Review Article

Adult Brainstem Gliomas

Sylvia C. Eisele, MD; and David A. Reardon, MD

Brainstem gliomas in adults are a rare and heterogeneous group of brain tumors that vary with regard to underlying pathology, radio-
graphic appearance, clinical course and prognosis. Diffuse intrinsic pontine gliomas represent the most common subtype. Although
still considered aggressive and most often lethal, these brain tumors are associated with a more insidious clinical course and more
favorable prognosis compared to the highly aggressive form in children. Treatment options for patients with brainstem gliomas still
are limited and insufficiently studied. A better understanding of the pathobiology of these tumors will be crucial for the development
of more specific and effective therapies. Cancer 2016;000:000–000. V C 2016 American Cancer Society.

KEYWORDS: adults, brainstem gliomas, diffuse intrinsic pontine gliomas, magnetic resonance spectroscopy, pathology.

INTRODUCTION
Although brainstem tumors are more commonly encountered in children and represent 10% of all pediatric brain tumors,
they represent only 1% to 2% of all brain tumors in adults.1 Adult brainstem tumors most commonly involve the pons
(60%-63% of tumors) but are also identified in the medulla oblongata (25% of tumors) and the midbrain (12%-15% of
tumors).2,3 In up to 80% of patients, a combination of these brainstem structures is involved.2 It is important to note, that
despite the similar clinical presentation and radiographic appearance, a number of different clinical entities in addition to
glial tumors has to be considered during the workup for a brainstem lesion in adults. Although glial tumors are most fre-
quent, metastatic lesions, lymphomas, and infectious or etiologies can be seen and may be difficult to differentiate based
on radiologic characteristics alone.4,5 Despite the challenging location, concern regarding diagnostic uncertainty argues
for the need for surgical biopsy and pathologic confirmation to guide further management. This review provides an over-
view of the clinical presentation and management of the different subtypes of brainstem gliomas in adults.

CLINICAL PRESENTATION AND COURSE

Brainstem gliomas in adults typically have been subdivided based on clinicopathologic and radiographic characteristics
into diffuse intrinsic, low-grade brainstem gliomas; focal, malignant brainstem gliomas; focal, tectal gliomas; and exo-
phytically growing tumors.2,6 Similar to brainstem gliomas in children, diffuse intrinsic brainstem gliomas account for the
majority of brainstem gliomas in adults (45%-50% of tumors). Focal malignant brainstem gliomas (25%-39% of
tumors), tectal gliomas (3%-8% of tumors) and other brainstem tumors (15% of tumors) are less frequent (Fig. 1).2,6,7
However, other classifications based on histologic grade and tumor location have been used.3,8,9 Attributable to the ana-
tomic location of these tumors, the presenting signs and symptoms include cranial nerve dysfunction (up to 87% of
patients), gait disturbances (up to 61% of patients), and long-tract signs (up to 58% of patients). Headaches and other
signs of increased intracranial pressure also can be observed (Table 1). The tempo of symptom onset and progression and
the radiographic appearance are variable, depending on underlying pathology, and may be indicative of the histopatho-
logic subtype, the future clinical course, and prognosis.7,10
Higher pathologic grade, age >40 years at the time of diagnosis, and non-Caucasian ethnicity have been identified
as unfavorable prognostic factors10 (Table 1). Similarly, a more recent study has confirmed age <40 years, lower patho-
logic grade, and a Karnofsky performance status >70 as favorable prognostic factors. Those authors also identified an asso-
ciation between improved overall survival and initial treatment with radiation or radiochemotherapy compared with
supportive care only. However, their study did not differentiate between different pathologic tumor types with regard to
outcome data; therefore, the results may be skewed toward more benign tumor types.11 Similar clinical risk factors were

Corresponding author: David A. Reardon, MD, Center for Neuro-Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215-5450; Fax:
(617) 632-4773; david_reardon@dfci.harvard.edu

Center for Neuro-Oncology, Dana-Farber/Brigham and Women’s Cancer Center, Boston, Massachusetts

