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Brainstem gliomas in adults Folder Path

Neurology > Neuro-
Contributors oncology > Tumors by
tissue type > Brain
Herbert B Newton MD, author. Dr. Newton, Director of the Division of
tumors > Primary brain
Neuro-oncology at Ohio State University, has received honorariums
tumors in adults >
from Schering-Plough and UCB Pharma for speaking engagements and Intraaxial brain tumors
from Genentech for service on an advisory board. > Gliomas > Brainstem
gliomas in adults
Edward J Dropcho MD, editor. Dr. Dropcho of Indiana University
Quick Reference
Medical Center received an honorarium from Merck for a speaking
Sections of Summary
engagement and a consulting fee from Genentech as a member of a
review panel. - Historical note and
- Clinical manifestations
Publication dates
Originally released February 20, 1996; last updated November 12, - Clinical vignette

2010; expires November 12, 2013 - Etiology

- Pathogenesis and
Synonyms pathophysiology

Medullary glioma; Midbrain glioma; Pontine glioma - Epidemiology

- Prevention
Key points - Differential diagnosis
• Brainstem gliomas are much less common in adults than in children. - Diagnostic workup
• Brainstem gliomas are a very heterogeneous group of tumors, but - Prognosis and
are often quite aggressive and difficult to treat, with relatively short complications
survival times. - Management
• Surgical resection of brainstem gliomas can be performed in - Pregnancy
selective focal tumors. For more diffuse tumors, resection is - Anesthesia
impossible, and a biopsy is preferred. In many cases of diffuse pontine - ICD codes
tumors, MRI can be diagnostic. - OMIM
• Radiotherapy is always necessary for high-grade tumors, but may Supplemental Content
not be needed for fully resected low-grade tumors. In general, - Associated disorders
radiotherapy is required for most brainstem gliomas.
- Related summaries
• Chemotherapy has minimal activity against most high-grade
- Differential diagnosis
brainstem gliomas, but it may be helpful in less aggressive tumor
- Demographics
- References cited
Historical note and nomenclature
The earliest descriptions of brainstem tumors in the literature were Related Items
made in the 1930s (Buckley 1930; Gibbs 1932; Hare and Woolf 1934; Illustrations
Bailey 1935). In a review of 1737 verified brain tumors operated on by - Brainstem glioma (01)
Harvey Cushing, Buckley found 25 located within the pons, the majority - Brainstem glioma (02)
of which were astrocytomas (Buckley 1930). Gibbs noted that
- Brainstem glioma (03)
brainstem tumors were most common in children and estimated that
- Brainstem glioma (04)
the comparative incidence in adults was only 10% (Gibbs 1932). A

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review by Hare and Woolf of 432 pediatric brain tumors seen at the - Brainstem glioma (05)
Neurological Institute of New York included only 7 tumors of the - Brainstem glioma (06)
brainstem (Hare and Woolf 1934). In a study evaluating diffuse pontine - Brainstem glioma (07)
gliomas in children, Bailey was one of the first authors to draw - Brainstem glioma (08)
attention to the high frequency of misdiagnosis in this population
- Brainstem glioma (09)
(Bailey 1935). Guillain and colleagues and Globus and colleagues were
- Brainstem glioma (10)
the first to document in detail brainstem tumors affecting the course of
- Brainstem glioma (11)
the aqueduct of Sylvius (Guillain et al 1936; Globus et al 1945). In a
- Brainstem glioma (12)
later review, Guillain was one of the first to document the behavior of
- Brainstem glioma (13)
exophytic brainstem tumors, in a review of 250 intracranial neoplasms
(Guillain et al 1945). The first author to study a population of adult Patient Handouts
patients with brainstem gliomas was White, who evaluated a series of - Brain anatomy
44 patients accumulated over 31 years at the Neurological Institute in - Brain basics
New York (White 1963). The mean age of the patients was 42 years - Brain tumors
(range 17 to 68 years); most of those studied pathologically had - Brain tumors:
astrocytic tumors of various grades. The clinical presentation and symptoms and
course of patients in this adult brainstem glioma series was similar to a diagnosis
comparable series of pediatric patients studied earlier at the - Brain tumors: tumor
Neurological Institute.
Web Resources
Clinical manifestations Clinical Trials
The clinical evolution and neurologic findings of adult patients with
- NIH: Gliomas
brainstem gliomas are similar to those seen in children and adolescents
Google Scholar
(White 1963; Tokuriki et al 1986; Maria et al 1993a; Freeman and
- Other articles on this
Farmer 1998; Selvapandian et al 1999; Donaldson et al 2006). The
length of time from onset of symptoms to diagnosis ranges from 2 to
10 months in most cases (median 4 to 5 months) and depends on the
- Other articles on this
location of the tumor within the brainstem, the severity of initial
symptoms, and the rapidity of progression of disease. In general, the
About Links
most common initial neurologic complaints consist of gait
- About Web Resources
abnormalities, visual disturbances, weakness, and headache (White
1963; Tokuriki et al 1986; Grigsby et al 1989b; Packer et al 1992;
Maria et al 1993a; Schild et al 1998; Selvapandian et al 1999;
Guillamo et al 2001). Gait disturbance occurs in 40% to 80% of
patients and is caused by weakness or spasticity from pyramidal tract
dysfunction, ataxia, or a combination of these factors. In the study by
White, 77% of an adult cohort of 44 patients complained of gait
disturbance, and in the study by Tokuriki and colleagues, 42% of adult
patients had a similar complaint (White 1963; Tokuriki et al 1986).
Visual disturbances, which develop in 20% to 70% of patients, usually
manifest as diplopia (horizontal more common than vertical). In the
study by White, diplopia was the second most common complaint
(White 1963). Headache and focal weakness develop in 15% to 55% of
adult patients (White 1963; Tokuriki et al 1986; Grigsby et al 1989b).
The headaches can be caused by several mechanisms, including
expansion of the brainstem with traction on surrounding meninges and
varying degrees of hydrocephalus. These headaches often occur in the

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suboccipital region, but their location can vary and may extend into the
upper cervical area. In some patients, there may be a periorbital
component of headache pain. Focal weakness can involve the face as
well as 1 or more limbs and is usually asymmetric. Other common
symptoms that developed in 15% to 40% of patients included
dysarthria, focal numbness of the face or body, dysphagia, nausea and
emesis, hearing loss, vertigo, tinnitus, and personality changes (White
1963; Tokuriki et al 1986; Schild et al 1998; Selvapandian et al 1999).
Dysarthria developed in 40% of patients in the study by White and was
usually caused by disturbance of cerebellar function or corticobulbar
pathways. Focal numbness was described by 35% of patients and
ranged from hemisensory loss to numbness in 1 section of a limb.
Dysphagia was a complaint in 10% to 30% of patients. The level of
swallowing dysfunction can vary from slight difficulty handling liquids or
solids to gross aspiration. Similar to other brain tumor patients, this
group may also underestimate their level of swallowing difficulty
(Newton et al 1994). Nausea, emesis, and other related symptoms
such as gastroesophageal reflux were present in 10% to 30% of
patients and, in rare cases, can be the sole presenting complaint
(White 1963; Wood et al 1985; Tokuriki et al 1986; Mahony et al 1987;
Frank et al 1989; Grigsby et al 1989b; Mann et al 1998). These
symptoms are probably caused by tumor-related compression of the
vomiting center in the floor of the fourth ventricle, nucleus ambiguus,
and dorsal vagal motor nucleus (Frank et al 1989; Mann et al 1998). It
is not uncommon for patients with this type of "gastrointestinal"
presentation to be extensively worked up for gastrointestinal problems
(eg, barium swallow, upper gastrointestinal series, endoscopy), often
delaying the necessary neurologic evaluation and diagnosis. Treatment
of the tumor may result in improvement of these "gastrointestinal"
symptoms (Wood et al 1985; Frank et al 1989). Mann and colleagues
reported a 30-year-old man who developed unremitting emesis over a
21-month period (Mann et al 1998). A complete gastrointestinal workup
was negative and neurologic function was normal. An MRI scan
revealed a small enhancing brainstem tumor in the low midbrain. The
emesis responded dramatically to dexamethasone. Alterations in
personality are well documented in children with brainstem gliomas and
can occur in adults as well; they were present in 15% to 18% of the
patients studied by White (White 1963; Packer et al 1992; Maria et al
At the time of diagnosis, the most common neurologic signs of
brainstem gliomas in adults are pyramidal tract and cerebellar
dysfunction, cranial nerve palsies, nystagmus, and gait difficulty (White
1963; Tokuriki et al 1986; Grigsby et al 1989b; Packer et al 1992;
Maria et al 1993a; Schild et al 1998; Selvapandian et al 1999;
Guillamo et al 2001). In 65% to 75% of patients, pyramidal tract
damage is noted, with contralateral weakness in an upper motor neuron

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pattern (White 1963; Tokuriki et al 1986). Over half of these cases will
have hemiparesis or hemiplegia; monoparesis and tetraparesis are
much less common. Two thirds of all patients have associated extensor
plantar responses and asymmetric reflexes. Cerebellar involvement
manifests as gait ataxia, limb dysmetria, or dysarthria in 65% to 80%
of patients, most often caused by damage to corticopontocerebellar
pathways or the cerebellar peduncles (White 1963; Tokuriki et al
1986). Cerebellar dysfunction contributes to the high incidence of
nystagmus in this population and is noted in approximately 80% of all
patients (Miller 1988). The nystagmus is usually horizontal (65% to
70%) and gaze-evoked, less often during primary position.
Infrequently, patients have vertical or rotary nystagmus.
Cranial nerve signs occur in the majority of patients (White 1963;
Tokuriki et al 1986). In general, abnormalities of the lower cranial
nerves (cranial nerves VIII through XII) are more common in adults
than children and are usually caused by medullary tumors (Tokuriki et
al 1986). The most frequent cranial nerve sign is palsy of cranial nerve
VII, manifested by facial weakness in 50% to 80% of patients. Facial
weakness is usually unilateral, but can be bilateral (5% to 7% of
cases). Dysfunction of cranial nerves V (sensory), VI, IX, and X are
next most common, each occurring in 45% to 55% of patients. Facial
sensory loss is ipsilateral and variable in severity and can involve any
or all of the trigeminal divisions depending on the region of tumor
growth. Bulbar dysfunction caused by palsy of cranial nerves IX and X
can range from mild palatal weakness to frank dysphagia, dysarthria,
and aspiration. Decreased hearing is found in 40% to 45% of patients
and can be caused by disturbance of the cochlear nuclei, trapezoid
body, or other structures along the cranial nerve VIII pathways.
Dysfunction of cranial nerves III, V (motor), XI, or XII can be noted in
20% to 30% of patients, whereas palsy of cranial nerve IV is rare.
Other neuro-ophthalmological cranial nerve signs include papilledema,
gaze paralysis (mainly horizontal), and anisocoria, each noted in
approximately 25% of patients in the study by White (White 1963).
Disturbances of sensation are found in 35% to 55% of patients and
usually present as a hemisensory deficit.
Unusual or rare neurologic signs and symptoms that may seem
unrelated to a brainstem neoplasm can develop, such as isolated
inability to sneeze, unilateral astereognosis, symptomatic cataplexy,
isolated knee pain, and pathological emotions (eg, laughter, lability
due to pseudobulbar palsy) (Feinsod et al 1980; Martin et al 1991;
Rutka et al 1991; D'Cruz et al 1994). Uncommon neuro-ophthalmologic
abnormalities can also occur, including relative afferent pupillary
defects, upbeat nystagmus, fatigable ptosis, and false-positive
edrophonium testing for cranial nerve palsies (Gilman et al 1977; Miller
1988; Dirr et al 1989; King et al 1991; Ragge and Hoyt 1992). Facial
myokymia and hemifacial spasm, which typically occur secondary to

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benign pathology outside the CNS, can occasionally be caused by

brainstem gliomas, especially those arising in the pons (Miller 1988;
Westra and Drummond 1991; Krauss et al 1993; Gutmann and Hopf
1994). In some cases, the facial manifestations may be the presenting
feature of the tumor and can persist for many years before the
diagnosis is confirmed.
Rarely, brainstem gliomas can affect regions within the medulla or
pons that are involved in control of respiration and blood pressure
(Rodriguez et al 1982; Hsu et al 1984; Tobias and Heideman 1991;
Valente et al 1993; Siderowf et al 1996; Wilken et al 1997; Gaviani et
al 2005). Apnea, apneusis, hypoventilation, and hyperventilation may
occur when a tumor damages the lower brainstem pathways and
nuclear regions responsible for respiratory control (Rodriguez et al
1982; Tobias and Heideman 1991; Valente et al 1993; Siderowf et al
1996; Wilken et al 1997). Apneusis is characterized by marked
prolongation of inspiration and can lead to life-threatening sequelae
such as bradycardia, reduced oxygen saturation, and hypercapnia
(Wilken et al 1997). Treatment with buspirone, a 5-HT1A serotonergic
receptor agonist, can convert apneustic breathing patterns to normal
(Wilken et al 1997). Gaviani and coworkers describe a patient who
developed central neurogenic hyperventilation from a brainstem tumor
that was associated with significant lactate peaks within the tumor
(Gaviani et al 2005). The hyperventilation responded to an oral
continuous release preparation of morphine. Symptoms related to blood
pressure dysregulation, especially orthostatic hypotension and
secondary cardiac syncope, can also develop due to abnormalities of
central autonomic control and disturbance of the afferent arc of the
baroreceptor reflex (Hsu et al 1984). Abnormalities of these vital
structures are conjectured to be responsible for the rare adult patients
who present with sudden death from brainstem tumors (Dolinak et al

