3rd article Flashcards
A 54-year-old man was admitted to this hospital because of
visual-field loss and a mass in the brain.
The patient had been well until 3 weeks before admission, when loss of vision in the right eye, associated with
diplopia, developed while he was jogging; it resolved spontaneously after several minutes.
Four days before admission, the symptoms recurred transiently, and he
bumped into a tree while running.
On the morning of admission,
dizziness and loss of vision in the right lower visual field in both eyes developed, which did not resolve and resulted in difficulty driving.
He went to the emergency department at another hospital. On examination,
nystagmus was present in both eyes on left and right gaze.
The vital signs and the remainder of the examination were
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.
Magnetic resonance imaging (MRI) of the brain, after the administration of gadolinium, revealed
two adjacent masses (2 cm by 2 cm and 1 cm by 1.5 cm) in the left occipital and posterior parietal regions.
Mass effect on the
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.
The patient was admitted to the hospital, and
- acetylsalicylic acid,
- dexamethasone, and
- phenytoin were administered.
Later that day, he was transferred to this hospital. The patient reported
- difficulty seeing objects in the right lower visual field and
- dizziness.
He reported no
headache, nausea, vomiting, numbness, weakness, bowel or bladder dysfunction, or seizures.
He had a history of
- gastroesophageal reflux disease and
2. Helicobacter pylori infection and had recently had hematuria.
A computed tomographic (CT) scan of the abdomen obtained 3 months before admission showed
prostatic enlargement and was otherwise normal. y.
He had had
inguinal herniorrhaphies in the past.
He took
esomeprazole and had no known allergies.
He drank
alcohol in moderation, had never smoked, and had no recent exposure to ill persons, tuberculosis, or asbestos.
An uncle had had an inoperable
primary brain tumor; the patient’s siblings and children were health
On examination, there was
- bilateral right inferior quadrantanopia;
2. the vital signs, oxygen saturation, and remainder of the general and neurologic examination were normal.
The administration of dexamethasone was continued, and
omeprazole was added.
the pt had high blood
high blood glucose and high lactate dehydrogenase
- 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
- lactate dehydrogenase level 217 U per liter (reference range, 110 to 210).
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
normal, as were tests of coagulation and renal function and a urinalysis.
A chest radiograph was normal. On the second day, an MRI scan of the brain, obtained after the administration of gadolinium, showed
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).
Within the enhancing portions of the lesions, there was
restricted diffusion.
Extensive signal abnormality on T2-weighted and FLAIR images was seen
in the surrounding white matter of
- the left occipital lobe,
- extending into the posterior left temporal lobe and
- the splenium of the corpus callosum.
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
no evidence of cancer.
The patient was discharged on the fourth hospital day, taking
- omeprazole and
2. dexamethasone.
Three days later, the patient was
readmitted, and a diagnostic procedure was performed.
MRI examination reveals
two masses in the left occipital lobe that are enhanced on images obtained after the administration of gadolinium (Fig. 1A).
There is abnormal T2-weighted signal in the
left occipital lobe surrounding the foci of enhancement and extending across the splenium of the corpus callosum (Fig. 1B), a feature consistent with edema.
Additional imaging studies showed
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.
Susceptibility-weighted MRI scans showed that the masses had small regions of very short T2-weighted signal that were consistent with
- microhemorrhages or
2. calcifications (Fig. 1C).
Dr. Batchelor: I cared for this patient and am aware of the diagnosis. This 54-year-old man presented with
- episodic,
2. reversible neurologic deficits, followed by persistent bilateral right inferior quadrantanopia.
Cranial MRI showed contrast enhancing masses in the
left occipital lobe, and
additional imaging showed
no evidence of lesions outside the brain.
A tumor was the leading diagnostic possibility, and a
primary brain tumor was more likely than a metastatic tumor.
Other neurologic diseases were in the differential diagnosis. On cranial MRI,
a cerebral abscess may have an appearance similar to that of a tumor;
cerebral abscess was ruled out
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.
Acute disseminated encephalomyelitis may present as a
contrast-enhancing mass lesion; however, the absence of more severe neurologic deficits would be somewhat atypical.
His transient neurologic symptoms raised the possibility of
transient ischemic attacks, with a subsequent infarct.
