active tumor, despite the presence of a clear mass effect.

Question 70

Dr. Batchelor: The changes observed on the first postradiation cranial MRI could represent either tumor progression or tumor pseudoprogression, which is

Answer 70

a reaction of the tumor and tumor microenvironment to the radiation and chemotherapy.

Question 71

Tumor pseudoprogression usually occurs within 3 months after

Answer 71

completion of radiation and chemotherapy. Since no imaging studies are specific for distinguishing pseudoprogression from actual tumor progression, we were concerned that the changes could represent tumor progression in this patient. Therefore, we performed a stereotactic biopsy of the enhancing abnormalities in the left occipital lobe.

Question 72

Dr. Louis: Three biopsy specimens of the left occipital lobe contained

Answer 72

extensive necrotic debris with microcalcifications (Fig. 2C).

Question 73

The specimens also contained

Answer 73

viable brain tissue with some

1. atypical glial cells and
2. marked hyalinization of small blood vessels that had plump endothelial cells with prominent nuclei.
   - -> These features are characteristic effects of radiation and other therapies. No areas of solid, mitotically active tumor were present. The pathological findings were consistent with pseudoprogression.

Question 74

Dr. Batchelor: Pseudoprogression, as observed in this patient, occurs in approximately 20 to 40% of patients with glioblastoma after chemoradiation. 5 Patients with tumors that have

Answer 74

methylation of the MGMT promoter may be at a higher risk for this complication — in one series, pseudoprogression was observed in 21 of 23 patients with MGMT-methylated glioblastomas that were treated with chemoradiation.5

Question 75

Interestingly, in cases of glioblastoma, patients with tumors that showed pseudoprogression had improved survival relative to patients with

Answer 75

tumors that did not develop pseudoprogression.

Question 76

Pseudoprogression may be associated with cerebral edema and increased intracranial pressure and can result in neurologic symptoms and signs, although

Answer 76

it did not in this patient. In symptomatic patients, the administration of glucocorticoids may alleviate edema and neurologic symptoms.

Question 77

Small clinical studies have investigated the use of anti-VEGF therapy for radiation necrosis,6 but

Answer 77

this treatment remains experimental.

Question 78

This patient was taking a VEGF inhibitor,

Answer 78

vatalanib, which may have suppressed symptoms caused by pseudoprogression.

Question 79

Since he was asymptomatic at the time of the radiographic findings, we made

Answer 79

no changes in his treatment. He continued taking

1. temozolomide and vatalanib as part of the phase 1 trial for 12 monthly cycles, and then he entered a period of observation. He returned to work parttime and adapted well to his only
   1) neurologic deficit,
   2) bilateral right inferior quadrantanopia.

Question 80

Fourteen months after the diagnosis of

Answer 80

pseudoprogression and 18 months after the initial diagnosis of glioblastoma,

Question 81

a routine follow-up MRI scan showed reduction in mass effect and markedly

Answer 81

decreased enhancement as compared with the earlier scans. One month later, he had a generalized seizure.

Repeat cranial MRI was performed.

Question 82

Dr. Sorensen: An MRI scan of the brain obtained after the administration of gadolinium showed reduced enhancement in the

Answer 82

left occipital lobe and no enhancement in the right temporal lobe 18 months after surgery (Fig. 2D),

Question 83

whereas an image obtained 1 month later showed a new enhancing mass in the

Answer 83

right temporal lobe with midline shift, compression of the right temporal ventricular horn, and sulcal effacement (Fig. 3A).

Question 84

T2-weighted FLAIR images showed marked

Answer 84

edema surrounding the mass (Fig. 3B).

Question 85

Dr. Batchelor: Because the imaging revealed a new

Answer 85

mass in the contralateral hemisphere, a subtotal resection of the mass in the right temporal lobe was performed.

Question 86

Dr. Louis: Specimens obtained from the right temporal lobe consisted of

Answer 86

densely cellular, viable, and mitotically active tumor, as well as tumor diffusely infiltrating the adjacent white matter, findings diagnostic of recurrent glioblastoma (Fig. 3C).

Question 87

There were also foci of necrosis, findings consistent with

Answer 87

treatment effects.

Question 88

Methylationspecific PCR confirmed the continued presence of

Answer 88

methylation of the MGMT promoter in the recurrent tumor.

Question 89

Studies of the methylation status of the MGMT promoter in primary and recurrent glioblastomas have shown that

Answer 89

recurrent tumors may change their methylation status, particularly if the primary tumor had a methylated MGMT promoter; however, methylation status of the MGMT promoter at recurrence does not appear to be predictive of subsequent outcome.7

Question 90

Dr. Batchelor: This patient now has

Answer 90

recurrent glioblastoma, 19 months after surgical excision,

remote from the original site and outside the original radiation field.