Clinical vignette
A 31-year-old woman with an unremarkable past medical history
initially presented with diplopia. A workup consisting of several
noncontrast CT scans of the brain and a neurologic examination was
essentially normal. The neurologic symptoms progressed over the next
5 months, prompting a second opinion and an enhanced MRI scan of
the brain. The MRI demonstrated an enhancing mass in the left pons,
compatible with brainstem glioma. A biopsy revealed fibrillary
astrocytoma grade II. Postoperatively the patient did well except for
loss of hearing on the left side. No further treatment was offered at
this point. Her neurologic status deteriorated further with significant
weakness and spasticity on the right side, gait instability, and
dysphagia. A follow-up MRI scan 6 months later showed further growth
of the tumor. A second surgery was then performed that removed
tissue that was of higher grade-fibrillary astrocytoma grade III. After

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recovery from surgery, she underwent 6 weeks of external beam

radiation therapy. Her function improved during radiation, with
reduction of right-sided weakness, dysphagia, and gait imbalance. Six
months later, she noted progressive right arm weakness and spasticity,
headache, and gait difficulty. During the next 7 weeks, left-sided
weakness and spasticity, dysarthria, and more severe dysphagia
developed. Another MRI scan demonstrated further progression and
growth of the brainstem tumor.
The patient was then referred for chemotherapy evaluation. Her
baseline neurologic examination was remarkable for normal mentation,
dysarthric speech, paralysis of abduction in both eyes, adduction in the
right eye, diminished corneal reflex in the left eye, lower motor neuron
facial paralysis on the left, reduced hearing and facial sensation on the
left, poor gag response bilaterally, spasticity of all 4 limbs right greater
than left, 3+/5 right hemiparesis, hyperactive reflexes right greater
than left, right-sided extensor plantar response, exaggerated Hoffman
signs bilaterally, and severe gait ataxia. She was placed into the
intraarterial carboplatin (200 mg/m2 X 2 days, q3 to 4 weeks) and
intravenous etoposide (100 mg/m2 X 2 days, q3 to 4 weeks) protocol.
After 6 cycles of chemotherapy the patient was improved neurologically
and had a partial response (ie, 50% to 99% reduction) by MRI. She
remained stable through 4 more cycles of intraarterial chemotherapy,
over a total of 9.5 months, before radiologic progression. Treatment
was changed to intravenous BCNU (200 mg/m2, q6 to 8 weeks). The
patient remained stable for 4 more months before further neurologic
deterioration developed. She was then taken off all treatment and died
6 weeks later.

The cells of origin of most brainstem gliomas are transformed
astrocytes. In rare cases, these tumors can occur after transformation
of oligodendroglial cells or ependymal cells or from mixtures of
neoplastic astrocytes and neurons (ganglionic cells; ie, ganglioglioma).

Pathogenesis and pathophysiology

On pathological examination, brainstem gliomas of adults are similar
in appearance to brainstem tumors from children. However, the
distribution of tumors is different in the 2 groups. In children, over
75% of brainstem gliomas arise within the pons, 20% occur in the
medulla, and 10% develop in the midbrain (Tokuriki et al 1986; Packer
et al 1992; Maria et al 1993a). In adult cases, 56% of tumors develop
in the pons, 30% arise from the medulla, and 12% occur in the
midbrain (Tokuriki et al 1986; Wang et al 2000). On gross inspection,
the brainstem is usually swollen or deformed. The swelling can be
diffuse, most commonly within the pons (ie, classic "pontine
hypertrophy"), or it can be a more focal, lobulated, or an asymmetric
alteration of normal medullary, pontine, or midbrain architecture.

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Tumors that cause symmetric expansion of the brainstem are usually

diffuse, infiltrative, fibrillary astrocytomas of varying grade (often
malignant). Intrinsic focal tumors, or those with a predominantly
exophytic growth pattern, are more commonly of lower grade and
reduced infiltrative potential (Tokuriki et al 1986; Packer et al 1992;
Maria et al 1993a; 1993b; Freeman and Farmer 1998). The exophytic
regions of tumor are typically located on the floor of the fourth
ventricle, within the cerebellopontine angles, or extending from the
anterior aspects of the pons or midbrain into the prepontine or
perimesencephalic cisterns. Ventrally exophytic tumor can frequently
encase and displace the basilar artery, usually without causing
secondary arterial thrombosis, ischemia, or infarction. Cysts may be
present in low- or high-grade brainstem gliomas in up to one third of
cases. In malignant tumors, the cysts often contain hemorrhage and
necrotic debris. Large cysts or regions of tumor that encroach on the
ventricular system (eg, floor of third ventricle, fourth ventricle,
cerebral aqueduct) may cause hydrocephalus (Packer et al 1992; Maria
et al 1993a). In slowly growing focal tumors of the midbrain tectum,
hydrocephalus may develop in an indolent fashion as the neoplasm
slowly compresses the cerebral aqueduct (Vandertop et al 1992;
Squires et al 1994). On rare occasions, gross deposits of tumor can be
seen at a distance from the primary site within the brainstem (Packer
et al 1983; Silbergeld et al 1988; Maria et al 1993a). Tumor deposits
are most common at the base of the brain, along the brainstem, and
on the surface of the spinal cord and cauda equina. Distant metastases
tend to occur more frequently in high-grade tumors, but can develop in
low-grade fibrillary or pilocytic astrocytomas.
At the microscopic level, the vast majority of brainstem tumors in
adults and children are of astrocytic lineage and appear similar to
astrocytic tumors in other CNS locations (White 1963; Mantravadi et al
1982; Tokuriki et al 1986; Maria et al 1993a; Schild et al 1998).
Fibrillary astrocytomas of various grades, growing in a diffuse or focal
pattern, are the most commonly diagnosed neoplasms. A small
subgroup of patients has pilocytic astrocytomas, whereas rare histologic
diagnoses include oligodendroglioma, ganglioglioma,
ependymoblastoma, hemangioma, mixed glioma, and primitive
neuroectodermal tumors (Queiroz et al 1975; Garcia et al 1984; Kuna
et al 1991; Alvarez et al 1996; Lee et al 1998; Fisher et al 2000;
Zagzag et al 2000). Initial antemortem histological evaluation discloses
low-grade, well-differentiated pathology in approximately 60% of
biopsy and resection specimens; malignant pathology, usually
anaplastic astrocytoma or glioblastoma multiforme, is found in 40%
(White 1963; Alvisi et al 1985; Tokuriki et al 1986; Shibamoto et al
1989; Bricolo et al 1991; Rajshekhar and Chandy 1995). In contrast,
autopsy studies demonstrate a higher percentage of malignant
pathology, approximately 60% to 90% (Mantravadi et al 1982; Grigsby

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et al 1989a; Shibamoto et al 1989). This discrepancy is explained by

the selection bias in autopsy materials toward more aggressive tumors
and the tendency of well-differentiated tumors to undergo malignant
degeneration during clinical progression. Furthermore, autopsy studies
suggest that tumor spread and grade of malignancy depend on the site
of origin of the neoplasm (Mantravadi et al 1982). In a study of 25
autopsied brainstem glioma patients (41% over 20 years of age),
Mantravadi and colleagues found that pontine tumors were more likely
than midbrain or medullary tumors to invade adjacent regions of brain
and to have malignant histology (71% of pontine tumors were either
anaplastic astrocytoma or glioblastoma multiforme) (Mantravadi et al
Low-grade fibrillary brainstem astrocytomas can demonstrate either a
diffuse or a focal growth pattern but appear similar histologically. They
are classified as astrocytoma, grade I or II, using the Kernohan or St.
Anne-Mayo classification schemes, or as astrocytoma grade II by the
World Health Organization (Coons and Johnson 1994). The tumors show
a mild increase in cellularity and are composed of cells with astrocytic
morphology. Cellular and nuclear atypia and pleomorphism are
minimal. Rosenthal fibers are densely eosinophilic rod-shaped
structures that may be present in some tumors. Low-grade tumors
generally stain strongly with glial fibrillary acidic protein. Malignant
features such as mitoses, endothelial proliferation, and regions of
necrosis are not present.
The growth pattern of low-grade fibrillary brainstem astrocytomas is
to insinuate cells from the growing edge of the tumor between and
along adjacent nerve fiber fascicles and pial-limiting membranes,
expanding in accordance with the surrounding anatomy down a "path of
least resistance" (Epstein and Farmer 1993; Maria et al 1993b; Coons
and Johnson 1994). Destruction of tissue and infiltration into gray
matter is minimal. Because of the orientation of the pial-limiting
membranes surrounding the brainstem and the alignment of the
internal fiber tracts, enlargement of slowly growing, low-grade tumors
is more likely to be directed toward the floor of the fourth ventricle and
cerebellopontine angle regions, where there is less resistance to
expansion (Epstein and Farmer 1993). This explains the high frequency
of exophytic growth noted in these areas. Low-grade tumors are also
less invasive and infiltrative than more malignant tumors because of a
reduced capacity to attach to, enzymatically degrade, and migrate
through localized tissue extracellular matrix proteins (Maria et al
High-grade fibrillary brainstem astrocytomas usually grow in a diffuse
fashion, but, on occasion, they may have a more focal or exophytic
presentation (Lee et al 1998). They are classified as either anaplastic
astrocytoma or glioblastoma multiforme, which correspond to
astrocytoma grades 3 or 4, respectively, of the Kernohan, St.

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Anne-Mayo, and World Health Organization classification schemes

(Coons and Johnson 1994). These tumors demonstrate medium to high
cellularity, with reduced amounts of cytoplasm, extensive nuclear and
cellular pleomorphism, endothelial proliferation, mitotic figures, and, in
some cases, necrosis. When tumor cells infiltrate into gray
matter, they tend to cluster around neurons (ie, perineuronal
satellitosis) and collect in subpial and subventricular zones. Both
anaplastic astrocytoma and glioblastoma multiforme are histologically
heterogeneous tumors, but this is especially so for glioblastoma
multiforme, in which it is not uncommon to have low-grade regions of
astrocytoma near areas containing numerous mitoses, endothelial
proliferation, and necrosis. High-grade astrocytomas also stain with
glial fibrillary acidic protein, but in general the staining is less intense
and more irregular than in low-grade tumors. Recent work by Jallo and
colleagues has investigated the development of a reliable animal model
that reproduces the aggressive growth characteristics of malignant
brainstem gliomas (Jallo et al 2006). The authors injected 9L
gliosarcoma cells or F98 glioma cells into the anterior pons of Fischer
rats, using stereotactic techniques. The growth of the tumors was very
reliable and led to the onset of hemiparesis within a mean of 16.5 days
in 100% of the animals. Histopathologically, the tumors were similar to
high-grade brainstem gliomas in humans.
The growth pattern of high-grade brainstem astrocytomas is different
from that of low-grade tumors. The extent of infiltration and
invasiveness into adjacent normal brain is more pronounced. In
addition, as these tumors enlarge, they more often damage or destroy
the underlying normal brain parenchyma. Structural limitations to
growth within the brainstem, such as the anterior and lateral
pial-limiting membranes and various large nerve fiber bundles, are not
effective against high-grade tumors and do not direct growth like
low-grade neoplasms (Epstein and Farmer 1993; Maria et al 1993b).
This indiscriminate growth pattern explains the reduced frequency of
exophytic extension in high-grade tumors, whose tendency is to
infiltrate axially within the brainstem, although exophytic growth can
occur in rare cases (Lee et al 1998). The invasive and infiltrative
nature of high-grade tumors is related to their highly developed ability
to interact with, degrade, and migrate through specific substrate
molecules found within the extracellular matrix of surrounding normal
brainstem parenchyma (Maria et al 1993b).
Pilocytic astrocytomas typically arise in the dorsal pons, with
subsequent growth rostrally through the brainstem, but can develop
anywhere (Fisher et al 2000). They are usually focal, indolent,
slow-growing neoplasms and often have an exophytic component
(Khatib et al 1994). Pilocytic astrocytomas are designated astrocytoma,
grade I by the World Health Organization (Coons and Johnson 1994).
On microscopic evaluation they most often display a biphasic pattern of

