Brain stem gliomas: a clinicopathological study from a single cancer center
Maysa Al-Hussaini, Usama Al-Jumaily, Maisa Swaidan, Awni Musharbash & Sameh Hashem Brain Tumor Pathology ISSN 1433-7398 Brain Tumor Pathol DOI 10.1007/s10014-012-0110-4
1 23
Your article is protected by copyright and all rights are held exclusively by The Japan Society of Brain Tumor Pathology. This eoffprint is for personal use only and shall not be self-archived in electronic repositories. If you wish to self-archive your work, please use the accepted author’s version for posting to your own website or your institution’s repository. You may further deposit the accepted author’s version on a funder’s repository at a funder’s request, provided it is not made publicly available until 12 months after publication.
1 23
Author's personal copy Brain Tumor Pathol DOI 10.1007/s10014-012-0110-4
ORIGINAL ARTICLE
Brain stem gliomas: a clinicopathological study from a single cancer center Maysa Al-Hussaini • Usama Al-Jumaily Maisa Swaidan • Awni Musharbash • Sameh Hashem
•
Received: 12 March 2012 / Accepted: 11 June 2012 Ó 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 diagnosis 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
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, King Hussein Cancer Center (KHCC), Amman, Jordan A. Musharbash Department of Surgery, King Hussein Cancer Center (KHCC), Amman, Jordan S. Hashem Department of Radiation Oncology, King Hussein Cancer Center (KHCC), Amman, Jordan
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 radiological 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 classification correlates well with the tumor histological type and grade [4, 5]. Fibrillary infiltrative astrocytoma represents the majority of DPGs, where high grade gliomas of anaplastic 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,
123
Author's personal copy Brain Tumor Pathol
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 followup 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 grading of tumors. Cutoff values to separate low- from highgrade 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 highgrade brain tumors, especially secondary glioblastoma, medulloblastoma with anaplasia and anaplastic meningioma. In addition, it is used to differentiate pilocytic from low-grade infiltrative fibrillary astrocytoma, being consistently negative in the former. We aim at describing our experience with cases of BSG in which pre-treatment biopsies were obtained. The clinical, radiological and pathological findings are described. The value of adding a limited panel of immunohistochemical 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),
123
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 clinical 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. Radiological 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 considered 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 chemotherapy 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 calculated. 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 eosinophilic granular bodies (EGBs) were assessed on a two-tier scale (present vs. absent). The presence of entrapped normal-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 glomeruloid 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, neurofilament 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 evaluated semi-quantitatively. The tumors were considered infiltrative only if neurofilament protein was diffusely
Author's personal copy Brain Tumor Pathol
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 statistics including the mean, median, and SD were calculated. 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 symptoms 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). Entrapped 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 astrocytomas, but not in pilocytic astrocytoma cases. Microvascular 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 pathological 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. Figures 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
123
Author's personal copy Brain Tumor Pathol 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
Cervicomedullary
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 14
F F
67 83.6
NA 3
Pons Pons
Typical Typical
Bx Bx*
GBM GBM
No 54
No No
Dead Dead
1 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, VCR vincristine a This was mentioned only in the referral notes. MRIs were not available for review b
Owing to the young age of the patient and long history of stable disease (9 months), chemotherapy was administered
c
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)
1
PA
1
2
–
0
2
PA
2
1
–
0
3
PA
1
1
–
4
FA
2
2
5
FA
2
6
AA
7 8
AA AA
Apoptosis (hpf)
VP
Necrosis
RF
EGBs
NFP
Ki67 (%)
p53
0
?
–
?
–
Occasional
1
–
1
?
–
?
–
Occasional
8
–
0
0
?
–
?
–
Negative
4
–
?
0
10
–
–
–
–
Occasional
2
–
1
?
0
3
–
–
–
–
Positive
1
–
2
1
?
0
4
–
–
–
–
NA
10
NA
2 3
1 3
? ?
1 1
0 1
– –
– –
– –
– –
Positive Positive
20 20
NA ?
