Brain stem gliomas--Brain Tumor Path -

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Brain Tumor Pathology ISSN 1433-7398 Brain Tumor PatholDOI 10.1007/s10014-012-0110-4

Brain stem gliomas: a clinicopathologicalstudy from a single cancer center

Maysa Al-Hussaini, Usama Al-Jumaily,Maisa Swaidan, Awni Musharbash &Sameh Hashem

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ORIGINAL ARTICLE

Brain stem gliomas: a clinicopathological study from a singlecancer center

Maysa Al-Hussaini • Usama Al-Jumaily •

Maisa Swaidan • Awni Musharbash •

Sameh Hashem

Received: 12 March 2012 / Accepted: 11 June 2012

� The Japan Society of Brain Tumor Pathology 2012

Abstract Brain stem gliomas (BSG) are rare tumors

occurring predominantly in childhood. They are mostly of

astrocytic origin and are divided into infiltrative versus

circumscribed types, with different prognoses. The diag-

nosis is mainly based on MRI findings, and biopsy is rarely

performed. This is a retrospective study of BSG with

available biopsies diagnosed at our center over 6-year

period. Fifteen cases were identified, with a predominance

of females. The median age was 7 years, and the mean

duration of symptoms was\6 weeks in 58.3 % (n = 7) of

cases. MRI was typical of diffuse pontine gliomas in

64.3 % (n = 9) of cases. Radiotherapy was the commonest

modality of treatment, and the median overall survival was

21.7 months. Twelve cases were consistent with infiltrative

astrocytoma of various grades (2 grade II, 7 grade III and 3

grade IV). Entrapped normal neurons and mitosis were the

commonest findings indicating infiltrative growth and high

grade, respectively, and those correlated significantly with

immunostaining for neurofilament protein and Ki-67 of

C3 %. Overall survival correlated only with the duration of

symptoms and tumor grade on biopsies. A limited panel of

immunostains might be useful in undetermined cases to

decide on the growth pattern and grade.

Keywords Brain stem glioma � Biopsy �Immunohistochemistry � Diffuse pontine glioma �Pilocytic astrocytoma

Introduction

Brain stem gliomas (BSG) are rare tumors. They are mostly

seen in childhood where they account for 10–20 % of brain

tumors [1]. Classification depends primarily on radiologi-

cal assessment of the location and pattern of growth [1–3].

Diffuse pontine glioma (DPG) is the most common type

accounting for 70 % of cases. MRI typically reveals diffuse

enlargement of the pons with encasement of at least one

half to two-thirds of the basilar artery. Exophytic tumors

on the other hand are seen primarily in the mid brain or

the medulla oblongata, and are characterized by a cystic

component that projects posteriorly into the ventricles with

an enhancing solid component. This radiological classifi-

cation correlates well with the tumor histological type and

grade [4, 5]. Fibrillary infiltrative astrocytoma represents

the majority of DPGs, where high grade gliomas of ana-

plastic astrocytoma and glioblastoma multiforme types

predominate [6], whereas exophytic tumors are mostly

grade I pilocytic astrocytoma [4]. The treatment modality,

outcome and prognosis differ drastically between both

groups [7]. DPGs are associated with a dismal outcome,

M. Al-Hussaini (&)

Department of Pathology,

King Hussein Cancer Center (KHCC), Queen Rania Street,

P.O. Box 1269, Al-Jubeiha, Amman 11941, Jordan

e-mail: [email protected]

U. Al-Jumaily

Department of Pediatric Oncology,

King Hussein Cancer Center (KHCC), Amman, Jordan

M. Swaidan

Department of Radiology,


A. Musharbash

Department of Surgery,


S. Hashem

Department of Radiation Oncology,


123

Brain Tumor Pathol

DOI 10.1007/s10014-012-0110-4

Author's personal copy

with 10 % survival at 1 year. Palliation radiotherapy and

disclosure of poor prognosis are offered once the diagnosis

has been made [8]. In contrast, exophytic tumors are

associated with excellent outcomes, with 5-year survival of

90 %. Surgical excision followed by conservative follow-

up is the treatment of choice [9].