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loose, microcystic areas, alternating with more dense regions composed

of elongated, "hairlike" astrocytic cells. Rosenthal fibers and
granular bodies are often numerous in the dense regions of tumor.
Aggressive features can be present, including cellular atypia, occasional
mitoses, multinucleated cells, focal necrosis, and prominent
vasculature. However, these elements do not indicate malignancy or
alter the more favorable prognosis and improved survival of patients
with this type of brainstem tumor. Some authors feel pilocytic
astrocytomas of the brainstem should be classified separately from
fibrillary astrocytomas in this region because of their vastly different
clinical presentation and extended survival (Fisher et al 2000).
Gangliogliomas of the brainstem are uncommon tumors composed of
an admixture of neoplastic neuronal (ie, ganglionic) and astrocytic cells
(Garcia et al 1984; Kuna et al 1991; Coons and Johnson 1994). The
astrocytic portion of the tumor predominates and is usually classified as
being fibrillary and of low grade. Mitoses and other aggressive features
are generally absent. Gangliogliomas are typically slow growing and
well circumscribed, without significant infiltration. In a literature review
of 14 patients with brainstem gangliogliomas by Garcia and colleagues,
5 were older than 18 years of age (36%), and in 11 of the patients
(78.5%) the medulla was the site of neoplastic origin (Garcia et al
1984). Rarely, other types of mixed glioma can develop within the
brainstem in adults (eg, mixed anaplastic oligodendroglioma or
ependymoma) (Lee et al 1998).
Techniques that can measure the biological potential of brainstem
gliomas include Ki-67 and bromodeoxyuridine labeling studies, and
functional brain imaging using SPECT or PET scans. Both labeling
methods quantitatively assess the proliferating fraction and, therefore,
the inherent aggressiveness of a tumor (ie, labeling index). Ki-67
reacts with cells in G1, S, and G2M phases, whereas
bromodeoxyuridine labels only cells in S phase. For fibrillary
astrocytomas, in general, Ki-67 and bromodeoxyuridine labeling indices
increase with grade, whereas for all pilocytic tumors the indices tend to
be low (Ito et al 1992; Jaros et al 1992). Several authors have
evaluated brainstem gliomas using functional imaging methods to
differentiate between tumor progression and radiation necrosis
(Bruggers et al 1993). Bruggers and colleagues studied a brainstem
glioma patient with serial MRI and 18-fluorodeoxyglucose PET scans
(Bruggers et al 1993). The PET scans demonstrated increasingly
hypermetabolic activity, which was helpful in differentiating between
tumor progression and radiation necrosis when MRI scans remained
stable. Autopsy revealed a diffuse, viable glioblastoma multiforme
without evidence of radiation necrosis.
Cytogenetic and chromosomal studies of brainstem astrocytomas are
uncommon, most likely due to the paucity of tissue available for
analysis following surgery, which is usually a small biopsy. However,

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they are probably similar to astrocytomas of the same grade from

other CNS locations (Rey et al 1987; Jenkins et al 1989).
Few studies have assessed the role of oncogenes and tumor
suppressor genes in the origin of brainstem gliomas. The most
complete study is by Louis and colleagues, who evaluated archival or
autopsy tissue from 7 patients with brainstem glioblastoma multiforme
(2 patients 16 years of age) for abnormalities related to epidermal
growth factor receptor amplification, loss of heterozygosity of
chromosomes 10 and 17, and mutations within the p53 gene using
polymerase chain reaction-based techniques (Louis et al 1993). None of
the tumors demonstrated any amplification of the epidermal growth
factor receptor gene. Four of 7 tumors (57%) had allelic loss of
chromosome 10. Four tumors were also shown to have lost portions of
the short arm of chromosome 17 (57%; all included the region
containing the p53 gene, 17p13.1). The p53 gene was mutated in 5 of
7 tumors (71%). Four of these 5 cases were p53 genes on the
remaining allele of tumors that had lost heterozygosity, whereas the
fifth was from a tumor with both copies of 17p. Two of the p53
mutations caused base changes that resulted in amino acid
substitutions (Arg Cys, Arg Leu), whereas a third resulted in a stop
codon. The authors concluded that these results were consistent with
previous data suggesting that a subset of glioblastoma multiforme that
develops in younger patients is derived from lower-grade, diffuse,
fibrillary astrocytomas (von Deimling et al 1993). The lower-grade
tumors and subgroup of glioblastoma multiforme are characterized by
allelic loss of 17p, p53 mutations, and a lack of epidermal growth
factor receptor amplification. These data are in agreement with Zhang
and colleagues, who found mutations within the p53 gene in 8 of 13
pontine anaplastic astrocytomas (62%; 4 patients 16 years of age)
(Zhang et al 1993). Of 15 total mutations detected, 11 were missense
mutations that resulted in amino acid substitutions. Another report has
demonstrated similar results using immunohistochemical methods, with
p53 accumulation more frequently noted in the higher-grade tumors
(Badhe et al 2004). A report by Lang and colleagues describes an adult
patient with a brainstem anaplastic astrocytoma that did not show
evidence for loss of heterozygosity of chromosomes 10 or 17p,
mutations within the p53 gene, or amplification of the epidermal
growth factor receptor gene (Lang et al 1994). Molecular analysis of 7
pediatric patients with primitive neuroectodermal tumors of the
brainstem did not disclose p53 mutations (Zagzag et al 2000). This is
similar to primitive neuroectodermal tumors of the cerebellum and
cerebrum, which are also lacking in abnormalities of p53. A molecular
analysis of 28 specimens of pediatric brainstem gliomas has detected a
high incidence of amplification and overexpression of ERBB1 (ie, EGFR)
(Gilbertson et al 2003). The degree of ERBB1 expression correlated
closely with increasing tumor grade (p<0.001) and was not related to

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p53 status. The percentage of EGFRvIII mutations in the amplified

specimens could not be determined with the techniques used. The
authors suggest that ERBB1 signaling is important for the pathogenesis
of many pediatric brainstem gliomas and that molecular therapeutic
agents designed to target this pathway (eg, ZD1839; Iressa) should be
evaluated. Verification of ERBB1 amplification and expression status in
brainstem gliomas in adults remains unclear. Using high-resolution
single nucleotide polymorphism (SNP)-based DNA microarray analysis,
a series of 11 samples from patients with diffuse pontine gliomas was
analyzed (Zarghooni et al 2010). In 36% of the cohort, gains in copy
number (range 4 to 18) were noted for platelet-derived growth factor
receptor alpha (PDGFR-alpha). Expression of PDGFR-alpha was noted
in all tumor samples. In 3 cases, low-level gains were present for
poly(ADP-ribose) polymerase (PARP)-1. Pathway analysis also noted
genes with loss of heterozygosity in the DNA repair pathway. The
authors suggested that PDGFR-alpha and PARP-1 might be rational
targets to consider for molecular therapy of brainstem gliomas.
Using an implanted C6 glioma model of brainstem glioma in rats, Liu
and coworkers attempted to discern differences in the growth patterns
and biology of the juvenile and adult animals (Liu et al 2008). Adult
rats presented with focal neurologic symptoms and had more focal
histology within the pons. In contrast, juvenile rats had a more rapid
presentation and a more diffuse neurologic presentation, with ataxia,
cranial nerve deficits, and incontinence. Histologically, the tumors were
more diffuse and infiltrative throughout the entire brainstem. In
addition, tumors in juvenile rats had a higher Ki-67 labeling index and
a lower rate of apoptosis. The median survival was significantly higher
in the adult rats (p < 0.05). The authors concluded that the immature
rat brainstem may offer or create a more permissive cellular
environment, allowing tumor cells to be more invasive.

The exact incidence and prevalence of brainstem gliomas in adults is
unknown. In children they make up 10% to 20% of pediatric primary
brain tumors (Newton 1994; Freeman and Farmer 1998; Donaldson et
al 2006). Furthermore, approximately 70% to 75% of these neoplasms
develop by 20 years of age (Maria et al 1993a). By comparison, the
incidence in the adult population is estimated to be 9 to 10 times lower
than that in children, roughly 0.5% to 2.0% (White 1963; Tokuriki et al
1986; Linstadt et al 1991; Newton 1994). In a study by Gibbs
examining 1383 primary intracranial tumors in patients aged 16 to 70
years, only 1% were located within the pons or midbrain (Gibbs 1932).
Tokuriki and colleagues reviewed 3044 adult primary brain tumors over
a 35-year period (Tokuriki et al 1986). Intrinsic tumors of the
brainstem were found in 16 cases, an incidence of only 0.52%.
However, in smaller series of brainstem glioma patients, the proportion
of adults may be larger, ranging from 10% to 35% (White 1963;

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Grigsby et al 1989b). The vast majority of brainstem gliomas are

sporadic, but they can be familial on rare occasions (Schianchi and
Kraus-Ruppert 1980; Fitzgerald 2000).

There are no known measures to prevent the development of a
brainstem glioma in de novo patients or in those at risk from
associated disorders (eg, neurofibromatosis type 1).

Differential diagnosis
The differential diagnosis of brainstem gliomas in adults consists of
other mass lesions or disease processes that can present with a
progressive brainstem syndrome and includes other neoplasms,
parasitic cysts, viral and postviral brainstem encephalitis, infarction,
tuberculoma, demyelinating syndromes, vascular malformations,
abscesses, radionecrosis, and chronic meningitis of various etiologies
(Frank et al 1988; Franzini et al 1988; Abernathy et al 1989; Smith
1990; Maria et al 1993a; Rajshekhar and Chandy 1995; Lakhan and
Harle 2009). Neoplastic considerations include metastases to the
brainstem or posterior fossa, as well as primary brain tumors of the
posterior fossa or skull base such as meningioma, acoustic
schwannoma, dermoid cyst, medulloblastoma, ependymoma, and
epidermoid cyst. Infectious considerations include parasitic cysts from
cysticercosis, which have a predilection for the fourth ventricular
region, tuberculomas or pyogenic abscess formation of the posterior
fossa, viral encephalitis involving the brainstem, and chronic meningitis
with basilar exudate (eg, tuberculosis, cryptococcus neoformans).
Demyelinating syndromes refer mainly to multiple sclerosis, which
often presents with multifocal brainstem signs and symptoms, and to
postinfectious brainstem encephalitis, which is considered to be an
autoimmune-mediated demyelinating process following viral exposure.
In a recent case report, a 48-year-old woman demonstrated a
progressive brainstem syndrome, along with encephalopathy and
hallucinations (Lakhan and Harle 2009). She was thought to have an
acute demyelinating encephalopathy or collagen vascular disease, and
she was treated with plasmapheresis, without benefit. At autopsy, a
large brainstem glioma was noted, which involved the pons, medulla,
and cerebellum. Cerebrovascular processes include brainstem infarction
(although these tend to occur rather acutely), hemorrhage, and various
vascular malformations (ie, arteriovenous malformation, capillary
telangiectasia, cavernous angioma) that can become symptomatic
because of mass effect or spontaneous hemorrhage.
Although CT and MRI will usually help to discriminate between
brainstem glioma and other disease processes within the posterior
fossa, they are not 100% sensitive or specific and may lead on
occasion to false-positive or false-negative diagnoses (Frank et al
1988; Franzini et al 1988; Abernathy et al 1989; Rajshekhar and

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Chandy 1995). In a study by Frank and colleagues, 17% of 38 patients

with a preoperative diagnosis of a brainstem tumor had a nonneoplastic
lesion at biopsy, usually a vascular abnormality or malformation (Frank
et al 1988). In 24 adult patients with expanding brainstem masses,
25% had nonneoplastic diagnoses following stereotactic biopsy (Franzini
et al 1988). Rajshekhar and Chandy describe a series of 71 patients
with brainstem lesions in which 19.4% had diagnoses other than
brainstem glioma following biopsy (Rajshekhar and Chandy 1995). This
group of nongliomatous lesions included nonspecific chronic
inflammation (4 patients), granulomatous inflammation (2 patients),
epidermoid cyst (2 patients), pyogenic abscess (2 patients), and
encephalitis (1 patient). In a subgroup of 7 patients with the
preoperative CT diagnosis of glioma in which benign lesions were found
at biopsy, the diagnoses included encephalitis, epidermoid cyst, and
tuberculoma. In the study by Abernathy and colleagues, 26 patients (20
over 18 years old) with pontine mass lesions were biopsied for
suspected brainstem tumors (Abernathy et al 1989). Ten of 26 patients
(38.5%) had a benign diagnosis, including cryptococcal abscess,
arteriovenous malformation, demyelination, infarction, and

Diagnostic workup
In patients with neurologic signs and symptoms suggestive of a
brainstem glioma, neuroimaging with CT or MRI is the most critical
diagnostic test. These studies should be performed with and without
contrast media for the most accurate visualization of the mass, to
assess the relationship of the mass to other posterior fossa anatomy,
and to assist in differential diagnosis. The appearance of brainstem
gliomas in adults on CT or MRI is similar to that in children. In general,
both CT and MRI demonstrate enlargement and asymmetry within the
brainstem, most commonly the pons, with minimal edema formation
around the tumor (Tokuriki et al 1986; Shibamoto et al 1989; Smith
1990; Packer et al 1992; Maria et al 1993a; 1993b; Donaldson et al
2006). However, MRI has been shown to be superior to CT for
diagnosing brainstem gliomas, with a sensitivity and specificity for
pathology approaching 100% (Bradac et al 1985; Hueftle et al 1985;
Lee et al 1985; Packer et al 1985; Zimmerman et al 1985; Raffel et al
1988; Barkovich et al 1990; Smith 1990; Packer et al 1992; Maria et al
1993a; 1993b; Bognar et al 1994; Fischbein et al 1996). This
improvement in diagnostic accuracy is due to several factors, including
a lack of bone artifact in the posterior fossa, increased sensitivity to
intratumoral water content, and the multiplanar capability of MRI,
especially the midsagittal view. In 10% to 20% of cases, MRI will
detect tumors that are not discernible by CT, especially small, focal
tumors or those that occur within the midbrain. This is important for
patients who have hydrocephalus on CT, but with no evidence on the
scan for an intrinsic brainstem tumor. All of these patients should be