Question 91

In patients treated with radiation alone, CT-based investigations of the patterns of glioblastoma recurrence revealed that

Answer 91

90% of patients had tumor progression within 2 cm of the original tumor site and within the region of the brain that had received radiation.8

However, more recent studies involving patients receiving temozolomide plus radiation have shown a higher proportion of patients with the development of tumor progression outside the radiation field, as well as a longer interval to recurrence and improved survival.9

Question 92

This patient had a relapse at 19 months, outside the radiation field; the timing and location are characteristic of

Answer 92

MGMT-methylated tumors that have been treated with temozolomide and radiation.

Question 93

Treatment options for this patient with recurrent glioblastoma are

Answer 93

limited. –> Bevacizumab, a monoclonal antibody that binds the circulating VEGF ligand, is approved by the Food and Drug Administration for recurrent glioblastoma.

In a randomized, noncomparative trial of bevacizumab with and without irinotecan (an inhibitor of topoisomerase II), radiographic responses were observed in 28% and 37% of patients, respectively.
10

These rates are higher than those observed in historical control patients not treated with bevacizumab.

Question 94

Carboplatin alone has limited activity in cases of recurrent glioblastoma, but it is not known

Answer 94

whether treatment with a combination of carboplatin and bevacizumab will confer an improved result.

Question 95

After subtotal resection of the recurrent tumor, this patient received a repeated 6-week course of

Answer 95

temozolomide plus radiation.

Question 96

He was then begun on treatment with

Answer 96

bevacizumab and carboplatin.

Question 97

Dr. Sorensen: Images obtained before the initiation of bevacizumab therapy show areas of enhancement in the

Answer 97

right temporal lobe (Fig. 4A) that are surrounded by extensive edema (Fig. 4B), confirmed on maps of the apparent diffusion coefficient (Fig. 4C).

Question 98

The effects of surgery in the right temporal lobe are evident: the enhancing region has been

Answer 98

removed (Fig. 4D), and the edema has been reduced (Fig. 4E). Of note, however, is a focus of markedly restricted diffusion (Fig. 4F), consistent with more cellular tissue and suggestive of active tumor.

Question 99

Dr. Batchelor: Despite radiographic improvement, the patient had progressive neurologic decline while on treatment.

Answer 99

It is possible that the reduction in contrast enhancement represented pseudoresponse (i.e., reduction of vessel permeability) and that the expanding regions of restricted diffusion were representative of progressive glioblastoma.

Question 100

In view of his neurologic decline, we elected, in consultation with the patient and his family, to stop therapy, and the patient was

Answer 100

transferred to hospice care. He died 8 months after the recurrence and 28 months after the initial diagnosis of glioblastoma.

Question 101

Unfortunately, this survival is typical of the best that can be achieved with current therapy for glioblastoma.

Dr. Louis: Are there any questions?
Dr. Jay Loeffler (Radiation Oncology): The imaging at the time of the recurrence,

Answer 101

in the right temporal lobe, did not reveal disease connecting that site to the originally affected left occipital lobe. Would you comment on that?

Question 102

Dr. Louis: In studies involving large sections of brains obtained at autopsy from patients with glioma,11-13 infiltrating tumor cells can be found between

Answer 102

foci of cerebral glioma in the majority of the cases, confirming the microscopical contiguity of most malignant cerebral gliomas.

Question 103

An autopsy was not performed in this patient to examine this question at a histologic or molecular level.

Dr. Andrew S. Chi (Neurology): Were there any histologic differences between the primary and the recurrent tumor?

Dr. Louis: Many recurrent glioblastomas look histologically

Answer 103

similar to the primary tumors, although recurrences within the treated field typically show changes characteristic of previous treatment, including necrosis with punctate mineralization or hyalinized blood vessels with activated-appearing endothelial cells. In this patient, there were no notable differences between the histologic appearances of the two tumors.

Question 104

Michelle R. Pisapia (Nurse Practitioner, Neurology): Are there any restrictions in the way the protocols are written for these new study drugs regarding whether

Answer 104

the diagnosis is pseudoprogression and whether a patient can stay on the drugs?

Question 105

Dr. Batchelor: Yes, clinical trials for recurrent glioblastoma are designed such that patients in whom radiographic progression develops in the radiation treatment field within 3 months after

Answer 105

the completion of chemoradiation are excluded unless there is a pathological diagnosis of recurrent tumor.

Question 106

Anatomical Diagnosis

Answer 106

Glioblastoma, WHO grade IV of IV, with methylation

of the MGMT promoter.