Pre-treatment biopsy is rarely performed in cases of

BSG [10]. Most clinico-pathological correlations were

originally made on post-mortem specimens [11]. An

atypical radiological appearance where the diagnosis, and

thus management and prognosis, cannot be determined

with certainty remains the strongest indication for biopsy

[12, 13]. Stereotactic biopsy has replaced open craniotomy

in many neurosurgical approaches. While this is associated

with less morbidity to patients [14], specimens sent to the

pathologists are considerably smaller in size, creating

diagnostic challenges.

Immunohistochemistry has been established as an

adjunct in supporting the diagnosis and grading of brain

tumors [15, 16]. Neurofilament protein is a commonly

used marker in neuro-pathology, useful in determining

the circumscribed versus the infiltrative growth pattern.

Pilocytic astrocytoma tends to be circumscribed with few

NFP-positive fibers seen mainly at the periphery of the

tumor. In contrast, tumor cells infiltrate extensively in

between pre-existing fibers in infiltrative astrocytic tumors

of all grades. Ki-67 is used to assess the proliferative

potential in brain tumors, and in conjunction with other

features, especially mitosis can help in guiding the grad-

ing of tumors. Cutoff values to separate low- from high-

grade tumors are variable, but low-grade tumors tend to

show a proliferative index of \3 %, while high-grade

glial tumors are diagnosed when 10 % or more of tumor

cells are positive [16]. TP53 is a tumor suppressor gene,

and positive immunostaining is detected in many high-

grade brain tumors, especially secondary glioblastoma,

medulloblastoma with anaplasia and anaplastic meningi-

oma. In addition, it is used to differentiate pilocytic from

low-grade infiltrative fibrillary astrocytoma, being con-

sistently negative in the former.

We aim at describing our experience with cases of BSG

in which pre-treatment biopsies were obtained. The clini-

cal, radiological and pathological findings are described.

The value of adding a limited panel of immunohisto-

chemical stains, namely NFP, Ki-67 and P53, in reaching

the final diagnosis in equivocal cases is described.

Materials and methods

This is a retrospective study. After obtaining approval from

the KHCC Institutional Review Board (which works in

accordance with Declaration of Helsinki and ICH-GCP),

files from cases diagnosed with brain stem glioma over a

6-year period (2003–2009) were reviewed, and cases with

available pathological diagnoses were retrieved. The clin-

ical as well as radiological findings were collected. The

duration of the symptoms prior to presentation was

obtained, and a cutoff of 6 weeks was used to separate

cases with short- versus long-term presentations. Radio-

logical findings were described as typical when brain MRI

showed evidence of diffuse expansion of the pons with

encasement of at least two thirds of the basilar artery with

or without enhancement; otherwise, radiology was con-

sidered atypical. The operative approach for obtaining the

biopsy, the site targeted, as well as any further surgical

resection was recorded when available. Modalities of

treatment offered including radiotherapy and/or chemo-

therapy were collected. The outcome of the patient was

determined as dead versus alive at the time of collection of

data. The date of death of the patient or last follow-up/

clinic visit was recorded, and overall survival was calcu-

lated. Details that might disclose the identity of the patients

were omitted, and only coded data were used for analysis.

Review of the available H&E slides was performed.

Pathological features were assessed semi-quantitatively.

