- Email: [email protected]
Clinical features and post-surgical outcome of patients with astroblastoma
Journal of Clinical Neuroscience 18 (2011) 750–754
Contents lists available at ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Review
Clinical features and post-surgical outcome of patients with astroblastoma Michael E. Sughrue , Jay Choi , Martin J. Rutkowski, Derick Aranda, Ari J. Kane, Igor J. Barani, Andrew T. Parsa ⇑ Department of Neurological Surgery, University of California, San Francisco, 505 Parnassus Avenue, California 94117, USA
a r t i c l e
i n f o
Article history: Received 28 September 2010 Accepted 2 November 2010
Keywords: Astroblastoma Surgery Gross total resection Radiotherapy Tumor control
a b s t r a c t Astroblastoma is a rare tumor, and thus experience with these lesions is very limited. The prognosis and appropriate treatment is not well understood, as few individual centers have enough experience with astroblastoma to guide treatment recommendations. We performed a systematic comprehensive search of the published English language literature on patients undergoing surgery for astroblastoma to summarize what is known about these tumors, and to provide some framework for future efforts in this area. A total of 62 references met our inclusion criteria, and contained individual patient data on 116 patients with astroblastoma. Determination of overall survival rates was performed using Kaplan–Meier analysis. This analysis suggests that the distribution is bimodal, with a prominent peak in young adulthood. Astroblastomas are generally amenable to complete tumor resection, even when very large, with gross total resection (GTR) achieved in 71/85 (84%) of reported patients, including both 9 cm tumors reported. Patients undergoing GTR experienced a significant improvement in survival compared to patients who underwent subtotal resection (STR) (5-year progression-free survival: GTR 83% versus [vs.] STR 55%, log rank p = 0.011). Although patients receiving external beam radiotherapy or fractionated threedimensional conformal radiotherapy (XRT) seemed to have lower survival rates, this was not statistically significant (5-year survival: GTR 94% vs. GTR + XRT 73%, log rank p = 0.463). Thus, we have reported the results of a summary of the literature on astroblastomas and have accurately described outcome characteristics using a data set that would be difficult to accumulate at a single center treating this tumor. Ó 2010 Published by Elsevier Ltd.
1. Introduction While the concept of the astroblastoma has been with us since the work of Bailey in the early 20th century, due to the exceeding rarity of this tumor, little is known about its biologic behavior, its prognosis, and the appropriate course of treatment.1 It is generally considered a pediatric tumor, and has been estimated to represent between 0.48% and 2.8% of all pediatric brain tumors.1 There are few sources from which to gain significant insight about the clinical behavior of these tumors, and there is no consensus regarding the best treatment goals for patients with astroblastoma. Management approaches described in the literature include surgery with a goal of gross total resection (GTR) when possible,2 subtotal resection (STR) alone, with or without radiotherapy3 and/or chemotherapy.3,4 Given the lack of detailed knowledge of the potential benefit of aggressive surgical resection, the risk-to-benefit ratio of these efforts is unclear. In an attempt to provide a comprehensive reference on astroblastoma, we systematically reviewed the published literature to ⇑ Corresponding author. Tel.: +1 415 353 9308.
E-mail address: [email protected] (A.T. Parsa). These two authors contributed equally to this article.
0967-5868/$ - see front matter Ó 2010 Published by Elsevier Ltd. doi:10.1016/j.jocn.2010.11.007
summarize what is known about the presentation and clinical course of patients with astroblastoma. Where possible, we make statistical determinations regarding the efficacy of various treatment approaches using the existing body of published individual patient data found in these reports. 2. Materials and methods 2.1. Article selection A comprehensive systematic review of the literature was conducted on tumor control and progression-free survival after treatment of astroblastoma, pooling data from the existing English language literature. Articles were identified via a Pubmed search with key words ‘‘astroblastoma’’ alone and in combination with ‘‘treatment,’’ ‘‘mortality,’’ and ‘‘morbidity.’’ After reviewing these articles, a thorough review of all referenced sources was also performed. All references that contained disaggregated data specifically addressing clinical behavior with adequate follow up in patients who had undergone surgery (biopsy or resection) of histologically confirmed astroblastoma were included in our analysis. Any paper that did not provide some follow-up data on these patients with
M.E. Sughrue et al. / Journal of Clinical Neuroscience 18 (2011) 750–754
imaging was excluded from survival comparisons, as these would not facilitate Kaplan–Meier analysis.