DOI: 10.1002/cncr.29920, Received: October 23, 2015; Revised: January 11, 2016; Accepted: January 19, 2016, Published online Month 00, 2016 in Wiley Online
Library (wileyonlinelibrary.com)

Cancer Month 00, 2016 1

Review Article

Figure 1. This is a schematic overview of the characteristic presentation of brainstem gliomas in adults and children. H3-K27M
indicates an H3 histone, family 3A (H3F3A) alteration replacing lysine 27 with methionine.

identified by another recent study that evaluated high-
grade brainstem gliomas in adults. However, this study
did not find a correlation between radiotherapy and out-
come.12 Of note, most of the available studies on brain-
stem gliomas in adults have used variable classification
schemes, thereby complicating comparison of these stud-
ies. Nevertheless, these data suggest that survival and over-
all prognosis depend on the underlying pathology,
pathologic grade, and other clinical factors (Table 1). A
recent comprehensive study identified statistically signifi-
cant differences in overall survival according to pathologic
grade, imaging appearance, and age at diagnosis. Thus,

2 Cancer Month 00, 2016

 TABLE 1. Synopsis of Key Studies on Brainstem Gliomas in Adults

No. of Age
Reference Patients (range) y Clinical Presentation Therapy Median Survival Miscellaneous Comments

Cancer
Landolfi 19987 19 40 (17–70) Diplopia, weakness, head- Radiation, chemotherapy (n 5 54 mo Higher clinical performance status
ache, cranial nerve paresis, 3; carmustine, procarbazine/ associated with longer survival
ataxia, dysarthria, vincristine/etoposide, carbo-
hemiparesis platin/vincristine) or observa-
tion until tumor progression

Massager 20005 30 30 (4–78) Walking disturbances, visual Radiation and/or chemother- NA MR imaging appropriately identified

Month 00, 2016

impairment, signs of apy or supportive care malignant tumors in 63 % of cases only
increased intracranial pres-
sure, dysphagia/dysarthria,
hemiparesis

Guillamo 20012 48 34 (16–70) Gait disturbance, diplopia, Initial observation, radiation, 5.4 y Duration of symptoms >3 mo identified
dysphagia, facial weakness and/or chemotherapy only favorable prognostic factor
(n 5 27; BCNU, BCNU 1
procarbazine, CCNU, or
platinum-based regimens)

Mursch 200514 6 36.9 Lower cranial nerve dysfunc- Radiation only 34.5 mo Longer duration of symptom history
tion, pyramidal tract involve- correlated with nonastrocytic pathology
ment, facial palsy, cerebellar and longer survival time
ataxia, nystagmus

Kesari 200810 101 36 (18–79) Cranial nerve deficits, head- Radiation, chemotherapy 85 mo Non-Caucasian ethnicity, pontine
ache, weakness, sensory (n 5 40; PCV, lomustine, vin- location, age >40 y at diagnosis, and
symptoms, ataxia, visual cristine, carboplatin, BCNU, higher tumor grade associated with
symptoms, dysarthria temozolomide, irinotecan) shorter survival

Salmaggi 20086 32 31 (14–78) Diplopia, ataxia, hemiparesis, Initial observation, radiation, 59 mo Onset of symptoms <4 mo predictive
facial paresis, nystagmus, ver- and/or chemotherapy (n 5 of shorter survival time
tigo, facial spasm, other 20; temozolomide or PCV)
symptoms

Dellaretti 20128 67 41 (18–75) Hemiparesis, difficulties
awakening, visual disturban-
ces, hemifacial paresis, dys-
phagia, signs of increased
intracranial pressure
NA NA Overall morbidity rate associated with
biopsy, 9%; 1 patient (1%) death was
associated with the biopsy procedure