The degree of cellularity and pleomorphism was evaluated

on a scale from 1 to 3 (1 = mild, 2 = moderate, 3 =

marked). Entrapped neurons, mitosis, apoptosis, vascular

proliferation, necrosis, Rosenthal fibers (RF) and eosino-

philic granular bodies (EGBs) were assessed on a two-tier

scale (present vs. absent). The presence of entrapped nor-

mal-looking neurons signifies an infiltrative growth pattern,

while their absence can be related either to sampling in an

infiltrative glioma or alternatively the circumscribed nature

of the tumor. Mitosis was assessed as present when C1

mitosis was identified in any biopsy fragment, which was

consistent with the diagnosis of anaplastic astrocytoma in

infiltrative tumors and absent when a search of all available

slide(s) failed to reveal any. Apoptosis was considered

present if C1 apoptotic bodies were seen in any high-power

field (HPF). Vascular proliferation in the form of glom-

eruloid blood vessels and necrosis, whether palisading or

not, were assessed as absent versus present. The presence

or absence of Rosenthal fibers and EGBs was recorded in

all cases.

Immunohistochemistry staining for three markers, neu-

rofilament protein (clone2F11, Ventana ready to use, with

heat retrieval using EDTA buffer), Ki-67 (DAKO; clone

M1B-1, 1:50 dilution with heat retrieval using EDTA

buffer) and P53 (clone D07, Venetana, ready to use, with

heat retrieval using EDTA buffer) was performed using

automated Ventana immunostainer. Positive and negative

controls were run for each antibody. Positivity was evalu-

ated semi-quantitatively. The tumors were considered

infiltrative only if neurofilament protein was diffusely

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positive in all biopsies evaluated in any single case, while

occasional positive NFP fibers or a totally negative NFP

staining could be related to circumscribed tumor growth

or sampling the middle zone of an infiltrative tumor. The

Ki-67 proliferative index cutoff of C3 % was used to

separate high- from low-grade infiltrative astrocytomas.

P53 was considered positive when strong nuclear staining

was seen in more than 50 % of tumor cells.

Statistical analysis was performed using SAS version

9.1 (SAS Institute Inc, Cary, NC, USA). Descriptive sta-

tistics including the mean, median, and SD were calcu-

lated. In addition, the counts and percentages were also

estimated. Fisher’s exact test was used to compare among

several factors and the pathological results. Kaplan-Meier

survival curves were used to describe the outcome in all

patients. Log rank was used to compare between survival

curves. The P value was considered significant if B5 %.

Results

A total of 15 cases were indentified, 12 females and 3

males, with a median age of 7.0 years (2.1–29.8 years),

representing 42 % of all BSG cases treated at our center.

Nine (60 %) patients were Jordanian. Seven (46.7 %)

patients were initially biopsied and diagnosed outside our

center, then referred for further management. These were

biopsied using MRI-guided stereotactic biopsy where areas

of enhancements corresponding to high-grade tumor areas

were targeted; otherwise, the most peripheral area of the

tumor was targeted. Cases biopsied at our center were

approached through endoscopic biopsies from parts of the

lesion bulging into the third ventricle. The mean duration

of symptoms was \6 weeks in seven (54.5 %) patients

with available data. The most common presenting symp-

toms were cranial nerve palsies (n = 12; 80 %), upper

limb/lower limb weakness (n = 10; 66.7 %), ataxic gait

(n = 9; 60 %), headache (n = 7; 46.7 %), and nausea and

vomiting (n = 6; 43.1 %). Initial and follow-up MRIs were

available for 14 patients to determine the primary site and

growth pattern of the tumor. The tumor was located in the

pons in ten (71.4 %) patients, the mid brain in two

(14.3 %) and the medulla oblongata in the remaining two

(14.3 %) patients. MRI was not available in a single patient

for evaluation of the exact site. MRI was typical of DPG in

nine patients (64.3 %), while the findings were considered

atypical in five patients (35.7 %), including one pontine

case. Radiotherapy only was the most common modality of

treatment offered to nine (64.3 %) patients, chemotherapy

alone was offered to two (14.3 %), and combination

chemo-radiotherapy was offered to a single (7.1 %)

patient. All radiotherapy-treated patients but one (case no.

10) received a total dose of 54 Gy (1.8 Gy daily/30

fractions, 5 days a week). Families of two patients

(14.3 %) with pontine gliomas elected no treatment.