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studied with MRI because some of them will harbor neoplasms that
might benefit from earlier diagnosis and treatment (Raffel et al 1988).
The anatomical configuration within the brainstem, extent of
infiltration, presence of an exophytic component or leptomeningeal
seeding, and degree of enhancement are visualized in more detail with
MRI (Bradac et al 1985; Hueftle et al 1985; Lee et al 1985; Packer et
al 1985; Zimmerman et al 1985; Donahue et al 1998). Despite these
advantages, MRI is similar to CT in its inability to consistently
differentiate between neoplastic and benign lesions or to correlate the
appearance of a given lesion with a specific pathologic diagnosis. In
addition, recent data would suggest that even with MRI, there is
significant interobserver variability in the measurement of diffuse
brainstem gliomas. Because of this variability, the authors suggest that
for clinical trial purposes, the measurements of brainstem gliomas
should be made by a single neuroradiologist (Hayward et al 2008).
When using MRI for the initial assessment of brainstem gliomas, it is
recommended that T1- and T2-weighted nonenhanced imaging, as well
as T1-weighted gadolinium-enhanced imaging, be performed in both
the axial and midsagittal planes (Barkovich et al 1990; Packer et al
1992; Donaldson et al 2006). Doing this will provide the most
information on the size, extent, and other characteristics of the tumor
necessary for treatment decisions such as extent of surgery and design
of radiation ports, and for detailed comparison at follow-up. On
nonenhanced T1-weighted images, brainstem gliomas generally
demonstrate hypointense signal compared to normal white matter
(Hueftle et al 1985; Lee et al 1985; Packer et al 1985; Zimmerman et
al 1985; Barkovich et al 1990; Packer et al 1992; Maria et al 1993a).
On proton density and T2-weighted images, increased signal intensity
is usually noted within the mass. Because the degree of
peritumoral edema is typically insignificant in these tumors, the extent
of abnormal T2-weighted signal is believed to represent bulky tumor
and any associated infiltration. Following administration of gadolinium,
T1-weighted images show variable amounts of enhancement, with
patterns similar to that seen on CT: negligible, ring-enhancing,
partial/focal, and diffuse. The exophytic components of tumors
are usually found in the basilar subarachnoid spaces or cerebellopontine
angles, and they frequently enhance in a diffuse fashion. Disturbance
or encasement of the basilar artery by exophytic tumor in the
prepontine cistern is clearly seen on MRI. Additional features that
can demonstrate enhancement and suggest more aggressive behavior
are subpial extension, subependymal extension, ill-defined tumor
margins, necrosis, and the presence of daughter nodules (Maria et al
1993a; 1993b). The presence of acute or old hemorrhage within tumor
is easily determined by MRI, although it is uncommon at presentation,
occurring in approximately 6.25% of cases as reported in a recent
paper (Broniscer et al 2006). However, symptomatic hemorrhage is

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noted in nearly 20% of patients after diagnosis during the course of

therapy. On rare occasions, MRI can demonstrate brainstem tumors
infiltrating along or encasing the lower cranial nerves (Yousry et al
2004; Ree et al 2005). Some authors report the importance of this
information in presurgical planning of exophytic brainstem tumors
(Yousry et al 2004). A recent study correlating MRI and PET findings
noted that diffuse pontine gliomas were always of high-grade pathology
(ie, glioblastoma multiforme or anaplastic astrocytoma), with variable
exophytic features (Kwon et al 2006). PET scans were hypermetabolic
only in the tumors with glioblastoma multiforme pathology. However,
some glioblastomas and all of the anaplastic astrocytomas were
hypometabolic, as were the low-grade tumors. New MRI techniques,
such as diffusion tensor imaging (DTI), are also being applied to
brainstem gliomas (Helton et al 2006; 2008). DTI allows for a more
detailed and quantitative evaluation of the fiber tracts in the brainstem
and shows the degree of involvement of these tracts by tumor.
Preliminary data suggest that DTI demonstrates superior visualization
and quantification of tumor involvement in the motor, sensory, and
transverse pontine tracts in comparison to conventional MRI. In
addition, DTI appears to be able to demonstrate axonal degeneration
within the motor and sensory tracts of the brainstem in these patients
(Helton et al 2008).
Several authors have applied MRI as a tool for classification of
brainstem tumors into groups with treatment-related and prognostic
significance (Epstein and Wisoff 1988; 1990; Barkovich et al 1990;
Epstein and Farmer 1993; Fischbein et al 1996; Guillamo et al 2001).
Epstein and colleagues have classified brainstem tumors into 4 groups:
diffuse, focal, cystic, and those that occur at the cervicomedullary
junction (Epstein and Wisoff 1988; 1990; Epstein and Farmer 1993).
Diffuse tumors are most common and have the worst prognosis,
generally arising within the pons and demonstrating a hypointense
signal that usually does not enhance after contrast. Extension into the
medulla and midbrain is often noted. Sagittal views typically
demonstrate significant pontine hypertrophy. Focal tumors generally
measure less than 2.5 cm in diameter, have no associated edema, and
enhance with contrast. They are more likely to have an exophytic
component, pilocytic histology, and a better prognosis than diffuse
tumors (Khatib et al 1994). Cystic tumors that contain an enhancing
mural nodule have an excellent prognosis similar to that of cerebellar
pilocytic astrocytomas. If the tumor has an enhancing solid component
in addition to an enhancing cyst wall, it is usually malignant and carries
a poor prognosis. Tumors of the cervicomedullary junction are often of
low grade, rarely extend above the pontomedullary junction (though
occasionally growing caudally into the cervical spinal cord), and have a
favorable prognosis. They are well delineated on sagittal MRI.
Barkovich and colleagues have characterized the MRI scans of 87

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"high-risk" brainstem glioma patients with respect to tumor location of

origin, focality, direction and extent of growth, degree of brainstem
enlargement, degree of exophytic growth, hydrocephalus, hemorrhage,
necrosis, and presence or absence of cyst (Barkovich et al 1990). The
authors found a significant difference in survival based on the primary
location of the tumor (p = 0.02): no deaths in 6 cases of midbrain
lesions, 50% survival at 2 years for medullary tumors, and only 20%
survival at 2 years for pontine tumors. The degree of brainstem
enlargement had an inverse relationship with survival (p = 0.05): no or
mild versus moderate or severe. Similarly, degree of infiltration was
inversely related to survival (p = 0.005). The presence of a tumor cyst
denoted a more favorable outcome (p = 0.03).
Some authors have begun to apply MRI technology to monitor
magnetic resonance spectroscopy (MRS) of tumors, including brainstem
gliomas. A recent report by Laprie and colleagues used a multivoxel
version of this technique to monitor brainstem gliomas during and after
treatment (Laprie et al 2005). A series of 24 MRS studies on 8 patients
was performed, and the data suggested that longitudinal multivoxel
MRS was feasible, reliable, and potentially superior to univoxel
techniques for evaluating response to radiotherapy and other treatment
modalities. Recently, 2 patients were described that had undergone
longitudinal MRS monitoring of their diffuse brainstem gliomas during
therapy (Thakur et al 2006). Although there was a brief interval of
clinical improvement after radiation therapy, the MRS signature
demonstrated further elevation of the Cho/Cr and Cho/NAA ratios,
more consistent with progression. This was confirmed at the next
follow-up visit, when both patients were noted to have clinical
deterioration. The authors suggest including MRS in the routine
radiological evaluation of patients with brainstem gliomas.
Although CT is not as accurate as MRI, it can still discern the presence
of a brainstem tumor over 90% of cases, especially if the lesion is
within the pons and has an exophytic component (Kingsley and Kendall
1979; Bilaniuk et al 1980; Abernathy et al 1989; Maria et al 1993a;
1993b; Selvapandian et al 1999). With unenhanced CT, the tumor
usually appears hypodense or isodense compared to normal surrounding
brain. Effacement of the basal cisterns, displacement and deformity
of the fourth ventricle, and disturbance of the basilar artery are
additional early signs of tumor. Tumor enhancement is variable,
occurring in approximately 50% of tumors. Exophytic portions are most
likely to demonstrate strong enhancement. Diffuse, infiltrative tumors
are generally hypodense and most often show partial or negligible
enhancement (Bilaniuk et al 1980; Tokuriki et al 1986; Shibamoto et al
1989; Smith 1990). Focal tumors, with or without exophytic
components, are more likely to demonstrate diffuse or ringlike
enhancement. Hydrocephalus is noted in 25% to 30% of tumors and is
especially common in tumors affecting the midbrain tectal region

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(Kingsley and Kendall 1979; Bilaniuk et al 1980; Bognar et al 1994).

Cystic changes are noted in 10% to 15% of cases and can be
associated with low- or high-grade tumors (Kingsley and Kendall 1979;
Bilaniuk et al 1980; Smith 1990). CT is limited by beam-hardening
artifact in the posterior fossa, which reduces sensitivity for small, focal
lesions and is often unable to properly gauge the extent of tumor
infiltration within the brainstem (Smith 1990; Packer et al 1992; Maria
et al 1993a; 1993b).
Cerebrospinal fluid analysis and evoked potentials are rarely indicated
for diagnosis of brainstem gliomas in the era of CT and MRI. If
cerebrospinal fluid is evaluated, it is usually normal (Packer et al
1992). In 15% to 20% of patients, there may be a mild pleocytosis
(less than 20 cells) and elevation of cerebrospinal fluid protein. Rarely,
malignant cells may be noted on cytologic examination in those
patients with leptomeningeal spread of tumor (Packer et al 1983).
Auditory evoked potentials have also been used for the diagnosis of
brainstem gliomas, although they may be more useful for the
monitoring of these patients during neurosurgical procedures (Nodar et
al 1980; Packer et al 1992).

Prognosis and complications

The overall prognosis for survival and intact neurologic function in
adults with brainstem gliomas is rather poor, but prognosis varies
somewhat depending on the histology, location, and type of tumor (ie,
diffuse, focal, exophytic, cystic) (Schild et al 1998; Fisher et al 2000).
Reports of survival from the time of onset vary widely among authors,
ranging from a mean of 19.2 months (median 12.5 months, 13 adult
cases) in the group described by Tokuriki and colleagues, to a mean of
27.7 months (30 adult cases) in the cohort analyzed by White (White
1963; Tokuriki et al 1986; Packer et al 1992; Maria et al 1993a). Data
from the radiation oncology literature are similar, with median
survivals ranging from 7.6 to 16.1 months (average median survival
13.6 months) in a collective cohort of 85 adult patients (Edwards et al
1989; Shrieve et al 1992; Guiney et al 1993; Prados et al 1995). In the
study by Guiney and colleagues, tumors located in the pons had a
significantly adverse affect (p=0.035) on survival when compared to
other brainstem locations (Guiney et al 1993). Similar results have
been noted by Schild and colleagues with 5-year survival of 54% with
lesions outside the pons and 21% for those with lesions within the pons
(p=0.04) (Schild et al 1998). However, some authors have not found
significant survival differences based on tumor location (Edwards et al
1989). In most of the studies from the radiation oncology literature,
the percentage of patients surviving at 2 years was between 40% and
50% (Kim et al 1980; Shrieve et al 1992). In a group of adult patients
with pontine gliomas, the 3-year survival was 33% in a study by
Guiney and colleagues (Guiney et al 1993). In contrast, a cohort of
patients with pontine gliomas reported by Grigsby and colleagues had

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5-year survivals of 46.6% (Grigsby et al 1989c). In studies that were

able to compare survival between groups of adult and pediatric
brainstem glioma patients who had received radiation therapy, results
were comparable (Kim et al 1980; Grigsby et al 1989c; Guiney et al
1993). In contrast, in a study by Landolfi and colleagues of 19 adult
patients (median age 40 years) with brainstem gliomas as diagnosed
by MRI scan, they noted a median survival of 54 months and a 5-year
survival of 45% (Landolfi et al 1998). The authors concluded that
brainstem tumors may be less aggressive in adults than in children,
even when located within the pontine parenchyma. Similar conclusions
have been made by Guillamo and colleagues, who suggest that diffuse
tumors may be less aggressive and of lower grade in adults than in
children (Guillamo et al 2001). In a review of 48 adult patients with
brainstem gliomas, 46% of the cohort had a diffuse presentation on
MRI. However, of the biopsied patients, 82% had benign histology with
a median survival of 7.3 years.
Numerous authors have evaluated brainstem glioma patients using
univariate and multivariate analyses to determine both positive and
negative prognostic factors. The vast majority of the data are derived
from pediatric brainstem glioma patients (Albright et al 1986; Cohen et
al 1986; Barkovich et al 1990; Packer et al 1992; Fischbein et al
1996). Fewer studies have included adult patients for prognostic
evaluation (Edwards et al 1989; Grigsby et al 1989b; 1989c;
Shibamoto et al 1989; Shrieve et al 1992; Guiney et al 1993; Prados
et al 1995; Schild et al 1998; Schulz-Ertner et al 2000; Guillamo et al
2001). In most of the studies, race, gender, extent of surgical
resection, and age did not reach significance in univariate or
multivariate analyses. The location of the tumor was a significant
factor in several studies. Patients with tumors located in the pons often
had shorter survival times (p = 0.035), whereas Shibamoto and
colleagues noted that patients with midbrain tumors often survived
longer (p < 0.05) (Grigsby et al 1989b; Shibamoto et al 1989; Guiney
et al 1993; Schild et al 1998). The histological grade of the tumor was
significant (p < 0.05) in a few studies, such that patients with
microscopically evident malignant features or the diagnosis of
glioblastoma multiforme had a poorer prognosis and shorter survival
(Grigsby et al 1989c; Shibamoto et al 1989). One of the most
consistently important prognostic factors was duration of symptoms
prior to diagnosis. In many studies, patients with longer symptom
duration had longer survival times; conversely, those patients with
shorter symptom duration had shorter survival times (Edwards et al
1989; Grigsby et al 1989c; Packer et al 1992; Guiney et al 1993;
Prados et al 1995; Fisher et al 2000). The type of tumor (ie, diffuse
vs. focal) had prognostic implications in several reports; patients with
diffuse tumors had significantly shorter survival and time to tumor
progression (p = 0.012 and p = 0.005, respectively) (Edwards et al

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1989; Prados et al 1995; Fischbein et al 1996; Schild et al 1998).