Reyes-Botero 201421 17 41 (18–65) Cranial nerve dysfunction,
imbalance, headache, limb
motor weakness, cerebellar
ataxia
Radiation and/or 48.7 mo (57 mo for Chromosome 14q and 16q losses less
chemotherapy LG-BSG, 16 mo for common than in pediatric DIBG; H3
HG-BSG) mutations (H3F3AK27M and
HIST1H3BK27M) detected in 3
of 8 pathology specimens

Hundsberger 20149 21 41 (20–81) Ataxia, oculomotor symp- Radiotherapy and/or chemo- 30.5 mo (LG-BSG), Survival significantly improved in WHO
toms, dizziness, sensory and/ therapy (n 5 11; temozolo- 11.5 mo (HG-BSG) grade 2 tumors compared with WHO
or motor hemisyndrome mide), supportive care grade 3/4 tumors

3
Adult Brainstem Gliomas/Eisele and Reardon
4
Review Article

TABLE 1. Continued

No. of Age
Reference Patients (range) y Clinical Presentation Therapy Median Survival Miscellaneous Comments

Dey 201412 240 48.7 Data not available in the Radiation (n 5 204; 83.8%), 7 mo HG-BSGs only; age >50 y and patho-
SEER database data regarding chemotherapy logic diagnosis of glioblastoma associ-
and other treatment regimens ated with reduced survival; radiation was
NA not associated with improved survival;
there was a trend toward improved sur-
vival for patients who underwent a surgi-
cal intervention (biopsy or resection)

Reithmeier 201411 104 41 (18–89) Sensory symptoms (29.8%), Radiation, chemotherapy, 18.8 mo Postsurgical complications occurred in
cranial nerve dysfunction interstitial radiosurgery with 11 of 93 patients (11.8%) after stereotac-
(28.8%), dyscoordination brachytherapy (I-125 seeds), tic biopsy and in 4 of 11 patients (36.4%)
(28.8%), paresis (21.2%), combined radiation and after microsurgery; median survival was
dysarthria/dysphagia (13.5%), chemotherapy, or supportive prolonged after radiation (26.4 mo) or af-
increased intracranial care ter radiotherapy/chemotherapy (13.4 mo)
pressure (12.5%) compared with supportive care (4.3 mo)
Theeler 20153 143 36 Data NA Radiation (n 5 118; chemo- 32.1 mo Testing for molecular markers: 3 of 43
therapy (n 5 27; temozolo- patients were positive for IDH1R132H
mide, cytotoxic (IHC), 2 of 9 had PIK3CA mutations, 1 of
chemotherapy, and/or 9 had a BRAFV600E mutation; MGMT
bevacizumab) methylation status and histone H3.3
mutations not tested

Abbreviations: BCNU, carmustine; BRAF V600E, B-Raf murine sarcoma viral oncogene homolog valine-to-glutamic acid mutation at codon 600; CCNU, lomustine; DIBG, diffuse intrinsic brainstem glioma; Gy,
grays; H3F3A K27M, histone H3F3A lysine-to-methionine mutation at codon 27; HG-BSG, high-grade brainstem glioma; HIST1H3B K27M, histone cluster 1, H3b lysine-to-methionine mutation at codon 27; IDH1
R132H, isocitrate dehydrogenase arginine-to-histidine mutation at codon 132; IHC, immunohistochemistry; LG-BSG, low-grade brainstem glioma; MGMT, O6-methyl-guanine-methyl-transferase; MR, magnetic
resonance; NA, not available; PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase; PCV, combined procarbazine, CCNU, and vincristine; SEER, Surveillance, Epidemiology, and End Results program of the
US National Cancer Institute; WHO, World Health Organization.