Debulking surgeries were offered to three patients, two

pilocytic astrocytoma cases (case nos. 1 and 2) and a single

glioblastoma case (case no. 15). Table 1 summarizes

patients’ demographics, clinical and radiological findings,

treatment modalities and outcomes.

Pathologically, the diagnosis in 12 (80 %) patients was

consistent with infiltrative fibrillary astrocytoma, including

2 (13.3 %) grade II fibrillary astrocytomas, 7 (46.7 %)

grade III anaplastic astrocytomas and 3 (20.0 %) grade IV

glioblastomas. Three (20.0 %) patients were diagnosed

with grade I pilocytic astrocytoma. Increased cellularity

was seen in seven (46.7 %) cases, all of high grade

(AA = 5, GBM = 2), while marked pleomorphism was

seen in five (33.3 %) cases (AA = 4, GBM = 1). Entrap-

ped neurons were identified in eight (53.3 %) infiltrative

astrocytoma cases (FA = 2, AA = 5, GBM = 1). The rest

of the cases showed no neurons (PA = 3, AA = 2,

GBM = 2). Mitosis was the most common high-grade

feature detected in eight (53.0 %) infiltrative astrocyto-

mas, but not in pilocytic astrocytoma cases. Microvascu-

lar proliferation was detected in six (40.0 %) cases

(GBM = 3, PA = 3), and necrosis was seen only in a

single (6.7 %) glioblastoma case. Apoptosis was detected

in all infiltrative astrocytoma cases but one (n = 11;

73.3 %). Rosenthal fibers were detected only in pilocytic

astrocytoma (3 cases). EGBs were not detected in any of

the cases.

Additional unstained slides/paraffin blocks to perform

immunostains were available in only 11 cases. All cases

with no additional slides/blocks were high-grade gliomas

where slides were only submitted for the initial diagnosis

from referring centers. NFP was diffusely positive in five

(45.5 %) cases, all of infiltrative astrocytoma type, while it

was totally negative or seen as occasional fibers within the

tumors in six (54.4 %) cases (PA = 3, FA = 1, AA = 1,

GMB = 1). Ki-67 was C3 % in eight (72.7 %) cases,

including two pilocytic astrocytoma cases and\3 % in the

remaining three cases (PA = 1, FA = 2). P53 was positive

in only two (18.2 %) high-grade glioma cases (AA = 1,

GBM = 1). Table 2 summaries the most important path-

ological and immunohistochemical findings.

When comparing high-grade (AA = 7, GBM = 3)

versus low-grade (PA = 3, FA = 2) tumor groups, patients

tended to be younger (median 74 vs. 100 months), showed

more predominance of females (90 vs. 60 %), a shorter

median duration of presenting symptoms (3.5 vs. 6 weeks),

and fewer alive patients (2/6 vs. 4/4), respectively, but

none of the features reached statistical significance. Fig-

ures 1 and 2 demonstrate radiological findings (Figs. 1a,

2a), routine hematoxylin and eosin-stained slides (Figs. 1b,

2b), and immunostains for NFP (Figs. 1c, 2c) and Ki-67

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Table 1 Patients’ demographics, clinical characteristics, radiological findings and outcomes

No. Sex Age

(months)

Symptoms

(weeks)

Location MRI Surgery Pathology RTX

(Gy)

CTX Status OS

(months)