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 highpower field, NFP neurofilament protein, PA pilocytic astrocytoma, Pleomo pleomorphism, RF Rosenthal fibers
123
Author's personal copy Brain Tumor Pathol
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 lowgrade infiltrative astrocytoma showing no evidence of mitosis,
vascular proliferation or necrosis. The entrapped neurons appear normal (H&E 940). c Neurofilament protein immunostain highlighting the infiltrative nature of the tumor cells (920). d Ki-67 proliferative index is low (1.2 %) (920)
(Figs. 1d, 2d) from two low grade astrocytoma cases, infiltrative WHO grade II fibrillary astrocytoma and pilocytic 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 findings (typical vs. atypical; p = 0.03). NFP correlated significantly 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 highgrade 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 survival 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, pathological 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
123
Author's personal copy Brain Tumor Pathol
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)
large in concordance with international literature apart from the marked predominance of female patients, a previously 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 phenomenon in grade II fibrillary astrocytoma, but not in pilocytic 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.,
123
Author's personal copy Brain Tumor Pathol
Fig. 3 a Overall survival for the group of patients. b Survival by duration of symptoms (weeks). c Survival by grade of tumor
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 multinucleated 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 infiltrative 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 circumscribed 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 astrocytoma, 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 immunostains 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]. Chemotherapy has not provided relief, and the use of new agents including temozolomide (TZM) has not been reported to
123
Author's personal copy Brain Tumor Pathol
add any survival benefit [26]. Searching for potential unique targets for treatment is currently under consideration 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 biopsies 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.
References 1. Jallo GI, Biser-Rohrbaugh A, Freed D (2004) Brainstem gliomas. Childs Nerv Syst 20:143–153 2. Epstein F (1985) A staging system for brain stem gliomas. Cancer 56:1804–1806 3. Broniscer A, Gajjar A (2004) Supratentorial high-grade astrocytoma and diffuse brainstem glioma: two challenges for the pediatric oncologist. Oncologist 9:197–206 4. Fisher PG, Breiter SN, Carson BS, Wharam MD, Williams JA, Weingart JD, Foer DR, Goldthwaite PT, Tihan T, Burger PC (2000) A clinicopathologic reappraisal of brain stem tumor classification. Identification of pilocystic astrocytoma and fibrillary astrocytoma as distinct entities. Cancer 89:1569–1576
123
5. Combs SE, Steck I, Schulz-Ertner D, Welzel T, Kulozik AE, Behnisch W, Huber PE, Debus J (2009) Long-term outcome of high-precision radiotherapy in patients with brain stem gliomas: results from a difficult-to-treat patient population using fractionated stereotactic radiotherapy. Radiother Oncol 91:60–66 6. Kwon JW, Kim IO, Cheon JE, Kim WS, Moon SG, Kim TJ, Chi JG, Wang KC, Chung JK, Yeon KM (2006) Paediatric brain-stem gliomas: MRI, FDG-PET and histological grading correlation. Pediatr Radiol 36:959–964 7. Hargrave D, Bartels U, Bouffet E (2006) Diffuse brainstem glioma in children: critical review of clinical trials. Lancet Oncol 7:241–248 8. Qaddoumi I, Ezam N, Swaidan M, Jaradat I, Mansour A, Abuirmeileh N, Bouffet E, Al-Hussaini M (2009) Diffuse pontine glioma in jordan and impact of up-front prognosis disclosure with parents and families. J Child Neurol 24:460–465 9. Recinos PF, Sciubba DM, Jallo GI (2007) Brainstem tumors: where are we today? Pediatr Neurosurg 43:192–201 10. Albright AL, Price RA, Guthkelch AN (1983) Brain stem gliomas of children. A clinicopathological study. Cancer 52:2313–2319 11. Cohen KJ, Heideman RL, Zhou T, Holmes EJ, Lavey RS, Bouffet E, Pollack IF (2011) Temozolomide