2.2. Data extraction We extracted all data presented in all manuscripts, which were entered into a database and cross-checked for accuracy. Because not all studies published all types of data, often the relevant analysis was performed on a subset of the whole cohort. Overall survival was determined from survival curves at the 5-year time points. Studies that did not present patient data in a way that variables could be reliably determined were excluded from survival analysis.
2.3. Statistical analysis Survival analysis was performed using Kaplan–Meier analysis with between-group differences being determined by the logrank test. Statistically significant between-group differences were subsequently analyzed using Cox regression analysis in which the covariates – the use of adjuvant radiotherapy, and histological tumor grade, which we hypothesized might be potential confounders – were forced into the regression model to ensure that the apparent between-group differences were not falsely created by confounding variables. Cox regression analysis of between-group survival comparisons were performed using Kendall’s tau.5 We also tested interaction terms between each of the variables. The statistical significance of the interactions was assessed with the use of backward conditional stepwise regression, in which statistical significance was estimated by means of the likelihood-ratio test to assess the effect of removing interaction terms for all strata of the given variable.6 After finding that none of the interaction terms would significantly (unadjusted p > 0.2 for all terms) alter the log likelihood of the regression model if removed, we calculated the adjusted hazard ratios (HR) (without adjusting for interactions). Pearson’s chi-squared (v2) test was used to analyze for differences in pre-operative categorical factors. Fisher’s exact test was used if there were fewer than five values per group. Analysis of variance (ANOVA) was used to evaluate for statistical differences in pre-operative continuous factors, including age. Kaplan–Meier estimates were used to generate time-to-progression curves. Differences in time to progression were analyzed by the log-rank test. Analyses were carried out using Statistical Package for the Social Sciences version 16.0 (SPSS, Chicago, IL, USA).
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3.2. Clinical presentation of astroblastoma While astroblastoma has typically been considered by many to be a pediatric brain tumor, an analysis of published reports suggests that the distribution is bimodal, with a prominent peak in young adulthood (Fig. 1). Of the 100 patients for which patient gender was clearly stated, there seemed to be a clear female predominance (70 females, 30 males) and this relationship seemed to persist in all age groups. Although tumor dimensions were inconsistently presented (detailed information was provided for only 20 patients), the available data suggest that astroblastomas can grow quite large prior to diagnosis. In 16/20 patients (80%) the largest diameter of the astroblastoma at the time of diagnosis was >3 cm; in 10/20 (50%) the largest diameter was >5 cm, and in 2/20 (10%), the largest diameter was >9 cm. Based on the data presented for 95 patients, astroblastoma location is overwhelmingly supratentorial (87 supratentorial, eight infratentorial) (Table 1). Although astroblastoma can occur in the brainstem (three patients), cerebellum (one patient), and intraventricularly (six patients), most patients present with a cerebral mass (85 patients), with a frontal lobe predominance (frontal 38 patients, parietal 22, temporal 16, and occipital four) (Table 1). Presenting symptoms were provided for 52 patients, and the symptom occurrence is summarized in Table 2. Many patients presented with non-localizing features suggestive of elevated intracranial pressure, such as headache (31 patients) and nausea/ vomiting (15 patients). Focal neurologic deficits occurred in 18 of 52 patients. There was one report of a preoperative hemorrhage into an astroblastoma.
3.3. Surgical resectability and post-surgical prognosis of astroblastoma patients Based on the data from 85 patients that included the extent of resection, astroblastomas are generally amenable to complete tumor resection, even when very large. Gross total resection (GTR) was achieved in 71/85 patients (84%), which included both of the 9-cm tumors. Survival analysis suggested that patients who underwent GTR had a significant improvement in survival compared to those receiving a subtotal resection (STR) (5-year survival: GTR 83% versus [vs.] STR 55%, log rank p = 0.011) (Fig. 2).
3. Results 3.1. Clinical characteristics of included patients The literature search yielded a total of 62 references that met our inclusion criteria,1–4,7–64 and contained individual patient data on 116 patients with astroblastoma. These reports were published from 1975 to 2009, and included eight case series of varying sizes (2, 2, 3, 6, 7, 8, 13, and 20 patients respectively), as well as 54 case reports (48/62 reports were published after 1990). Due to the small number of multiple patient series, comparison of interinstitutional variability, and statistical correction for the effects of this source heterogeneity, was not possible. The length of post-operative follow-up was stated for 76 patients in these studies and ranged from 3 months to 244 months (median, 24 months). All survival data were provided in reports since 1990.
Fig. 1. Bar graphs depicting the patient age at time of diagnosis for all reported patients with astroblastoma showing a bimodal distribution, with a prominent peak in young adulthood.