Cancer
Month 00, 2016
 Adult Brainstem Gliomas/Eisele and Reardon

World Health Organization (WHO) grade 4 pathology
and the presence of contrast enhancement on magnetic
resonance imaging (MRI) were associated with a more
unfavorable prognosis. Midbrain location was associated
with a trend toward improved survival in this study.3
In general, although brainstem gliomas in adults
represent malignant tumors, the overall prognosis appears
to be more favorable compared with that for brainstem
gliomas in children. In adults, 5-year survival rates from
45% to 58% have been reported.10 In contrast, in chil-
dren with diffuse intrinsic brainstem gliomas 5-year sur-
vival rates are typically <5% (Fig. 1).13
Diffuse intrinsic brainstem gliomas, by definition,
involve >50% of the greatest dimension of the brainstem
(Fig. 2). These tumors typically occur in relatively young
adults in their third to fifth decade of life.3,7 In contrast to
children with diffuse intrinsic brainstem gliomas, in
whom symptoms and neurologic deterioration often

Figure 2. Axial (A) and sagittal (B) images were optained by (left) fast fluid-attenuated inversion-recovery and (right) T-1 post-
contrast magnetic resonance imaging from a woman aged 62 years old who had a low-grade brainstem astrocytoma (World
Health Organization [WHO] grade 2) with piloid features. IDH-1 indicates isocitrate dehydrogenase 1, BRAFV600E indicates B-raf
murine sarcoma viral oncogene homolog B (BRAF) valinetoglutamic substitution at codon 600.

Cancer Month 00, 2016 5

Review Article

occur in <3 months, adults can present with a much
more insidious onset of neurologic symptoms that pro-
gress over many months.6,14 Although cranial nerve defi-
cits and gait imbalance are most common, there have
been cases of patients presenting with a long history of fa-
cial palsy, hemifacial myokymia, or hemifacial spasms.15
Other rare presentations include neurogenic respiratory
disturbances,16,17 hemiparkinsonism,18 and pseudomyas-
thenia19 (Table 1). Pathologically, these tumors are most
often characterized as low-grade gliomas (WHO grade 2)
(Fig. 2), although high-grade gliomas also occur (Fig. 3
and Fig. 4). Whereas diffuse intrinsic brainstem gliomas
in children are typically highly aggressive with a rapid
clinical deterioration and a median survival <1 year13,20;

Figure 3. (A) Sagittal images were obtained by (left) fast fluid-attenuated inversion-recovery (FLAIR) and (right) T-1 postcontrast
magnetic resonance imaging (MRI) from a man aged 20 years who had a malignant pontine glioma (World Health Organization
[WHO] grade 3; isocitrate dehydrogenase 2 [IDH-2] mutated). (B) Axial images were obtained by (left) FLAIR and (right) and T-1
postcontrast MRI from a woman aged 57 years who had high-grade brainstem glioma (WHO grade 3; O6 methyl-guanine-
methyl-transferase [MGMT]-methylated).