1 F 63 4 Cervico-

medullary

Atypical Bx and excision of

cyst

PA No Carbo/

VCR

Alive AWD

2 M 98 6 Pons and

midbrain

Atypical Bx and subtotal

excision

PA No No Alive AWD

3 F 100.3 2 Tectum/

midbrain

Atypical Bx PA 54 Carbo/

VCR

NA NA

4 F 132 8 Pons Typical Bx* FA/grade

II

54 No Alive AWD

5 M 357 78 Medulla

oblongata

Atypical Bx FA/grade

II

54 No Alive AWD

6 F 25 36 Pons Typical Bx AA Nob Carbo/

VCR

NA NA

7 F 50 16 Pons Typical Bx* AA 54 No Alive AWD

8 F 62 2 Pons Typical Bx* AA 54 No Dead 4.7

9 F 64.9 3 Pons Typical Bx* AA 54 No Dead 21.7

10 M 81.1 4 Pons Typical Bx* AA 10.8c No Dead 2.1

11 F 225 12 Midbrain Atypical Bx* AA 40 No Alive AWD

12 F 240 NA Brain stema NA Bx* AA NA NA NA NA

13 F 67 NA Pons Typical Bx GBM No No Dead 1

14 F 83.6 3 Pons Typical Bx* GBM 54 No Dead 21

15 F 171 2 Pons Typical Bx and debulking GBM 54 No Dead 3

AA anaplastic astrocytoma, AWD alive with disease, Bx biopsy at KHCC, Bx* biopsy outside KHCC, Carbo carboplatinum, CTX chemotherapy,

FA fibrillary astrocytoma, GBM glioblastoma, NA not available, OS overall survival, PA pilocytic astrocytoma, RTX radiotherapy, VCRvincristinea This was mentioned only in the referral notes. MRIs were not available for reviewb Owing to the young age of the patient and long history of stable disease (9 months), chemotherapy was administeredc Deteriorated clinically after the sixth session of radiotherapy and treatment was stopped

Table 2 Pathological and immunohistochemical findings

No.. Pathology

DX

Cellularity Pleomo Entrapped

neurons

Mitosis

(hpf)

Apoptosis

(hpf)

VP Necrosis RF EGBs NFP Ki67

(%)

p53

1 PA 1 2 – 0 0 ? – ? – Occasional 1 –

2 PA 2 1 – 0 1 ? – ? – Occasional 8 –

3 PA 1 1 – 0 0 ? – ? – Negative 4 –

4 FA 2 2 ? 0 10 – – – – Occasional 2 –

5 FA 2 1 ? 0 3 – – – – Positive 1 –

6 AA 2 1 ? 0 4 – – – – NA 10 NA

7 AA 2 1 ? 1 0 – – – – Positive 20 NA

8 AA 3 3 ? 1 1 – – – – Positive 20 ?

9 AA 3 3 – 3 4 – – – – NA NA NA

10 AA 3 3 ? 2 8 – – – – NA NA NA

11 AA 3 2 ? 1 3 – – – – Positive NA NA

12 AA 3 3 – 1 2 – – – – Negative 10 –

13 GBM 2 1 – 0 4 ? – – – Negative 30 –

14 GBM 3 2 – 1 10 ? Yes – – NA NA NA

15 GBM 3 3 ? 1 4 ? – – – Positive 40 ?

AA anaplastic astrocytoma, DX diagnosis, EBGs eosinophilic granular bodies, FA fibrillary astrocytoma, grade II, GBM glioblastoma, hpf high-

power field, NFP neurofilament protein, PA pilocytic astrocytoma, Pleomo pleomorphism, RF Rosenthal fibers

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(Figs. 1d, 2d) from two low grade astrocytoma cases,

infiltrative WHO grade II fibrillary astrocytoma and pilo-

cytic astrocytoma, respectively. P53 was negative in both

cases (not shown).

Several variables were tested for possible significant

correlation. The infiltrative versus the circumscribed

growth pattern of tumor correlated significantly with tumor

location (pons vs. outside pons; p = 0.01) and MRI find-

ings (typical vs. atypical; p = 0.03). NFP correlated sig-

nificantly with the presence of entrapped neurons within

the tumor (p = 0.02). Mitosis and the Ki-67 proliferative

index correlated significantly with the tumor grade

(p = 0.01 and p = 0.02, respectively). P53 was the least

useful marker, and although it was positive in two high-

grade glioma cases, it failed to differentiate infiltrative

grade II fibrillary astrocytoma from circumscribed grade I

pilocytic astrocytoma (p = 0.17).