in the treatment of children with newly diagnosed diffuse intrinsic pontine gliomas: a report from the children’s oncology group. Neuro Oncol 13:410–416 12. Broniscer A, Laningham FH, Sanders RP, Kun LE, Ellison DW, Gajjar A (2008) Young age may predict a better outcome for children with diffuse pontine glioma. Cancer 113:566–572 13. Cartmill M, Punt J (1999) Diffuse brain stem glioma. A review of stereotactic biopsies. Childs Nerv Syst 15:235–238 14. Khatua S, Moore KR, Vats TS, Kestle JR (2011) Diffuse intrinsic pontine glioma-current status and future strategies. Childs Nerv Syst 27:1391–1397 15. Takei H, Bhattacharjee MB, Rivera A, Dancer Y, Powell SZ (2007) New immunohistochemical markers in the evaluation of central nervous system tumors: a review of 7 selected adult and pediatric brain tumors. Arch Pathol Lab Med 131:234–241 16. Dunbar E, Yachnis AT (2010) Glioma diagnosis: immunohistochemistry and beyond. Adv Anat Pathol 17:187–201 17. Mauffrey C (2006) Paediatric brainstem gliomas. Prognostic factors and management. J Clin Neurosci 13:431–437 18. Jansen MH, van Vuurden DG, Vandertop WP, Kaspers GJ (2012) Diffuse intrinsic pontine gliomas: a systematic update on clinical trials and biology. Cancer Treat Rev 38:27–35 19. MacDonald TJ (2012) Diffuse intrinsic pontine glioma (DIPG): time to biopsy again? Pediatr Blood Cancer 58:487–488 20. Becker AJ, Wiestler OD, Figarella-Branger D, Blumcke I (2007) Ganglioglioma and gangliocytoma. In: Louis DN, Ohgaki H, Wiestler OD, Cavenee WK (eds) WHO classification of tumours of the central nervous system. International Agency for Research on Cancer, Lyon, pp 103–105 21. Yoshimura J, Onda K, Tanaka R, Takahashi H (2003) Clinicopathological study of diffuse type brainstem gliomas: analysis of 40 autopsy cases. Neurol Med Chir (Tokyo) 43:375–382 22. Zarghooni M, Bartels U, Lee E, Buczkowicz P, Morrison A, Huang A, Bouffet E, Hawkins C (2010) Whole-genome profiling of pediatric diffuse intrinsic pontine gliomas highlights plateletderived growth factor receptor alpha and poly (ADP-ribose) polymerase as potential therapeutic targets. J Clin Oncol 28:1337–1344 23. Oka H, Utsuki S, Tanizaki Y, Hagiwara H, Miyajima Y, Sato K, Kusumi M, Kijima C, Fujii K (2012) Clinicopathological features of human brainstem gliomas. Brain Tumor Pathol [Epub ahead of print] 24. Freeman CR, Bourgouin PM, Sanford RA, Cohen ME, Friedman HS, Kun LE (1996) Long term survivors of childhood brain stem gliomas treated with hyperfractionated radiotherapy. Clinical
Author's personal copy Brain Tumor Pathol characteristics and treatment related toxicities. The Pediatric Oncology Group. Cancer 77:555–562 25. Negretti L, Bouchireb K, Levy-Piedbois C, Habrand JL, Dhermain F, Kalifa C, Grill J, Dufour C (2011) Hypofractionated radiotherapy in the treatment of diffuse intrinsic pontine glioma in children: a single institution’s experience. J Neurooncol 104:773–777 26. Chassot A, Canale S, Varlet P, Puget S, Roujeau T, Negretti L, Dhermain F, Rialland X, Raquin MA, Grill J, Dufour C (2012) Radiotherapy with concurrent and adjuvant temozolomide in children with newly diagnosed diffuse intrinsic pontine glioma. J Neurooncol 106:399–407 27. Monje M, Mitra SS, Freret ME, Raveh TB, Kim J, Masek M, Attema JL, Li G, Haddix T, Edwards MS, Fisher PG, Weissman IL, Rowitch DH, Vogel H, Wong AJ, Beachy PA (2011) Hedgehog-responsive candidate cell of origin for diffuse intrinsic pontine glioma. Proc Natl Acad Sci USA 108:4453–4458
28. Puget S, Philippe C, Bax DA, Job B, Varlet P, Junier MP, Andreiuolo F, Carvalho D, Reis R, Guerrini-Rousseau L, Roujeau T, Dessen P, Richon C, Lazar V, Le Teuff G, Sainte-Rose C, Geoerger B, Vassal G, Jones C, Grill J (2012) Mesenchymal transition and PDGFRA amplification/mutation are key distinct oncogenic events in pediatric diffuse intrinsic pontine gliomas. PLoS One 7:e30313 29. Li G, Mitra SS, Monje M, Henrich KN, Bangs CD, Nitta RT, Wong AJ (2012) Expression of epidermal growth factor variant III (EGFRvIII) in pediatric diffuse intrinsic pontine gliomas. J Neurooncol 108:395–402 30. Grill J, Puget S, Andreiuolo F, Philippe C, MacConaill L, Kieran MW (2012) Critical oncogenic mutations in newly diagnosed pediatric diffuse intrinsic pontine glioma. Pediatr Blood Cancer 58:489–491
123