6 Cancer Month 00, 2016

 Adult Brainstem Gliomas/Eisele and Reardon

diffuse intrinsic brainstem gliomas in adults often pro-
gress at a slower pace and are characterized by a more in-
sidious neurologic decline. They portend a better overall
prognosis, with a median survival between 4.1 and 7.3
years (Table 1). Depending on the pathologic subtype,
the median overall survival ranges from 9.8 months for
patients with WHO grade 4 tumors to 26.2 months for
those with WHO grade 2 tumors11 (Fig. 2).
The molecular biology of diffuse intrinsic brainstem
gliomas among adults is poorly understood because of the
small numbers that have been historically sampled and an-
alyzed. A recently published small study of 17 diffuse
intrinsic brainstem gliomas in adults suggested that these
tumors differ from supratentorial gliomas in adults. Similar
to pediatric diffuse intrinsic brainstem gliomas and in con-
trast to supratentorial gliomas in adults, gain of chromo-
some 7 appeared to be less frequent. Loss of either
chromosome 14q or 16q was observed less often compared
with that in pediatric diffuse intrinsic brainstem gliomas.
The histone H3.3 alterations (histone 3F3A [H3F3A]
lysine-to-methionine mutation at codon 27 [H3F3AK27M]
and histone cluster 1, H3b [HIST1H3BK27M]), which are
now considered characteristic for a subset of pediatric dif-
fuse intrinsic brainstem gliomas, may also play a role in
adult diffuse intrinsic brainstem gliomas and were identi-
fied in 3 of 8 tumors (37.5%) for which DNA material
was available compared with 6 of 205 DNA samples
(2.9%) of supratentorial gliomas.21 Another recent study
reported histone H3F3AK27M alterations in 15 of 28 sam-
ples (53.6%) of adult midline brainstem glioma. It is note-
worthy that histone H3F3AK27M and isocitrate
dehydrogenase 1 (IDH-1) mutations were mutually exclu-
sive. In addition, presence of the H3F3AK27M mutation
was associated with a trend towards worse overall sur-
vival.22 If the role of the H3F3AK27M in adult brainstem
gliomas can be further confirmed and validated, the evalua-
tion of molecular therapies targeting H3F3AK27M could be
considered similar to the ongoing efforts in the pediatric
population.23,24
Focal malignant brainstem gliomas are localized, dis-
crete mass lesions that involve <50% of the greatest
dimension of the brainstem. These tumors are typically
diagnosed in patients aged >40 years, and the clinical
course is characterized by rapid onset and progression of
signs and symptoms of brainstem dysfunction.7,25 Radio-
graphically, these tumors often exhibit heterogeneous or
ring-like contrast enhancement, suggesting intrinsic areas
of necrosis (Fig. 4). Pathologically, these tumors most

Figure 4. Axial images were obtained by (left) fast fluid-attenuated inversion-recovery and (right) T-1 postcontrast magnetic res-
onance imaging from a man aged 25 years who had a malignant brainstem glioma (World Health Organization [WHO] grade 4).
EGFR indicates epidermal growth factor receptor; MGMT, O6 methyl-guanine-methyl-transferase.