At the time of the study, six patients were alive with

disease, six patients were dead of disease and three patients

were lost to follow-up. The median overall survival for the

whole group was 21.7 months (Fig. 3a). The overall sur-

vival correlated with \6 weeks’ duration of symptoms at

the time of presentation (log rank p = 0.045) (Fig. 3b) and

with a higher grade of tumors as seen on biopsies (log rank

p = 0.023) (Fig. 3c). Other clinical, radiological, patho-

logical and immunohistochemical findings did not correlate

with survival.

Discussion

We report our findings in 15 cases of brain stem glioma

with biopsies that were managed at our center, five of

which were previously reported [8]. The findings are at

Fig. 1 A case of diffuse pontine glioma. a Axial T2W MRI showing

encasement of the basilar artery by a hyperintense lesion (typical

MRI). b Biopsy shows infiltration of pre-existing neurons by low-

grade infiltrative astrocytoma showing no evidence of mitosis,

vascular proliferation or necrosis. The entrapped neurons appear

normal (H&E 940). c Neurofilament protein immunostain highlight-

ing the infiltrative nature of the tumor cells (920). d Ki-67

proliferative index is low (1.2 %) (920)

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large in concordance with international literature apart

from the marked predominance of female patients, a pre-

viously described observation by our group.

Obtaining diagnostic biopsy from BSG continues to be

controversial in the literature [4, 17]. Recently, new tests

have been introduced that might help in confirming the

diagnosis, and predicting the prognosis and response to

potential targeted therapy, thus advocating the need for

obtaining biopsies from pontine glioma [18, 19]. However,

these tests are still expensive, demanding special specimen

collection and storage facilities, and until they become

readily feasible, the reporting (neuro)pathologist has to

deal with small stereotactic biopsies during routine clinical

daily practice, on which depend further management and

disclosure of the prognosis.

Although pilocytic astrocytoma and infiltrative WHO

grade II fibrillary astrocytoma are both low-grade tumors,

they carry different prognoses and natural histories,

necessitating their differentiation [4]. Low-grade fibrillary

astrocytoma might only be one component in an otherwise

heterogeneous infiltrative astrocytoma with additional

high-grade components that were not biopsied. In addition,

progression to high-grade glioma is a well-known phe-

nomenon in grade II fibrillary astrocytoma, but not in pil-

ocytic astrocytoma. While radiotherapy can be offered to

infiltrative tumors, it is usually contraindicated in pilocytic

astrocytomas.

One of the first challenges in segregating pilocytic from

infiltrative astrocytoma is deciding on the growth pattern of

the tumor, i.e., circumscribed versus infiltrative. Although

the presence of entrapped normal-looking neurons should

serve as a clue to the infiltrative nature of the tumor, this

feature can sometimes be misleading. Normal-looking

entrapped neurons can be misinterpreted as an integral

component of the tumor, leading to an erroneous diagnosis

of another WHO grade I circumscribed tumor, i.e.,

Fig. 2 A case of exophytic brain stem glioma. a Sagittal T1W MRI

showing a hyperintense mass at the junction between the mid-brain

and the pons (atypical MRI). b Biopsy shows low cellularity of the

tumor with many Rosenthal fibers and perivascular lymphocytic

infiltration. No evidence of entrapped neurons, mitosis, vascular

proliferation or necrosis (H&E 940). c Neurofilament protein

immunostain highlighting scattered filaments at the edge of the

tumor only (920). d Ki-67 proliferative index is low (\1 %) (920)

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ganglioglioma. Paying attention to the microscopic details

of the neurons should be helpful in this respect [20]. In

ganglioglioma the neurons are dysplastic with bi- and mul-

tinucleated forms, show abnormal membranous aggregation

of Nissel substance and on low-power display abnormal

aggregation, features that all are lacking when innocent

by-standing pre-existing neurons are overrun by the infil-

trative astrocytoma. The infiltrative nature of tumors can be

further supported by the diffuse positive NFP staining

highlighting the pre-existing neuronal fibers. Occasional

NFP-positive fibers can still be seen in biopsies from cir-

cumscribed tumors. However, they are few in number and

widely scattered within the biopsy.