Although infarcts may be contrast enhancing, the appearance of two discrete,
contrast-enhancing mass lesions is more typical of tumor than of cerebral infarcts.
Moreover, there was
no restricted diffusion on the initial cranial MRI scan to suggest acute infarction.
The leading diagnosis in this case was therefore a
primary malignant tumor of the brain parenchyma.
The appearance on imaging and the patient’s age make
glioblastoma the most likely diagnosis.
Resection of a suspected malignant brain tumor confers several benefits. A resection specimen provides representative tumor tissue for
pathological diagnosis, including molecular genetic tests.
A debulking resection may also reduce
- mass effect and
- intracranial pressure, leading to clinical improvement and decreasing the need for medications such as glucocorticoids to reduce intracerebral edema.
A prospective, randomized trial showed that, in a subset of patients with
- glioblastoma,
2. gross total resection conferred a survival benefit as compared with subtotal resection.1
Therefore, craniotomy for
both diagnosis and resection of the mass was recommended and performed.
Malignant primary brain tumor, most likely
glioblastoma.
Examination of the specimen of the tumor in the left
occipital lobe showed a
- densely cellular glial tumor with
- mitoses,
- microvascular (so-called endothelial) proliferation, and 4. necrosis (Fig. 1D), features diagnostic of glioblastoma (World Health Organization [WHO] grade IV of IV).
Methylation-specific polymerase chain reaction (PCR) to evaluate the methylation status of the
O6-methylguanine–DNA methyltransferase (MGMT) gene promoter, performed on DNA extracted from the formalin-fixed, paraffin-embedded block of tumor, showed methylated alleles.
MGMT is a
DNA-repair protein;
the methylation status of the MGMT promoter has
prognostic and potentially predictive significance in glioblastoma.
Fluorescence in situ hybridization with the use of a probe to the epidermal growth factor receptor gene (EGFR) revealed
a normal number of EGFR signals.
EGFR amplification is found in about
one third of glioblastomas and may have adverse prognostic relevance.
The diagnosis was glioblastoma, WHO grade IV,
- with methylation of the MGMT promoter and
2. without EGFR amplification.
This patient has a newly diagnosed
glioblastoma that has been surgically resected.
Examination of a specimen of the tumor shows MGMT methylation but
no EGFR amplification.
Glioblastoma is a highly malignant tumor,
with a median survival of 9 to 14 months and 5-year survival in less than 10% of patients.
Radiation was shown in the 1970s and 1980s to be superior to supportive care or chemotherapy alone in
prolonging survival and is a critical component of the management of glioblastoma.
Radiation is delivered as
focal, fractionated, external-beam treatments.
Temozolomide is an oral
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.
(Temozolomide) This regimen is now considered the standard of care for patients with
newly diagnosed glioblastoma, regardless of the methylation status of MGMT.
However, in patients with glioblastoma who are treated with this regimen,
the methylation status of the MGMT promoter has prognostic implications.
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
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
Since drugs that target the vascular endothelial growth factor (VEGF) signal-transduction pathway and consequently inhibit
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
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
asymptomatic, physically active, and managing all his activities of daily living.
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
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).
Diffusion weighted images showed
- increased water mobility (i.e., increased diffusion of water), a feature consistent
- with edema, and perfusion-weighted images showed no evidence of elevated cerebral blood volume or hypervascularity in the region.
Positron-emission tomography after the administration of 18F-fluorodeoxyglucose revealed
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.
Dr. Batchelor: The changes observed on the first postradiation cranial MRI could represent either tumor progression or tumor pseudoprogression, which is
a reaction of the tumor and tumor microenvironment to the radiation and chemotherapy.
Tumor pseudoprogression usually occurs within 3 months after
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.
Dr. Louis: Three biopsy specimens of the left occipital lobe contained
extensive necrotic debris with microcalcifications (Fig. 2C).
The specimens also contained
viable brain tissue with some
- atypical glial cells and
- 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.
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
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
Interestingly, in cases of glioblastoma, patients with tumors that showed pseudoprogression had improved survival relative to patients with
tumors that did not develop pseudoprogression.