Fisher and colleagues report a series of 76 patients in which the
presence of an abducens nerve palsy at diagnosis was associated with
poor survival (p less than 0.0001) (Fisher et al 2000). Schulz-Ertner
and colleagues evaluated 26 adults in their analysis of prognostic
factors in a series of 41 brainstem glioma patients (Schulz-Ertner et al
2000). The only significant prognostic factors for survival in the
univariate and multivariate analyses were the presence of clinical or
radiological response 6 weeks after treatment. A few authors have
reported that patients with neurofibromatosis type 1 and brainstem
gliomas have an improved prognosis over those tumor patients without
neurofibromatosis type 1 (Milstein et al 1989; Raffel et al 1989; Molloy
et al 1995; Pollack et al 1996; Bilaniuk et al 1997). In a review of 21
neurofibromatosis type 1 patients with brainstem tumors, only 10 had
radiographic or clinical progression during a 9-year follow-up period
(Pollack et al 1996). In 4 of these patients specific therapy was
required; 1 required biopsy, 3 required excision, and 2 required
radiotherapy. All 4 lesions were histologically low-grade and remained
stable after treatment. Bilaniuk and colleagues studied 25 patients with
neurofibromatosis type 1 that had brainstem tumors (diffuse in 12 of
25 patients) (Bilaniuk et al 1997). MRI evidence of tumor growth
occurred in 8 patients (32%), all with diffuse tumors. Two patients with
diffuse tumors died of progressive disease. The authors concluded that
although patients in their series had a better overall prognosis than
brainstem glioma patients without neurofibromatosis type 1, the
tumors did not always behave in a benign, indolent manner (especially
diffuse lesions) and were more dangerous than other tumor types found
in patients with neurofibromatosis type 1. Some authors recommend
using pontine midsagittal diameters in combination with magnetic
resonance spectroscopy to differentiate “benign” pontine enlargement
associated with neurofibromatosis type 1 from the more malignant
diffuse brainstem glioma (Broniscer et al 1997). Patients with
neurofibromatosis type 1 and pontine enlargement had lesions that
were significantly smaller than diffuse brainstem gliomas. In addition,
the N-acetylaspartate peaks were consistently preserved in the
neurofibromatosis type 1 patients without diffuse tumors, suggesting
retained neuronal elements within the brainstem. In a study of
prognostic factors in a large adult cohort, univariate analysis suggested
that age of onset less than 40 years, duration of symptoms greater
than 3 months before diagnosis, Karnofsky performance status greater
than 70, low-grade histology, and absence of "necrosis" on MRI were
all favorable prognostic variables (Guillamo et al 2001). On
multivariate analysis, only duration of symptoms, histological grade of
the tumor, and presence of "necrosis" on MRI were significant and
independent prognostic variables.
A recent study by Kesari and colleagues evaluated prognostic

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variables in a cohort of 101 adult patients with brainstem glioma

(Kesari et al 2008). On multivariate analysis, ethnicity, tumor location,
clinical grade of the tumor, and patient age at diagnosis all had a
significant effect on survival. Non-Caucasian patients had a hazard ratio
4.19 times larger than Caucasian patients (p = 0.0004). Patients with
diffuse pontine tumors had a hazard ratio 3.58 times larger than
patients with tumors of the cervicomedullary junction (p = 0.0006).
The hazard ratio for patients with clinically high-grade tumors was 2.81
times larger than those with low-grade tumors (p = 0.0017). Patients
with an older age at diagnosis had a hazard ratio 1.34 times larger than
younger patients (p = 0.0032). In general, adults with brainstem
gliomas had a better prognosis than children with similar tumors. The
overall survival for all patients at 5 and 10 years was 58% and 41%,
Several authors have studied prognostic factors in relation to
information obtained from CT or MRI scans. Shibamoto and colleagues
evaluated the correlation between prognostic factors and CT features
(Shibamoto et al 1989). They found a significant association between
estimated tumor volume and survival. Patients with tumors less than 6
cm3 survived longer than those with tumors between 6 and 20 cm3 (p
less than 0.05) and larger than 20 cm3 (p less than 0.005).
Furthermore, patients with tumors demonstrating diffuse contrast
enhancement survived longer than patients with tumors that had ring
enhancement (p less than 0.05). In an MRI study by Barkovich and
colleagues, a significant (p = 0.02) survival advantage was evident for
midbrain tumors (Barkovich et al 1990). The 2-year survival for
patients with midbrain tumors was 100%, whereas for patients with
medullary and pontine tumors it was 50% and 20%, respectively. It
was further noted that patients in whom tumors produced only limited
enlargement of the brainstem, or were focal with limited infiltration,
had significantly better survival than patients with more diffuse tumors.
This is in contrast to the study by Nelson and colleagues, who noted a
significant correlation (p=0.005) between the onset of necrosis, as
imaged by CT or MRI, and subsequent survival (Nelson et al 1994).
Over one third of patients with pontine tumors had evidence of necrosis
at diagnosis and had a median survival of 6.5 months. For those
patients who developed necrosis after diagnosis, the median survival
was 9.0 months. Similar results regarding the presence of necrosis
have been reported by others (Guillamo et al 2001). In an MRI study
evaluating the impact of gadolinium enhancement on outcome, no
correlation was noted overall or within specific subgroups (eg, pons,
midbrain) (Fischbein et al 1996). However, only a small number of
patients were evaluated with both MRI and histological data. These
results are in contrast to data from Lesniak and colleagues, who
studied 89 patients with brainstem gliomas and noted that
enhancement within the tumor imparted a positive prognosis (Lesniak

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et al 2003). The majority of these tumors were low-grade and

responded well to aggressive surgical resection. A recent review of MRI
findings in 39 cases of diffuse intrinsic pontine glioma evaluated the
prognostic significance of several pretreatment and posttreatment
imaging features, including rostral or caudal tumor extension,
metastases, basilar artery encasement, necrosis, intratumoral
hemorrhage, enhancement, hydrocephalus, and dorsal exophytic
components (Hargrave et al 2008). None of the MRI parameters had
any prognostic significance. In a similar study, Liu and colleagues
attempted to correlate MRI features at presentation with response to
radiotherapy (Liu et al 2009). Thirty patients with brainstem glioma
were analyzed; 23 were rated as responders to treatment, whereas 7
were classified as nonresponders. There were no statistically significant
differences in MRI features between the groups. However, necrosis and
enhancement were more common in responders, whereas tumor
surrounding the basilar artery, compression of the fourth ventricle, and
extension into the cerebellum were more common in nonresponders.
Complications of brainstem gliomas vary depending on the size,
location, and type of tumor. The most common complication is
hydrocephalus, which occurs in 25% to 30% of patients as seen on CT
or MRI (Kingsley and Kendall 1979; Bilaniuk et al 1980; Bognar et al
1994; Guillamo et al 2001). Hydrocephalus is especially common in
tumors of the midbrain, midbrain tectum, and cerebral aqueduct, where
the incidence at diagnosis approaches 100% (Ho 1982; Bognar et al
1994; Squires et al 1994). Leptomeningeal tumor spread is a
complication that occurs in 10% to 50% of patients antemortem, but is
often detected more frequently in autopsy studies (Kepes et al 1976;
Mantravadi et al 1982; Packer et al 1983; 1992; Silbergeld et al 1988;
Grigsby et al 1989a; Shibamoto et al 1989; Maria et al 1993a;
Donahue et al 1998; Guillamo et al 2001). The symptoms may be
present at diagnosis but more often develop during local tumor
progression. Rarely, brainstem tumors can spread outside the CNS,
causing extraneural metastases (Kepes et al 1976; Choi et al 1981;
Rosemberg et al 1988; Newton et al 1992). Extraneural metastases
usually develop in the context of tumors that have already extended
into the leptomeninges. Common sites for extraneural metastases from
astroglial brainstem tumors include the lung, pleura, and lymph nodes
(Newton et al 1992). In patients with leptomeningeal tumor and a
shunting device, spread to the intraperitoneal cavity may occur and
cause increased abdominal girth, ascites, and abdominal pain (Newton
et al 1992). Although rare (ie, less than 5%), seizures and other
episodes of altered consciousness have been reported in brainstem
glioma patients (White 1963; Grigsby et al 1989c; Packer et al 1992).
Patients with dysphagia may develop pneumonia as a complication of
tracheal aspiration of food or oral secretions (Newton et al 1994).
Symptoms of aspiration include coughing or choking during intake of

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solids or liquids. However, in some patients with dysphagia, symptoms

can be minimal or nonexistent, such that aspiration remains clinically
silent until pneumonia is well established (Newton et al 1994).

The role of surgical therapy is more limited for patients with
brainstem gliomas than for patients with tumors at other sites because
of the intrinsic risks of aggressive surgery in this location (Packer et al
1992; Maria et al 1993a; Mursch et al 2005; Donaldson et al 2006).
This is especially true for more diffuse and infiltrative tumors. Despite
these restrictions and limitations, surgical intervention is still an
important aspect of management for many patients with brainstem
neoplasms. The morbidity and mortality associated with surgery of the
brainstem have been substantially reduced over the past 15 to 20 years
due to improved neuroimaging with MRI, advances in microsurgical
instrumentation and technique, use of intraoperative real-time
ultrasound and evoked potential monitoring, application of the CO2
laser and ultrasonic aspirator, and improvements in both open and
stereotactic approaches to the brainstem (Albright and Sclabassi 1985;
Fasano et al 1986; Hood et al 1986; Pimenta et al 1986; Abernathy et
al 1989; Hood and McKeever 1989; Epstein and Wisoff 1990; Rusyniak
et al 1992; Rajshekhar and Chandy 1995). In addition, the application
of computerized 3-D surgical navigation systems for removal of
brainstem tumors has further improved the ability to resect with
minimal morbidity (Wang et al 2000). The ability of MRI to more
accurately define the anatomy and infiltrative extent of brainstem
tumors improves the ability of the neurosurgeon to decide if surgery is
feasible and, more importantly, if it is appropriate (Epstein and Wisoff
1990; Packer et al 1992). By MRI classification, tumors most amenable
to surgical intervention include focal lesions of the midbrain or pons,
cystic astrocytomas without cyst wall enhancement, cervicomedullary
neoplasms, and the exophytic components of tumors (Epstein and
Wisoff 1988; 1990; Giunta et al 1989; Barkovich et al 1990; Bricolo et
al 1991; Packer et al 1992; Pollack et al 1993; Freeman and Farmer
1998; Selvapandian et al 1999; Wang et al 2000; Yeh et al 2002).
Real-time ultrasound imaging has been reported by many authors as an
excellent method during surgery to verify tumor location, depth, and
boundaries (Fasano et al 1986; Rusyniak et al 1992). Variations in
echogenicity allow for differentiation of solid tumor from areas of
calcification, cyst, and edema. Similarly, the use of evoked potentials
(auditory or somatosensory) during surgery allows for real-time
monitoring of potential damage to the brainstem and often decreases
morbidity (Albright and Sclabassi 1985; Fasano et al 1986; Epstein and
Wisoff 1990; Rusyniak et al 1992). Significant improvements in
computerized CT- and MRI-guided stereotactic techniques have also
contributed to the reduction of surgical morbidity and mortality
associated with brainstem tumors. In the majority of reports, surgical

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mortality was 1% to 3%, whereas morbidity ranged between 3% and