Cancer Month 00, 2016 7

Review Article
often correspond to anaplastic astrocytomas (WHO grade
3) and glioblastomas (WHO grade 4). Therefore, as a
group, these tumors resemble the highly aggressive supra-
tentorial high-grade gliomas in adults.2,26 Patients often
deteriorate rapidly, and their prognosis is poor with me-
dian survival of 11.2 to 25 months.6,10 A more recent ret-
rospective study on high-grade brainstem gliomas in the
elderly reported a median overall of 13.5 months.27 That
study and other recent studies have incorporated testing
for the prognostic markers O6-methyl-guanine-methyl-
transferase (MGMT), phosphatase and tensin homolog
(PTEN) loss, IDHR132H, and epidermal growth factor re-
ceptor (EGFR) amplification/EGFRvIII variant, with
inconclusive results to date.3,11,28 Although certainly use-
ful, in addition to the molecular markers used in these
studies, the molecular panels used for characterization of
brainstem gliomas should include testing for other molec-
ular alterations, such as histone H3.3 and activing A re-
ceptor type 1 (ACVR1) mutations, among others.
Focal tectal gliomas in adults are very similar to their
pediatric counterparts. Their clinical presentation is often
innocuous, and they can even be incidentally identified. If
symptomatic, they most commonly present with signs
and symptoms of obstructive hydrocephalus. Because of
their characteristic clinical presentation and radiologic
appearance, surgical biopsy in general is not necessary. If
biopsied, they are often classified as low-grade glial
tumors and most commonly represent WHO grade 2 oli-
goastrocytomas.2 High-grade gliomas have been described
but are exceedingly rare.29 Typically, focal tectal gliomas
have an indolent clinical course and are associated with a
more favorable prognosis. The median survival based on 1
retrospective study in 16 patients with tectal glioma was
84 months irrespective of tumor-directed treatment. In
the same study, the death of only 1 patient was attribut-
able to the midbrain tumor itself. Therefore, clinical and
radiographic observation may be a reasonable approach to
these lesions. Extraventricular cerebrospinal fluid drainage
to relieve intracranial pressure may be necessary in symp-
tomatic patients and often is the only required therapeutic
intervention.30
Other brainstem gliomas include dorsally exophytic
brainstem gliomas, glial tumors associated with neurofi-
bromatosis 1, and oligodendroglial tumors. In children,
dorsally exophytic tumors are considered more favorable,
because they are amenable to surgical intervention. In
addition, pathologically, they often represent low-grade
pilocytic astrocytomas and thus portend a somewhat bet-
ter prognosis with a median survival of >5 years.31,32 In
contrast, exophytically growing and contrast-enhancing
8 Cancer
brainstem masses in adults may represent highly aggres-
sive gliomas.33-35 Therefore, surgical resection and patho-
logic evaluation are warranted if possible.
IMAGING APPEARANCE AND DIAGNOSIS
Similar to the MRI appearance in children, adult brain-
stem gliomas are characterized as T1-hypointense and
T2-hyperintense mass lesions with variable contrast
enhancement (Figs. 2–4).4,36 Diffusely infiltrating brain-
stem gliomas in adults are characterized as poorly
defined, T2-hyperintense lesions that infiltrate >50% of
the greatest dimension of the brainstem. Focal brainstem
gliomas are typically better circumscribed, involve <50%
of the greatest dimension of the brainstem, and may
demonstrate a heterogeneous enhancement pattern simi-
lar to that observed in supratentorial high-grade gliomas.
The presence of contrast enhancement within the tumor
often signifies a higher pathologic grade and a worse
prognosis.37 Cystic tumor components occur but are
uncommon.6
There are currently significant efforts to develop and
improve advanced imaging technologies to reliably differ-
entiate brain tumors from nonneoplastic lesions. Single-
voxel magnetic resonance spectroscopy (MRS) is an imag-
ing technology that may be helpful in this regard. N-
Acetyl-Aspartate (NAA) is a marker of neuronal integrity,
and the NAA peak is typically reduced in brain tumors.
Choline (Cho) reflects cell membrane turnover, and the
choline peak often is increased in dividing tissues. The
creatine (Crea) peak is commonly stable in tumors and is
used as a reference. In patients with adult brainstem gli-
oma, Salmaggi et al observed that an elevated Cho/NAA
ratio, an elevated Cho/Crea ratio, and an abnormal Crea/
NAA ratio caused by loss of NAA signal was predictive of
brainstem glioma in 9 patients. These changes are similar
to the MRS characteristics reported in supratentorial adult
gliomas. Salmaggi et al also reported an elevation in the
lactate peak—a metabolite that is not present in healthy
brain.6 It is believed that an increase in the lactate peak
reflects tissue necrosis, which is commonly observed in
high-grade brain tumors. In pediatric diffuse intrinsic
pontine gliomas, elevation of the lactate peak represents a
poor prognostic factor.38 However, MRS of the brainstem
remains technically difficult because of the small size of
anatomic structures and artifact from bone and fatty
structures in the vicinity. Therefore, the utility and prog-
nostic significance of MRS in adult brainstem gliomas
remain unclear.
18
F-fluoro-deoxy-glucose–positron emission tomog-
raphy (FDG-PET) is another imaging technology that
Month 00, 2016