Assigning a grade to the tumor is essential once the

growth pattern and thus tumor group has been determined

[10]. The presence of a single mitotic figure in small

biopsies of infiltrative astrocytoma is sufficient to support

the diagnosis of WHO grade III anaplastic astrocytoma.

Elevated Ki-67 proliferative indices can be used to assist in

guiding the grade of infiltrative astrocytoma, especially

when mitosis or other high-grade features are not detected

in the submitted biopsy [21]. Additionally, the presence of

tumor-cell apoptosis was supportive of infiltrative astro-

cytoma, where their number increased in higher grade

tumors. Tumor cell apoptosis, however, did not correlate

with staining with P53, which was positive in only two

high-grade glioma cases [16]. This is similar to the p53

immunostain frequency reported by Zarghooni et al. [22],

in which a single case only stained for P53. In addition,

P53 was negative in all low-grade tumors and could not

discriminate between low-grade infiltrative and pilocytic

astrocytoma cases in this series. Recently, IDH1 immu-

nostains were negative in cases of BSG as well [23].

Treating DPG has always remained a challenge with

poor overall survival in most studies. Radiotherapy remains

the standard of care [24, 25], offered in the setting of

palliative care. Disclosure of the poor outcome to parents is

encouraged and is well accepted by parents [8]. Chemo-

therapy has not provided relief, and the use of new agents

including temozolomide (TZM) has not been reported to

Fig. 3 a Overall survival for the group of patients. b Survival by duration of symptoms (weeks). c Survival by grade of tumor

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add any survival benefit [26]. Searching for potential

unique targets for treatment is currently under consider-

ation by several research groups. Monje et al. [27]

described a subset of Nestin?, vimentin?, Olig2? neural

precursor-like cells in the developing human ventral pons

that is responsive to the hedgehog signaling pathway, thus

representing a potential therapeutic target. Zarghooni et al.

[22] reported gains in PDFGRA (4 tumors) and PDGFA (2

tumors) representing 50 % of the tumor samples examined,

suggesting that PDGFR inhibitors may potentially be used

as therapeutic agents. Similar results were obtained by

Puget et al. [28] in which oligodendroglial-differentiating,

PDGFRA-driven tumors had worse outcomes than those of

other tested groups of patients, supporting the potential role

of PDGFRA in the tumorigenesis of DPG. Additionally,

PARP-1 overexpression was reported in few patients,

offering a possible explanation for temozolomide and

radiotherapy resistance in DPG [22]. Other identified

genetic abnormalities include epidermal growth factor

variant III (EGFRvIII) [29] and PI3KCA [30], all acting as

a potential source for future targeted therapy.

In conclusion, this study summarizes the experience of a

cancer center on a limited number of cases of BSG that

were biopsied. Duration of symptoms prior to presentation

of \6 weeks and grade of tumor as evaluated on biopsies

were the only parameters with a significant relation to

survival. Paying attention to a few details on the H&E

slides can help in clarifying two important parameters of a

tumor: the circumscribed versus infiltrative growth pattern

and the grade of an infiltrative tumor, both of which have

important implications for management, survival and

prognosis. A limited panel of immunohistochemistry can

be used as an adjunct in equivocal cases. Obtaining biop-

sies from brainstem gliomas should be encouraged to

enhance understanding of the pathogenesis and potentially

to guide treatment through targeted therapy.

Acknowledgments The authors would like to thank Dr. Luna Zaru

and Ms. Dalia Remawi for their help in the statistical analysis and

interpretation.

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