7% (Hood et al 1986; Frank et al 1988; Giunta et al 1989; Rajshekhar
and Chandy 1995). A transfrontal or transcerebellar approach to biopsy
was used in most of these studies, with diagnostic yields between 90%
and 100%.
Although modern neurosurgical techniques allow for acceptable
morbidity and mortality when accessing masses within the brainstem of
adults, the literature remains unclear about which lesions should be
surgically approached and how aggressive that intervention should be.
Many authors feel strongly that all brainstem lesions should at least be
biopsied because of the high rate (10% to 30%) of nonneoplastic
lesions that have been reported in many surgical series (Fasano et al
1986; Hood et al 1986; Artigas et al 1988; Frank et al 1988; Franzini
et al 1988; Abernathy et al 1989; Giunta et al 1989; Rajshekhar and
Chandy 1995; Xu et al 1997; Massager et al 2000). Nonneoplastic
lesions found at biopsy include chronic inflammation, granulomatous
inflammation, gliomatosis, cysts, abscesses, infarction, necrosis,
tuberculoma, encephalitis, vascular malformations, and regions of
demyelination. Biopsies are strongly recommended to provide definitive
histological diagnosis prior to further therapeutic recommendations.
This approach would prevent patients with nonneoplastic lesions from
receiving empiric radiation therapy. A significant counter argument is
that biopsies provide small pieces of tissue that may not be diagnostic
or that may suggest a lower-grade tumor (Packer et al 1992; Albright
1996). In tumors as heterogeneous as gliomas, this can be a significant
shortcoming of the technique. Other authors do not feel all patients
should undergo biopsy or attempted surgical resection, reserving these
procedures for carefully selected, prognostically favorable patients.
Epstein and colleagues recommend an aggressive approach (ie, radical
subtotal excision) for the more "benign" tumors, based on their review
of a series of 92 patients classified by MRI and clinical criteria (Epstein
and Wisoff 1988; 1990). Tumors in this "benign" group usually had
low-grade pathology and included focal, nonenhancing cystic and
cervicomedullary lesions. Radical subtotal excision of 50% to 60% of
focal and cystic tumors and 80% to 90% of cervicomedullary tumors
could be achieved with the use of evoked potential monitoring,
Cavitron ultrasonic surgical aspirator, laser, and intraoperative
ultrasound. Most of these patients were neurologically stabilized or
improved following resection and enjoyed prolonged survivals. In
contrast, all diffuse tumors and those with contrast-enhancing cyst
walls were histologically malignant and did not benefit from surgical
intervention, except for cyst drainage in tumors with mass effect.
Epstein and colleagues recommend surgery only for the carefully
selected "benign" tumors, especially if the intent is to perform a
resection. For most diffuse and malignant cystic tumors, the typical
clinical presentation and MRI findings will obviate the need for surgical

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intervention. This view is in agreement with Albright and others, who

argue that in patients with a typical history and clinical presentation of
a brainstem glioma in which the MRI shows a diffuse lesion, surgical
intervention is unnecessary because the histology is virtually always
malignant (Albright et al 1993; Albright 1996; Freeman and Farmer
1998; Landolfi et al 1998). More aggressive, open surgical approaches
are advocated by other groups to allow for microsurgical resections
within the brainstem (Alvisi et al 1985; Fasano et al 1986; Bricolo et al
1991; Xu et al 1997). However, radical extirpation has only proved
possible in low-grade tumors (mainly focal or cervicomedullary) that
had pilocytic or grade I/II fibrillary astrocytic histology. Focal tumors of
the midbrain are reported by some authors as ideal lesions for an
aggressive, open approach for microsurgical resection (Pendl et al
1990; Pendl and Vorkapic 1991; Lapras et al 1994; Wang et al 2000).
In 7 adult patients with focal midbrain tumors who underwent
aggressive microsurgical resection by Pendl and Vorkapic, all had either
stable or improved Karnofsky ratings following surgery (Pendl and
Vorkapic 1991). The mean survival following surgery was 31.0 months,
even though only 2 patients received postoperative radiation therapy.
Tumors of the midbrain tectum are also thought to be accessible for
resection, although this approach involves more severe mortality
(8.3%) and morbidity (33.3%) than a simple biopsy (Lapras et al
1994). In a series of 35 midbrain gliomas (mean age 26.6 years),
Wang and colleagues used a neuronavigation system to perform
aggressive resections (Wang et al 2000). Total resection was possible
in 19 cases. Nine patients with malignant histology (AA or glioblastoma
multiforme) received postoperative radiotherapy. Twenty-three of the
patients (65.7%) were able to resume independent living. Cystic
brainstem gliomas should be considered for cyst drainage if they are
not amenable to radical excision, as this may improve localized
pressure on brainstem structures (Hood and McKeever 1989; Akhtar
and Lewis 1994). In patients with cysts that have recurred following
prior aspiration, after external radiation therapy, or that are causing
rapid neurologic deterioration, stereotactic intracavitary placement of
32-phosphorus may stabilize further cyst development and result in
neurologic improvement (Hood and McKeever 1989). Another subgroup
of brainstem tumors that are candidates for aggressive, open surgical
extirpation is dorsally exophytic lesions (Epstein and Wisoff 1990;
Bricolo et al 1991; Packer et al 1992; Maria et al 1993a; Pollack et al
1993; Xu et al 1997). These tumors are typically slow growing,
histologically benign, and noninfiltrative. The majority of patients with
dorsally exophytic tumors can undergo radical subtotal resection and
enjoy prolonged survival without further therapy (Pollack et al 1993).
Recent reports suggest that stereotactic biopsy can be guided by a
combination of MRI and PET data (Massager et al 2000; Pirotte et al
2007). In a series of 30 patients with brainstem masses, MRI and PET

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were considered complementary in determining the proper location for

biopsy and obtaining diagnostic tissue. In some cases, PET defined a
“hot spot” appropriate for biopsy more clearly than the corresponding
MRI. However, in 37% of the cases, MRI and PET were discordant with
the pathology and the clinical treatment plan as defined by the final
histological diagnosis. The authors concluded that although MRI and PET
improve the diagnostic yield when biopsying brainstem mass lesions,
neuroimaging alone cannot provide the necessary information to direct
treatment in all cases, and histological examination will often be
required. A more recent update by the authors, in a new series of 20
patients, verified the original observations of the utility of PET to
improve the targeting of stereotactic biopsy for brainstem gliomas
(Pirotte et al 2007). In addition, authors have been using intraoperative
MRI for more detailed information regarding surgical approach and
extent of resection (Lam et al 2001). The use of MRI guidance should
be even more helpful in adults with brainstem gliomas because there
will be more room to maneuver in the posterior fossa.
Adult patients with dorsal midbrain tumors (ie, tectal) are considered
a special, indolent subgroup that should be carefully evaluated before
attempting aggressive intervention (Yeh et al 2002). After a review of
5 patients, Yeh and colleagues concluded that most of these patients
can be followed by serial MRI scans and may remain stable without
intervention, except for occasional diversionary shunting. Tumor-
specific therapy should be reserved for patients with clinical or MRI
evidence of growth.
A recent review of microneurosurgical treatment in a series of 16
consecutive adult patients was not as favorable as some of the results
noted above (Mursch et al 2005). Of the 16 patients, 9 had diffuse
pontine tumors, 6 had more craniocaudal-oriented lesions, and 1 had a
cystic tumor of the pons. Gross total resection was achieved in only 2
patients, whereas another 9 had subtotal resections. Postoperatively,
11 patients experienced neurologic deterioration, with significant
recovery noted in only 4 of the cohort. The authors suggested that the
rate of recovery after surgery was much less than what is reported in
pediatric brainstem glioma patients treated with surgery. In addition,
they questioned the benefit of surgical intervention in adult patients
with brainstem glioma.
After reviewing the neurosurgical literature, the current author does
not recommend a surgical biopsy or attempted resection in those
patients with a classic, diffuse brainstem glioma as defined by MRI.
The vast majority of these tumors will have high-grade histology and
behave in a malignant fashion. All other brainstem masses should at
least undergo an attempted biopsy, due to the high rate of
nonneoplastic lesions found in many series. In the hands of an
experienced neurosurgeon, carefully selected brainstem tumors (focal
midbrain, dorsally exophytic, nonenhancing cystic, cervicomedullary,

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etc.) can undergo radical subtotal resection.

Once the diagnosis of brainstem glioma has been made, by either
surgery or MRI, the mainstay of therapy in most adult patients will be
external beam radiation therapy. Early reports from the pre-CT and CT
era demonstrated a dose-response effect in brainstem gliomas.
Extended survival only occurred in those patients receiving 4500 cGy or
more. Additional conventional radiation therapy trials have used focal
ports utilizing doses ranging from 4400 to 6500 cGy, with the majority
of patients receiving more than 5000 cGy (Grigsby et al 1989b; 1989c;
Shibamoto et al 1989; Guiney et al 1993; Guillamo et al 2001;
Donaldson et al 2006; Hargrave et al 2006). In the study by Shibamoto
and colleagues, which included 27 adults (61% with high-grade
tumors), 77% of patients with noncontrast-enhancing tumors, 64% of
those with diffuse contrast-enhancing tumors, and 50% of tumors with
ring enhancement demonstrated a complete or partial response
(Shibamoto et al 1989). Despite these promising initial results, the
overall 5-year survival rate was only 23%. A similar 5-year survival
rate of 28.7% was noted by Grigsby and colleagues in a cohort of 27
adult patients (Grigsby et al 1989b). In an analysis of 21 adult patients
with pontine gliomas, Guiney and colleagues noted clinical or
radiological improvement in 77% (Guiney et al 1993). However, the
median survival was only 15 months, with a 3-year survival rate of
33%. In a review of 37 patients with midbrain tumors (16 over 16
years of age) treated with conventional radiation doses of 4500 to 5000
cGy, Franklin noted an overall median survival of 10 months, with a
2-year survival rate of 23% (Franklin 1991). If the patients receiving
more than 5000 cGy were analyzed separately, the median survival
increased to 14.5 months.
Because of the evidence for a dose-response effect with conventional
irradiation and the fact that brainstem tumors are mainly a focal
disease, alternative treatment schedules have been studied in an
attempt to administer higher total doses without an increase in
neurotoxicity (Packer et al 1992; Maria et al 1993a). The most
promising alternative schedule is hyperfractionated radiation therapy, in
which a larger number of smaller fractions (eg, 100 to 120
cGy/fraction, twice daily) are administered over an equivalent
treatment interval to a larger total dose (eg, 6800 to 7800 cGy). The
rationale for hyperfractionation relates to frequency of fractions, dose
per fraction, total dose, repair of sublethal radiation damage, and
oxygen dependence, which have been reviewed elsewhere (Edwards et
al 1989; Linstadt et al 1991; Packer et al 1992; Shrieve et al 1992;
Maria et al 1993a). Hyperfractionated protocols have demonstrated
marginal improvement in overall and progression-free survival in
pediatric patients with brainstem gliomas at doses between 7000 and
7200 cGy (Packer et al 1992; Maria et al 1993a; Hargrave et al 2006).
There have been few reports of hyperfractionated protocols for adult

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patients with brainstem gliomas. The earliest study was from Edwards
and colleagues, who evaluated 19 adults as part of a larger cohort in a
phase I-II trial of 100 cGy twice a day to a total dose of 7200 cGy
(Edwards et al 1989). After the completion of radiotherapy, the
majority of patients had stable disease as indicated by MRI, whereas
less than a third showed reduction in tumor volume. The median
survival was 7.6 months, with a median time to tumor progression of
5.5 months. In the study by Linstadt and colleagues, 14 adult patients
were treated with hyperfractionated radiation (100 cGy twice a day) to
a median dose of 7200 cGy (Linstadt et al 1991). All but 1 patient
improved or remained neurologically stable following treatment. The
3-year actuarial survival rate was 59%, with a projected median
survival in excess of 5 years. However, there were no glioblastoma
multiforme patients in this cohort; most had moderately anaplastic
astrocytomas. Shrieve and colleagues analyzed the results of a cohort
that included 45 adult patients who received between 6600 and 7800
cGy of hyperfractionated radiotherapy (Shrieve et al 1992). The
median survival was 15.8 months, with 1- and 2-year survival rates of
68% and 53%, respectively. Survival was not significantly different for
patients who received doses greater than 7200 cGy and those with
doses less than or equal to 7200 cGy. When comparing these results
with their previous experience in adult brainstem glioma patients using
conventional radiotherapy, there was a trend toward improved outcome
with hyperfractionation (p = 0.08). Their conclusion was that
hyperfractionated radiotherapy was an effective treatment for adults
with brainstem gliomas and that 7200 cGy was the preferred dosage. In
a review of patients who had received 7800 cGy of hyperfractionated
radiotherapy, Prados and colleagues included 45 adults (Prados et al
1995). Tumor size, as indicated by CT or MRI, decreased in 30%, was
stable in 39.5%, and increased in 29.6%. The median survival of the
adult patients was 16.1 months, with a median time to tumor
progression of 11.4 months. The median survival was almost identical
to that reported by Shrieve and colleagues using 7200 cGy, prompting
the authors to conclude that hyperfractionated radiation therapy to
7800 cGy did not improve survival and was associated with greater
toxicity. Several studies in adults and children suggest that
hyperfractionated protocols do not impart a survival advantage over
conventional radiation treatment (Botturi and Fariselli 1998; Freeman
and Farmer 1998; Schild et al 1998; Mandell et al 1999; Hargrave et al
2006). In a pediatric study by Mandell and colleagues, 132 children with
diffuse brainstem tumors were randomized to receive either
conventional (180 cGy/day, 5400 cGy total) or hyperfractionated (117
cGy twice per day, 7020 cGy total) irradiation over 6 weeks in
combination with cisplatin chemotherapy (Mandell et al 1999). The
median time to progression was 6 months for conventional therapy and
5 months for hyperfractionated treatment. Similarly, median survival