measures high 18F-FDG uptake in metabolically hyperac-
tive tumors compared with healthy brain. In the study by
Salmaggi et al, all 9 brainstem tumors exhibited increased
18
F-FDG avidity.6 PET imaging technology for brain
tumors so far lacks wide availability. Also, it can be diffi-
cult to differentiate small areas of metabolically active tu-
mor from the background of already highly metabolically
active brain, thus limiting sensitivity and specificity.
Therefore, alternative tracers are investigated.
It is important to highlight that the imaging
appearance of brainstem lesions in adults is heterogene-
ous and not reliably predictive of the underlying pathol-
ogy. Although a recent study reported concordance of
the diagnosis made by MRI and histopathologic evalua-
tion in up to 95% of patients,37 this is in contrast to sev-
eral other studies in which the presurgical radiographic
diagnosis of brainstem glioma was correct in only 50%
to 69% of patients, and alternative pathologic diagnoses
are encountered, including metastases, lymphoma, cav-
ernomas, vascular abnormalities, inflammatory or
demyelinating lesions, and infectious lesions, such as
abscesses.5,39,40 Furthermore, even in patients with
pathologically confirmed brainstem glioma, the seem-
ingly characteristic imaging findings of a diffuse versus
focal and enhancing versus nonenhancing lesion is
insufficient to differentiate between high-grade and
low-grade brainstem gliomas.4 Therefore, to exclude a
potentially treatable diagnosis, a surgical biopsy of
brainstem lesions in adults should be considered when
feasible. Several studies support the safety of stereotactic
brainstem biopsies, and a definite diagnosis can be made
in up to 95% of patients. The associated risk of morbid-
ity is low, and the risk of mortality is almost
negligible.4,11,40
TREATMENT OPTIONS
Effective therapy regimens for brainstem gliomas in adults
have not been defined by prospective clinical studies, but
radiation with concurrent or adjuvant chemotherapy is
most commonly used (Table 1). Delays in the develop-
ment of new and effective targeted treatments are attribut-
able at least in part to an insufficient understanding of the
pathologic and molecular characteristics of adult brain-
stem gliomas because of their rare occurrence and a pau-
city of sufficient tumor tissue for molecular analyses.21
Surgery
Most often, surgical resection of brainstem gliomas is not
possible because of their location; therefore, surgery does
not play a significant role in the treatment of diffuse
Cancer Month 00, 2016
Adult Brainstem Gliomas/Eisele and Reardon
intrinsic or focal brainstem gliomas in adults. However, in
exophytically growing tumors, surgical debulking or even
resection of the tumor may relieve mass effect and associ-
ated neurologic symptoms and may be curative in some
patients.14,41 Surgical biopsy for diagnostic purposes, as
discussed above, should be considered if feasible in
contrast-enhancing brainstem lesion, because these lesions
may reflect a highly heterogeneous group of diagnoses. A
recently published retrospective study on high-grade
brainstem gliomas in adults even indicated a possible
impact on overall survival in patients who underwent sur-
gical intervention compared with those who did not
undergo surgery.12 These results underline the impor-
tance of making an accurate diagnosis.
Radiotherapy
Radiotherapy remains the standard treatment for adult
brainstem gliomas, and focal radiation and a total dose of
54 grays (Gy) in 1.8 Gy to 2.0 Gy fractions is most com-
monly used3,21 although higher doses have been
reported.25
In patients with diffuse intrinsic brainstem glioma,
clinical and radiographic stabilization or even improve-
ment after radiation can be observed, although the
reported response rates in the literature are highly variable
(Table 1). Nonetheless, in up to 64% of patients, radio-
graphic disease stabilization can be achieved.6,9,10 How-
ever, because of concerns about affecting vital structures
in the vicinity of the radiation field, the time point of radi-
ation is commonly subject to debate. In selected patients,
radiation may be deferred until definite clinical and radio-
graphic disease progression occurs.6
In contrast, focal enhancing malignant brainstem glio-
mas appear to be relatively radioresistant. In the series by
Guillamo and colleagues, only 13% of patients exhibited
clinical and radiographic improvement after radiation.2
On the basis of a more recent retrospective study on high-
grade brainstem gliomas from the Surveillance, Epidemi-
ology, and End Result (SEER) database, it can be ques-
tioned whether radiation even has an impact on survival.
Although this study indicated a correlation between age
and Karnofsky status at time of diagnosis and suvival,