Pseudoprogression may be associated with cerebral edema and increased intracranial pressure and can result in neurologic symptoms and signs, although
it did not in this patient. In symptomatic patients, the administration of glucocorticoids may alleviate edema and neurologic symptoms.
Small clinical studies have investigated the use of anti-VEGF therapy for radiation necrosis,6 but
this treatment remains experimental.
This patient was taking a VEGF inhibitor,
vatalanib, which may have suppressed symptoms caused by pseudoprogression.
Since he was asymptomatic at the time of the radiographic findings, we made
no changes in his treatment. He continued taking
- 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.
Fourteen months after the diagnosis of
pseudoprogression and 18 months after the initial diagnosis of glioblastoma,
a routine follow-up MRI scan showed reduction in mass effect and markedly
decreased enhancement as compared with the earlier scans. One month later, he had a generalized seizure.
Repeat cranial MRI was performed.
Dr. Sorensen: An MRI scan of the brain obtained after the administration of gadolinium showed reduced enhancement in the
left occipital lobe and no enhancement in the right temporal lobe 18 months after surgery (Fig. 2D),
whereas an image obtained 1 month later showed a new enhancing mass in the
right temporal lobe with midline shift, compression of the right temporal ventricular horn, and sulcal effacement (Fig. 3A).
T2-weighted FLAIR images showed marked
edema surrounding the mass (Fig. 3B).
Dr. Batchelor: Because the imaging revealed a new
mass in the contralateral hemisphere, a subtotal resection of the mass in the right temporal lobe was performed.
Dr. Louis: Specimens obtained from the right temporal lobe consisted of
densely cellular, viable, and mitotically active tumor, as well as tumor diffusely infiltrating the adjacent white matter, findings diagnostic of recurrent glioblastoma (Fig. 3C).
There were also foci of necrosis, findings consistent with
treatment effects.
Methylationspecific PCR confirmed the continued presence of
methylation of the MGMT promoter in the recurrent tumor.
Studies of the methylation status of the MGMT promoter in primary and recurrent glioblastomas have shown that
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
Dr. Batchelor: This patient now has
recurrent glioblastoma, 19 months after surgical excision,
remote from the original site and outside the original radiation field.
In patients treated with radiation alone, CT-based investigations of the patterns of glioblastoma recurrence revealed that
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
This patient had a relapse at 19 months, outside the radiation field; the timing and location are characteristic of
MGMT-methylated tumors that have been treated with temozolomide and radiation.
Treatment options for this patient with recurrent glioblastoma are
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.
Carboplatin alone has limited activity in cases of recurrent glioblastoma, but it is not known
whether treatment with a combination of carboplatin and bevacizumab will confer an improved result.
After subtotal resection of the recurrent tumor, this patient received a repeated 6-week course of
temozolomide plus radiation.
He was then begun on treatment with
bevacizumab and carboplatin.
Dr. Sorensen: Images obtained before the initiation of bevacizumab therapy show areas of enhancement in the
right temporal lobe (Fig. 4A) that are surrounded by extensive edema (Fig. 4B), confirmed on maps of the apparent diffusion coefficient (Fig. 4C).
The effects of surgery in the right temporal lobe are evident: the enhancing region has been
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.
Dr. Batchelor: Despite radiographic improvement, the patient had progressive neurologic decline while on treatment.
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.
In view of his neurologic decline, we elected, in consultation with the patient and his family, to stop therapy, and the patient was
transferred to hospice care. He died 8 months after the recurrence and 28 months after the initial diagnosis of glioblastoma.
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,
in the right temporal lobe, did not reveal disease connecting that site to the originally affected left occipital lobe. Would you comment on that?
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
foci of cerebral glioma in the majority of the cases, confirming the microscopical contiguity of most malignant cerebral gliomas.
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
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.
Michelle R. Pisapia (Nurse Practitioner, Neurology): Are there any restrictions in the way the protocols are written for these new study drugs regarding whether
the diagnosis is pseudoprogression and whether a patient can stay on the drugs?
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
the completion of chemoradiation are excluded unless there is a pathological diagnosis of recurrent tumor.
Anatomical Diagnosis
Glioblastoma, WHO grade IV of IV, with methylation
of the MGMT promoter.