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was 8.5 months for conventional therapy and 8 months for patients
receiving hyperfractionation. In a study from the Mayo Clinic, 40
patients (median age 29.5 years) with brainstem tumors were reviewed
for response to irradiation; 9 of the patients received hyperfractionated
therapy (Schild et al 1998). No survival advantage could be
demonstrated in the cohort treated with hyperfractionated radiotherapy.
In an attempt to improve efficacy of radiotherapy, several
investigators have begun to use radiosensitizers. Marcus and colleagues
added etanidazole, a hypoxic-cell sensitizer, to 66 Gy of
hyperfractionated irradiation in a phase I study of 18 children with
brainstem glioma (Marcus et al 2003). The maximum tolerated dose of
etanidazole was 42 mg/m2, with cutaneous rash as the dose-limiting
toxicity. A similar phase I study by Sanghavi and colleagues used
topotecan in combination with conventional radiotherapy for 17 children
with brainstem tumors (Sanghavi et al 2003). Topotecan is a
topoisomerase I inhibitor that is known to convert sublethal radiation-
induced DNA damage into lethal double-strand DNA breaks. The
maximum tolerated dose of topotecan was 0.40 mg/m2 per day during
radiotherapy, with neutropenia as the dose limiting toxicity. A
subsequent phase II study of topotecan and concomitant irradiation
used the same dosing schedule in a series of 32 patients with
malignant diffuse brainstem gliomas (Bernier-Chastagner et al 2005).
In 40% of the cohort, partial responses were noted. However, the
responses were short-lived, and the 12-month survival rate was only
25.5%. In addition, the overall median survival was only 8.3 months,
similar to other studies of radiation therapy alone. The authors
concluded that the addition of topotecan could not be recommended.
Another recent approach has been to add weekly RMP-7 (300 ng/kg)
and intravenous carboplatin (35 mg/m2 per day) during the course of
irradiation in a phase I trial of newly diagnosed brainstem glioma
patients (Packer et al 2005). RMP-7 is a bradykinin analog that
transiently increases permeability across the blood-brain barrier and
may allow higher concentrations of carboplatin to reach tumor cells.
The treatment was relatively well tolerated, but no conclusions could be
drawn regarding efficacy of the protocol, although the estimated
median survival of the cohort was more than 11 months. A similar
phase II study using a different dosing regimen of RMP-7 (600 ng/kg)
and intravenous carboplatin (target AUC of 3.5 mg per min/ml per day)
was applied to 12 patients with brainstem and other high-grade gliomas
(Warren et al 2006). Although the regimen was relatively well tolerated
except for hematological toxicity, none of the brainstem glioma
patients responded.
Although brachytherapy has demonstrated improved survival for
patients with supratentorial gliomas, few authors have applied this
technique to brainstem tumors because of the inherent dangers of
radiation exposure in this location. Mundinger and colleagues have used

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iodine-125 and iridium-192 as temporary or permanent radiation

sources for 55 patients (mean age 22.5 years) with nonresectable
low-grade brainstem gliomas, most of which were focal lesions of the
midbrain (Mundinger et al 1991). The majority of patients (61%) had
pilocytic astrocytomas, whereas all others had low-grade protoplasmic
or fibrillary astrocytomas. The 5-year survival rates were 54.8% for the
iodine-125 group and 26.9% for the iridium-192 group; these rates
were marginally significantly different (p = 0.03). Mortality for the
procedure was 2.4%, with a morbidity of 6.2%.
Radiosurgery is a technique that is able to deliver photon radiation to
well-circumscribed volumes of tumor deep within the brain. Several
authors have applied it to patients with brainstem gliomas (Loeffler et
al 1992; Kihlstrom et al 1994; Schulz-Ertner et al 2000; Fuchs et al
2002; Donaldson et al 2006; Yen et al 2007; Combs et al 2009). In
their series of 7 patients with midbrain tectal low-grade gliomas who
ranged in age from 6 to 40 years (mean 18 years), Kihlstrom and
colleagues administered doses of 1400 to 3500 cGy in 1 fraction using a
single isocenter (Kihlstrom et al 1994). In 5 of the 7 cases, the tumor
shrank progressively after treatment. All 7 patients remain alive, with
mean follow-up time of 6 years. Patients treated with the higher doses
(eg, 1800 to 3500 cGy) developed significant complications, including
radionecrosis and progression of neurologic deficits. The authors
concluded that radiosurgery was useful adjunctive therapy in this group
of tumors when using a recommended dose of 1200 to 1400 cGy.
Loeffler and colleagues, in their series of 41 malignant glioma patients
treated with radiosurgery, included 1 adult with a brainstem
glioblastoma multiforme (Loeffler et al 1992). That patient received
1000 cGy to the 80% isodose line following external beam
radiotherapy. Treatment has resulted in a partial response, with clinical
improvement and cessation of steroids after 6 months of follow-up. In
a series of 41 patients with brainstem glioma (26 adults), Schulz-Ertner
and colleagues used fractionated stereotactic conformal radiosurgery
with a linear accelerator (Schulz-Ertner et al 2000). The field was
shaped with a multileaf collimator, for a median total dose of 5400 cGy
to the 90% isodose line. Clinical improvement was noted in 19 of 41
patients (46.3%), whereas objective radiological responses occurred in
12 of 41 patients (29.3%). Median time to progression was 23 months,
with a median overall survival of 40 months. The treatment was
tolerated well and the authors concluded that this approach was
superior to conventional irradiation with parallel-opposed ports due to
the use of a smaller, more precise treatment volume. Fuchs and
colleagues used gamma knife radiosurgery with a median dose of 12
Gy for a series of 21 patients with brainstem gliomas that were mostly
adult (median age 23 years) (Fuchs et al 2002). Ten patients
responded with stable disease, whereas 3 had objective responses.
Clinical improvement was noted in 5 patients. The median overall

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survival was 20.7 months. A recent report describes the use of Gamma
Knife as the primary method of treatment in 20 patients with focal
brainstem lesions (Yen et al 2007). There were 4 complete responses
and 12 partial responses/minor responses during a mean follow-up
period of 78.0 months. The remaining patients were stable or clinically
A recent report by Combs and colleagues described the results of
using fractionated stereotactic radiosurgery in a cohort of 85 patients
with brainstem gliomas (Combs et al 2009). The median age at
primary diagnosis was 26 years of age, with only 31 patients under 18
years of age. A median dose of 54 cGy was administered in 1.8 Gy
fractions to a median target volume of 101 mL. The median
progression-free survival (PFS) was 52 months, with PFS rates at 12
and 24 months of 70% and 63%, respectively. Radiosurgery was well
tolerated and did not appear to have a dose-response relationship in
this group of patients.
Patients who are suspected of having leptomeningeal metastasis from
a brainstem glioma should be evaluated on an individual basis and, if
clinically indicated, undergo an evaluation of CSF (including cytology
and tumor markers such as beta-glucuronidase and beta2-
microglobulin), MRI of the spine with gadolinium, and myelography
(Packer et al 1983; 1992). In patients without evidence of infection,
abnormal levels of tumor markers can improve diagnostic sensitivity.
Patients with proven leptomeningeal seeding should then be considered
for craniospinal axis irradiation and intrathecal chemotherapy. Typical
doses for craniospinal axis irradiation are 3000 to 3500 cGy. In patients
with clinical and imaging evidence for focal bulky involvement by
leptomeningeal tumor, radiation can be administered to a localized
field with generous margins, using doses of 3500 to 4500 cGy.
Over the past 2 decades, chemotherapy has had little impact on the
overall survival of patients with brainstem gliomas (Packer et al 1992;
Maria et al 1993a; Freeman and Perilongo 1999; Donaldson et al 2006;
Hargrave et al 2006). The vast majority of data regarding
chemotherapy are from the pediatric literature, as summarized by
Maria and colleagues (Maria et al 1993a). A compilation of 18 studies
using various chemotherapy regimens for brainstem tumors in children
encompasses 261 patients. Of this cohort, 48 patients (18.4%)
responded, including 21 with partial responses and 27 with stable
disease; there were no complete responses. The most effective single
agents were carboplatin and cyclophosphamide. Unfortunately, all of
the responses were brief, as tumors rapidly progressed through
chemotherapy. A phase III trial of irradiation with or without adjuvant
lomustine, vincristine, and prednisone was reported by Jenkin and
colleagues (Jenkin et al 1987). The overall 5-year survival rate was
20% for both groups, suggesting that chemotherapy did not
significantly affect outcome. In the study by Levin and colleagues, 28

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patients (including 2 adults) were treated with 5-fluorouracil and

lomustine before irradiation, followed by hydroxyurea and misonidazole
during radiotherapy (Levin et al 1984). The median survival was 11
months, which, when compared with prior trials, was no better than
radiation therapy alone. Similarly, a Children's Cancer Group study
combining hyperfractionated radiotherapy (7200 cGy) and intravenous
recombinant beta-interferon did not demonstrate improved efficacy
over conventional radiotherapy alone (median time to progression 5
months; median survival 9 months) (Packer et al 1996). Several
studies have attempted high-dose chemotherapy with autologous bone
marrow transplantation in pediatric brainstem glioma patients (Bouffet
et al 1997; 2000; Dunkel et al 1998). Bouffet and colleagues used
high-dose BCNU (800 mg/m2) on 8 patients with brainstem glioma
(Bouffet et al 1997). One patient briefly stabilized for a few months
whereas the other 7 patients rapidly progressed. In a similar study of
24 children with diffuse pontine gliomas, Bouffet and colleagues used
high-dose busulfan (150 mg/m2) and thiotepa (300 mg/m2) followed
by autologous bone marrow transplantation (Bouffet et al 2000). The
median time to clinical progression was 5 months, with an overall
median survival of 10 months. Dunkel and colleagues used high-dose
thiotepa and etoposide, either alone or in combination with BCNU or
carboplatin, in 16 patients with diffuse pontine tumors (Dunkel et al
1998). The median survival was 4.7 months for patients with recurrent
disease and 11.4 months for patients with newly diagnosed tumors.
High-dose therapy did not improve survival over conventional
treatment and was associated with considerable toxicity. A Children's
Cancer Group study used intravenous idarubicin (5 mg/m2 per day for
3 days, every 21 days) for patients with relapsed brain tumors,
including 13 with brainstem gliomas (Arndt et al 1998). None of the 12
brainstem glioma patients able to be evaluated responded to
treatment. In an attempt to increase dose intensity for newly
diagnosed malignant glioma patients, Jakacki and colleagues used
time-compressed, dose-intensive lomustine, procarbazine, and
vincristine in combination with peripheral blood stem-cell support and
concurrent irradiation (Jakacki et al 1999). Of their cohort of 6 patients
with diffuse pontine brainstem gliomas, 2 had partial responses and 1
had a minor response. The median time to radiographic progression
was 5 months, with a median overall survival of 11 months. In a
similar study of 22 assessable patients with newly diagnosed brainstem
gliomas, Broniscer and colleagues used a combination of irradiation and
concurrent tamoxifen (200 mg/m2 per day) (Broniscer et al 2000).
There were 8 partial responses, 3 minor responses, and 8 patients with
stable disease. The overall median survival was 10.3 months. Allen and
colleagues performed a phase I/II trial of intravenous carboplatin and
hyperfractionated irradiation (100 cGy twice a day; 7200 cGy total
dose) in 34 children with brainstem gliomas (Allen et al 1999). The

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maximum tolerated dose of carboplatin was 110 mg/m2 over 7 weeks

of radiation. The median progression-free survival was 8 months and
the overall survival was 12 months. A phase II study by the Children's
Cancer Group compared preirradiation carboplatin, etoposide, and
vincristine versus cisplatin, cyclophosphamide, etoposide, and
vincristine (Jennings et al 2002). Neither regimen was able to improve
response rate, time to progression, or overall survival relative to prior
studies of brainstem glioma patients treated with radiotherapy with or
without chemotherapy. In a phase II study by Burzynski and
colleagues, intravenous bolus injections of antineoplaston A10 and
AS2-1 were administered to a series of 12 patients with recurrent
brainstem gliomas, including 1 adult and 4 teenagers (Burzynski et al
2003). Five patients had brief objective responses, for a 2-year survival
rate of 33.3%. More recently, Ronghe and colleagues reported their
experience using vincristine and carboplatin for pediatric patients with
unresectable and/or recurrent low-grade astrocytomas of the brainstem
(Ronghe et al 2010). Sixteen patients received treatment, and all were
still alive at the time of the report, with 9 objective responses on
neuroimaging (1 complete response, 8 partial responses/minor
responses), and another 4 that remained stable. Overall, 68% of the
cohort remained progression-free, with a median follow-up of 57
Few chemotherapy studies of brainstem gliomas have included more
than a few adult patients. However, the experience with chemotherapy
in adults has been similar to that of children, with few durable
responders (Landolfi et al 1998; Schild et al 1998). In a review of 21
patients treated with 5-fluorouracil, lomustine, hydroxyurea, and
6-mercaptopurine at progression after radiation therapy, Rodriguez and
colleagues included 4 adults (Rodriguez et al 1988). The ages ranged
from 16 to 25 years, with a mean of 19.75 years. The overall mean
survival of the adult cohort was 11.9 months, with a mean time to
progression of 5.1 months. Chamberlain has used chronic oral etoposide
(50 mg/m2 per day for 21 days every 5 weeks) to treat 12 patients,
including 4 adults (age range 18 to 49 years), with recurrent brainstem
gliomas (Chamberlain 1993). The overall results demonstrated 6
radiographic responses with a median duration of response of 8
months. Of the adult patients, 2 had partial responses of 4 and 12
months' duration, whereas the remaining 2 had progressive disease. In
a group of 3 adult patients (age range 18 to 59 years) with pontine
gliomas given chemotherapy after irradiation, Fujiwara and colleagues
used monthly intraarterial ACNU (80 mg/m2), cisplatin (40 mg/m2), or
carboplatin (300 mg/m2) in addition to oral etoposide (25 mg/day) and
intravenous beta-interferon (Fujiwara et al 1994). One patient with a
grade II astrocytoma had a complete response after 8 cycles of
intraarterial carboplatin and remained in remission 24+ months after
diagnosis. Another patient with an anaplastic astrocytoma had a partial