there was no difference in outcome in patients that
received radiotherapy compared to supportive care
alone.12
In addition to conventional focal radiation, hyper-
fractionated radiation schemes with total doses up to 72
Gy have been evaluated but failed to improve efficacy and
carried a higher risk of radiation-related complica-
tions.7,42 Also, fractionated stereotactic radiotherapy of
9
Review Article
brainstem gliomas was evaluated in a prospective clinical
trial that included 41 adult patients and led to clinical sta-
bilization or improvement in 70% of patients and radio-
graphic stability or response in 68% of patients. Reported
treatment-related toxicity in general was low, but 3
patients died during radiation, although it is unclear
whether this was related to underlying disease progression
or treatment-related effects.36 Therefore, the feared risk of
radiation-induced necrosis and edema leading to neuro-
logic deterioration currently precludes the general applica-
tion of high-dose focal radiation.
Chemotherapy
The role of chemotherapy in the treatment of adult brain-
stem gliomas remains unclear, and the available literature
is limited (Table 1). In the retrospective study by Sal-
maggi et al, 20 patients received either temozolomide
(n 5 18 patients; 75 mg/m2 daily during radiation and
200 mg/m2 daily for 5 days every 28 days after radiation)
or combined procarbazine, lomustine (CCNU), and vin-
cristine (PCV) (n 5 2 patients; procarbazine 75 mg/m2
daily on days 8-21; CCNU 110 mg/m2 daily on day 1;
and vincristine 1 mg/m2 on days 8 and 28) with radiation
(48-54 Gy in 1.8-Gy fractions). Although the addition of
chemotherapy did lead to clinical improvement in 15
patients, the best radiographic treatment response was dis-
ease stabilization in only 50% of patients. In addition,
grade 3 and 4 myelotoxicity was encountered in 6
patients, including both patients who had received PCV.6
At the time of tumor recurrence, the role of chemo-
therapy for brainstem gliomas is even less clear. A recent
study reported clinical improvement in 60% of patients
and radiographic improvement or stability in 80% of
patients after treatment with monthly cycles of temozolo-
mide for low-grade brainstem gliomas. However, that
study did not provide information on other factors that
may have influenced the clinical and radiographic out-
come, ie, steroid use, thereby limiting the conclusions that
could be drawn from those results.43 Furthermore, the use
of PCV, cisplatin, or carboplatin as well as irinotecan has
been reported in the recurrent setting without clear treat-
ment response but with an increased risk for myelotoxic-
ity.2,9,10 In addition, there are some reports of salvage
chemotherapy with bevacizumab and experimental treat-
ments like etoposide, paclitaxel, and tamoxifen10 (Table
1). To date, the scarcity of these data does not justify de-
finitive treatment recommendations. If chemotherapy
options are considered, then patients should be carefully
monitored for signs of toxicity.
10
SUMMARY
Brainstem gliomas in adults represent a heterogeneous
group of tumors, and diffuse intrinsic brainstem gliomas
represent the majority of these tumors. In contrast to chil-
dren, in whom brainstem gliomas typically progress rap-
idly and portend a poor prognosis, the presentation and
course of brainstem gliomas in adults depends on the
pathologic and molecular subtype and may be associated
with a less aggressive clinical course and more favorable
prognosis. Therapeutic options for adult brainstem glio-
mas are limited, and these patients most commonly
receive radiotherapy, with a subsequent improvement of
clinical symptoms but an unclear impact on survival.
Therefore, more effective therapies are clearly needed.
The recent advances in our understanding of the molecu-
lar characteristics of diffuse intrinsic brainstem gliomas in
children give hope for similar progress in the treatment of
adult brainstem gliomas in the near future provided that
similar surgical strategies for the sampling of tumor tissue
are implemented. Such an approach is critical to gain a
better understanding of the molecular pathobiology and
will ultimately lead to the development of new targeted
therapies specific to the molecular characteristics of these
tumors.
FUNDING SUPPORT
No specific funding was disclosed.
CONFLICT OF INTEREST DISCLOSURES
The authors made no disclosures.
AUTHOR CONTRIBUTIONS
Sylvia C. Eisele: Conceptualization, writing–original draft, and
visualization. David A. Reardon: Conceptualization, methodol-
ogy, formal analysis, investigation, resources, data curation, writ-
ing–original draft, writing–review and editing, visualization,
supervision, project administration, and funding acquisition.
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