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M.E. Sughrue et al. / Journal of Clinical Neuroscience 18 (2011) 750–754
Table 1 Tumor location in published reports of patients with astroblastoma Supratentorial Infratentorial
87 8
Frontal Parietal Temporal Occipital Brainstem/cerebellum Intraventricular
38 22 16 4 5 6
Table 2 Presenting symptoms in published reports of 52 patients with astroblastoma Headache Focal deficits Nausea/vomiting Non-specified visual disturbance Seizure Hemorrhage Altered mental status
31 18 15 13 11 1 1
Fig. 3. Comparison of progression-free survival between patients treated with gross total resection (GTR) versus GTR plus external beam radiotherapy or fractionated three-dimensional conformal radiotherapy, XRT) (GTR + XRT) showing no significant difference in survival rates between the groups (log-rank p = 0.463; NS = not significant).
94% vs. GTR + XRT 73%, log rank p = 0.463) (Fig. 3). We identified only two patients who received STR without radiation; thus, this was not a meaningful subgroup comparison for the effect of XTR.
4. Discussion
Fig. 2. Comparison of progression-free survival between patients treated with gross total resection (GTR) compared to subtotal resection (STR) and post-operative radiotherapy showing significant difference in survival rates between the groups (log-rank p = 0.011).
To address the possibility that between-group differences in histologic grades in the use of adjuvant radiotherapy might be artificially creating the appearance of a survival benefit, we performed a Cox regression analysis, which demonstrated a significant survival benefit for patients who underwent GTR compared to STR, even after controlling for stated histologic tumor grade (HR for GTR = 0.25, 95% confidence interval = 0.07–0.86, p = 0.028). 3.4. Does the use of adjuvant radiation improve survival in patients with astroblastoma? Our analysis of the published data identified survival statistics for 36 patients who received adjuvant focal radiation (either external beam radiotherapy or fractionated three-dimensional conformal radiotherapy) (XRT), and 23 patients who did not. Although patients who received XRT seemed to experienced worse survival rates, this was not statistically significant (5-year survival: GTR
Astroblastoma is a rare central nervous system (CNS) lesion about which little is known to guide clinical management. In this study, we systematically reviewed the published literature in English on astroblastoma in an attempt to better understand expected outcomes after surgery for astroblastoma, with or without postoperative radiotherapy. Our principle goal was to identify features of these tumors not described thoroughly by isolated case reports (the predominant source of information in the published literature). According to the latest World Health Organization (WHO) classification of CNS tumors,65 astroblastoma is considered a high grade glial neoplasm. However, an analysis of the published data does not support this premise as we found 5-year survival rates for patients receiving GTR at around 95%, with reports of survival exceeding 10 and even 20 years. Furthermore, these tumors often can grow to a large size prior to causing symptoms that prompt a diagnostic imaging study. In our experience, we have seen very few patients with WHO grade III or IV brain tumors reach such a large size without causing death, or serious symptoms far sooner. Together, we feel these observations support the view that astroblastoma is a low grade glial neoplasm, and should be reclassified as such.29 Another aim of this study was to characterize the clinical presentation and behavior of astroblastoma, which is not well understood. We found that astroblastoma is overwhelmingly a supratentorial, intracerebral tumor, which can be intraventricular, and that it is rare in the occipital lobes and posterior fossa. Symptoms are non-specific and related to elevated intracranial pressure, with focal deficits occurring less commonly. Additionally, we found that while astroblastoma is generally considered a pediatric brain tumor, the incidence of this tumor is bimodal with many young adult patients. The appropriate management of these tumors is not clear, as there is no Class 1 or 2 data. Based on what is known, GTR alone provides excellent tumor control rates, and STR should be avoided,
M.E. Sughrue et al. / Journal of Clinical Neuroscience 18 (2011) 750–754
if possible. Furthermore, the addition of adjuvant focal radiotherapy after STR does not appear to provide equivalent outcomes to GTR. There are few data as to whether functional white matter tracts are displaced by these lesions, or whether these tumors are infiltrative, and have tracts running through them. Astroblastomas are usually not histologically infiltrative lesions,39 but until this is better elaborated upon, given the importance of GTR, we would recommend the use of intraoperative mapping in these instances, including subcortical motor mapping, if functional brain is potentially involved. Adjuvant external beam radiotherapy has been tried for astroblastoma with variable results. While the data are not definitive, we cannot recommend empirically administering radiotherapy after the first operation for patients with astroblastoma who have undergone GTR, given the lack of evidence supporting the efficacy of this approach, and the good results obtained with GTR alone. Where patients have undergone STR, adjuvant radiotherapy has been administered to most patients, but lacking a control group, it is impossible to assess whether this approach truly benefits these patients. 4.1. Study limitations It is impossible for us to control for the quality of the data reported in the literature and an overly stringent definition of ‘‘tumor recurrence’’ in some studies may contribute to variability in rates of tumor control. Furthermore, subjectively defined variables, such as histologic grade, extent of resection, and the adequacy of radiation therapy likely vary between studies, and we cannot independently confirm the validity of these definitions in other groups’ publications. Also, as the astroblastoma literature largely consists of case reports, it is impossible to use statistical meta-analysis methods to assess the effects of between-center heterogeneity on patient outcomes, and to control for this heterogeneity.