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response to ACNU that lasted through 4 cycles of treatment, followed

by progression and expiration 14 months after diagnosis. The last
patient had a grade II astrocytoma that did not initially respond to
ACNU, but did demonstrate a partial response to intraarterial cisplatin
that lasted for 3 cycles (survival 15 months). The authors concluded
that this regimen was well tolerated and effective in brainstem glioma
patients. In 2 studies of adult brainstem glioma patients reported from
Memorial Sloan-Kettering Cancer Center and the Mayo Clinic,
chemotherapy was unable to significantly impact survival (Landolfi et
al 1998; Schild et al 1998). Trofosfamide is an alkylating agent with a
similar structure to cyclophosphamide but with improved lipid solubility
and excellent enteral absorption. Wolff and colleagues were unable to
demonstrate any survival benefit in a trial of trofosfamide (100 mg/m2
per day) and etoposide (40 mg/m2 per day) when added to irradiation
in a group of pediatric patients with glioblastoma multiforme, including
8 with tumors of the brainstem (Wolff et al 2000). These results were
corroborated by the same group in another study with an enlarged
cohort of 20 patients with pontine glioma (Wolff et al 2002).
A recent multi-institutional study evaluated the use of temozolomide
(200 mg/m2 x 5 days every 28 days for 6 cycles) after the completion
of irradiation in newly diagnosed patients with brainstem glioma
(Broniscer et al 2005). Thirty-three patients were treated, including
several young adults. The median time to progression was 8.8 months,
with a median overall survival and 1-year survival rate of 12 months
and 48%, respectively. The authors concluded that temozolomide was
not very active in this group of patients and did not improve their poor
prognosis. An Italian study in adult patients with brainstem glioma
seems to corroborate this pediatric data. Salmaggi and colleagues
treated 18 adults with chemoradiation using temozolomide (75
mg/m2/day), followed by up to 9 cycles of adjuvant temozolomide
(200 mg/m2/day x 5 days). The addition of temozolomide to
irradiation did not seem to add any survival benefit and did not result
in any complete or partial responses (Salmaggi et al 2008). The lack of
improved treatment response when temozolomide is added to
radiotherapy has been verified in a recent report of a group of pediatric
brainstem glioma patients (Chiang et al 2010). Hall and colleagues
report an aggressive approach to chemotherapy of diffuse pontine
glioma, using intraarterial carboplatin or methotrexate in combination
with blood-brain barrier disruption (BBBD) and intravenous
cyclophosphamide and etoposide (Hall et al 2006). Eight patients (1
adult, 2 teenagers) received the regimen, resulting in 2 partial
responses and 5 stable diseases, with a median time to tumor
progression of 15 months. The overall median survival of the cohort
was 27 months.
Bevacizumab is a new chemotherapy drug recently approved by the
U.S. Food and Drug Administration for treatment of recurrent

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glioblastoma multiforme (Newton 2009). It is a humanized monoclonal

antibody targeted against vascular endothelial growth factor and has
potent antiangiogenic and antiedema activity. Several recent case
reports suggest that bevacizumab may have activity in some adult
patients with brainstem gliomas (Raza and Donach 2009; Torcuator et
al 2009). In the first report by Torcuator and colleagues, the authors
described a 43-year-old woman with a diffuse pontine tumor who
initially received chemoradiation with temozolomide (Torcuator et al
2009). She progressed after only 1 cycle of adjuvant temozolomide and
was then started on combination therapy with bevacizumab and
irinotecan every 2 weeks. After 8 months of treatment, the patient
experienced improvement in neurologic function, and the MRI scan
showed some reduction in FLAIR abnormality and enhancement.
Irinotecan was stopped because of fatigue and neutropenia;
bevacizumab was continued for another 4 months. The patient has
remained stable off treatment. Raza and Donach described an adult
patient with a newly diagnosed brainstem glioma who received
radiotherapy in combination with temozolomide and bevacizumab,
followed by adjuvant treatment with both drugs (Raza and Donach
2009). This patient also had improvement of FLAIR and enhancement
on MRI scan, and now remains stable off treatment after 30 months.
Another case report describes the use of intraarterial bevacizumab, in
combination with mannitol-induced disruption of the blood-brain
barrier, in a 43-year-old male with a recurrent malignant brainstem
glioma (Riina et al 2010). The procedure was well tolerated, with
postprocedure imaging showing a reduction in enhancement within the
tumor. There were no procedural or vascular complications from the
treatment. In a recent report from the Pediatric Brain Tumor
Consortium of 17 patients with recurrent diffuse pontine glioma, the
combination of bevacizumab and irinotecan did not appear to have any
significant activity in terms of clinical stabilization or by neuroimaging
criteria (Gururangan et al 2010).
Animal work by Sandberg and colleagues suggests that convection-
enhanced delivery of chemotherapy may be applicable to brainstem
gliomas (Sandberg et al 2002). In studies using rats, it was determined
that one-time convection-enhanced chemotherapy infusions could be
safely applied to the brainstem. Convection-enhanced delivery
bypasses the blood-brain barrier and can achieve high local
concentrations of infusate. Further studies will evaluate the tolerability
of multiple infusions and the use of various forms of chemotherapy.
Another series of studies in rats has tested the safety and tolerability
of interstitial infusion of IL13-PE38QQR into the brain stem
(Souweidane et al 2004). IL13-PE38QQR is a recombinant immunotoxin
comprised of a modified Pseudomonas exotoxin moiety conjugated to
the human derived T-cell cytokine, IL-13. Infusion of IL13-PE38QQR
into the pons at a concentration of 10 µg/ml for up to 2 weeks was well

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tolerated without clinical or histological toxicity. Similar studies in

primates have evaluated the safety and toxicity of chronic carboplatin
infusions directly into the pons (Storm et al 2003). Overall, infusion of
carboplatin up to 0.26 mg/ml for 1 month was well tolerated without
significant clinical or radiographic toxicity. Neurotoxicity was noted for
infusion doses of 2.6 mg/ml for 1 month. Further studies from the
same authors in a monkey model have infused carboplatin into the
pons at 0.42 µl/h to deliver 0.025, 0.075, 0.25, and 0.75 mg/kg by day
30 (Strege et al 2004). Lethargy and ataxia were noted after 2 weeks
in animals given 0.25 mg/kg and after 4 weeks in animals given 0.075
mg/kg. Lower doses were tolerated well without systemic or
neurotoxicity. More recent studies of convection-enhanced delivery
using a rat model verified the safety of infusion using 1, 2, or 3
catheters. However, when the catheters were used to infuse
carboplatin, drug-related neurotoxicity was noted. Mild neurologic
deficits that developed in the animals after cannula implantation
resolved in the placebo group but were more permanent in the
carboplatin treated animals. The authors stressed the development of
less neurotoxic chemotherapy drugs to be used for this kind of regional
chemotherapy (Thomale et al 2009).
The current author has used chemotherapy to treat 3 adult patients
with brainstem glioma who ranged in age from 33 to 63 years (mean
47.3 years). The first patient was a 63-year-old man with a right
midbrain anaplastic astrocytoma that remained stable for 7 months
during monthly intravenous carmustine (200 mg/m2). The
tumor was unchanged when the patient expired from aspiration
pneumonia. The second patient is a 47-year-old woman with a pilocytic
astrocytoma of the left middle cerebellar peduncle that had progressed
before and after radiation therapy. She has been treated with oral
lomustine (110 mg/m2) and intravenous vincristine (1.4 mg/m2) every
6 weeks and remains stable during the first 9 months of therapy. The
third patient is a 32-year-old woman with a large brainstem anaplastic
astrocytoma centered in the pons. She has been treated with 6
monthly cycles of intraarterial carboplatin (200 mg/m2 for 2 days) and
intravenous etoposide (100 mg/m2 for 2 days), resulting in a partial
response (defined as a 50% to 99% reduction in tumor volume on CT
or MRI). The management of the general aspects of care of adult
patients with brainstem gliomas is similar to that of patients with other
brain tumors (Newton 1994). In those rare patients with seizures,
adequate control can usually be achieved with first-line agents like
phenytoin or carbamazepine. Monotherapy should always be attempted
with both agents before considering a second-line agent such as
valproic acid, gabapentin, or phenobarbital. Because the majority of
brainstem glioma patients have some degree of elevated intracranial or
localized tumor-related pressure, dexamethasone should be prescribed
in the lowest dose that will improve symptoms (eg, 1 to 4 mg 4 times

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daily) (Packer et al 1992; Newton 1994). Following stabilization of

pressure-related symptoms and initiation of more definitive therapy,
dexamethasone should be carefully tapered to minimize potential
complications (Newton 1994). Dysphagia is a relatively common
problem in brainstem glioma patients because of tumor-related
damage to medullary swallowing centers (Newton et al 1994). In all
patients with symptoms of dysphagia, regardless of the apparent
severity of the complaints, a thorough swallowing evaluation should be
performed. Patients with incipient or well-established hydrocephalus
should be evaluated and, if appropriate, treated with a CSF
diversionary shunt procedure (Packer et al 1992; Maria et al 1993a).

Pregnancy does not affect the clinical behavior of brainstem gliomas.

Several anesthetic concerns specific to brainstem gliomas are not
typically encountered with other brain tumors. In rare patients,
especially adults, tumors may involve regions within the medulla or
pons that affect respiration and blood pressure control (Rodriguez et al
1982; Hsu et al 1984; Tobias and Heideman 1991; Valente et al 1993).
Apnea, hypoventilation, and hyperventilation may occur when a
brainstem tumor damages the lower brainstem pathways and nuclear
regions responsible for respiratory control (Rodriguez et al 1982; Kuna
et al 1991; Tobias and Heideman 1991; Valente et al 1993). The
alterations in PaO2, PaCO2, and pH caused by these respiratory
conditions may affect the approach to anesthesia. Abnormal blood
pressure control, especially orthostatic hypotension and secondary
cardiac syncope, can also develop in these patients due to disturbances
of central autonomic control and the afferent arc of the baroreceptor
reflex (Hsu et al 1984). In those patients particularly at risk, cardiac
pacing should be considered.
In addition, concerns regarding the presence or absence of elevated
intracranial pressure during the induction, maintenance, and emergence
from anesthesia are common to surgical therapy of any brain tumor
(LaSala et al 1991). In patients with brainstem gliomas who have
elevated intracranial pressure, care should be taken with
premedications to avoid agents that produce excessive sedation and
ventilatory depression, as these could exacerbate intracranial pressure.
Hypotonic fluids should also be avoided whenever possible. During the
induction and maintenance of anesthesia, agents should be chosen that
minimize hypertension, cerebral vasodilation, chest wall rigidity, and
hypercapnia (LaSala et al 1991).

The author would like to thank Dr. Carl Boesl for his efforts in
preparing the neuropathological slides and Mr. David Carpenter for
expert editorial assistance.

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ICD codes
Malignant neoplasm of brain stem: 191.7

Malignant neoplasm of brain stem: C71.7

Glioma of brain, familial: #137800

Associated disorders
Medullary astrocytoma
Midbrain astrocytoma
Neurofibromatosis type 1
Pilocytic brainstem glioma
Pontine astrocytoma

Related summaries
Brainstem gliomas in childhood
Cerebellar astrocytoma
Low-grade gliomas (astrocytomas)
Malignant astrocytomas
Neurofibromatosis type 1
Neurofibromatosis type 1 and intracranial neoplasms of childhood
Pilocytic astrocytoma in adults

Differential diagnosis
other mass lesions or diseases
progressive brainstem syndrome
other neoplasms
parasitic cysts
viral brainstem encephalitis
postviral brainstem encephalitis
demyelinating syndromes
vascular malformations
chronic meningitis
metastases to brainstem or posterior fossa
primary brain tumors of posterior fossa or skull base
acoustic schwannoma
dermoid cyst

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epidermoid cyst
viral encephalitis involving brainstem
chronic meningitis with basilar exudate
cryptococcus neoformans
multiple sclerosis
postinfectious brain encephalitis
brainstem infarction
brainstem metastases
vascular malformations
arteriovenous malformation
capillary telangiectasia
cavernous angioma
nonneoplastic lesion
nonspecific chronic inflammation
granulomatous inflammation
epidermoid cyst
pyogenic abscess
cryptococcal abscess
posterior fossa metastases

For more specific demographic information, see the Epidemiology,
Etiology, and Pathogenesis and pathophysiology sections of this clinical

19-44 years
45-64 years
65+ years

None selectively affected.

None selectively affected.


Family history
family history may be obtained

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heredity may be a factor

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