5. Conclusion We report the results of a summary of the published literature in English on tumor control rates of astroblastoma after treatment with various modalities. Given the relatively rarity of this tumor, this study aims to accurately describe outcome characteristics using a data set that would be difficult to accumulate at a single center treating this tumor. References 1. Navarro R, Reitman AJ, de Leon GA, et al. Astroblastoma in childhood: pathological and clinical analysis. Childs Nerv Syst 2005;21:211–20. 2. Alaraj A, Chan M, Oh S, et al. Astroblastoma presenting with intracerebral hemorrhage misdiagnosed as dural arteriovenous fistula: review of a rare entity. Surg Neurol 2007;67:308–13. 3. Bonnin JM, Rubinstein LJ. Astroblastomas: a pathological study of 23 tumors, with a postoperative follow-up in 13 patients. Neurosurgery 1989;25:6–13. 4. Salvati M, D’Elia A, Brogna C, et al. Cerebral astroblastoma: analysis of six cases and critical review of treatment options. J Neurooncol 2009;93:369–78. 5. Zethelius B, Berglund L, Sundstrom J, et al. Use of multiple biomarkers to improve the prediction of death from cardiovascular causes. N Engl J Med 2008;358:2107–16. 6. Hosmer DW, Lemeshow S. Applied logistic regression. 2nd ed. New York: John Wiley; 2000. 7. Baka JJ, Patel SC, Roebuck JR, et al. Predominantly extraaxial astroblastoma: imaging and proton MR spectroscopy features. AJNR Am J Neuroradiol 1993;14: 946–50. 8. Bannykh SI, Fan X, Black KL. Malignant astroblastoma with rhabdoid morphology. J Neurooncol 2007;83:277–8. 9. Bell JW, Osborn AG, Salzman KL, et al. Neuroradiologic characteristics of astroblastoma. Neuroradiology 2007;49:203–9. 10. Berger MS. The impact of technical adjuncts in the surgical management of cerebral hemispheric low-grade gliomas of childhood. J Neurooncol 1996;28: 129–55.
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11. Black PM, Alexander 3rd E, Martin C, et al. Craniotomy for tumor treatment in an intraoperative magnetic resonance imaging unit. Neurosurgery 1999;45: 423–31 [discussion 31–3]. 12. Brat DJ, Hirose Y, Cohen KJ, et al. Astroblastoma: clinicopathologic features and chromosomal abnormalities defined by comparative genomic hybridization. Brain Pathol 2000;10:342–52. 13. Cabello A, Madero S, Castresana A, et al. Astroblastoma: electron microscopy and immunohistochemical findings: case report. Surg Neurol 1991;35:116–21. 14. Caroli E, Salvati M, Esposito V, et al. Cerebral astroblastoma. Acta Neurochir (Wien) 2004;146:629–33. 15. Christensen JC. Exposure time and frequency of irradiation in brain tumours. Neurol Res 1987;9:202–4. 16. De Reuck J, Van de Velde E, vander Eecken H. The angioarchitecture of the astroblastoma. Clin Neurol Neurosurg 1975;78:89–98. 17. Denaro L, Gardiman M, Calderone M, et al. Intraventricular astroblastoma. Case report. J Neurosurg Pediatr 2008;1:152–5. 18. 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Astroblastoma: report of a case with ultrastructural, cell kinetic, and cytogenetic analysis. Pediatr Pathol 1993;13:323–32. 31. Kaji M, Takeshima H, Nakazato Y, et al. Low-grade astroblastoma recurring with extensive invasion. Neurol Med Chir (Tokyo) 2006;46:450–4. 32. Kantar M, Ertan Y, Turhan T, et al. Anaplastic astroblastoma of childhood: aggressive behavior. Childs Nerv Syst 2009;25:1125–9. 33. Kemerdere R, Dashti R, Ulu MO, et al. Supratentorial high grade astroblastoma: report of two cases and review of the literature. Turk Neurosurg 2009;19: 149–52. 34. Kim BS, Kothbauer K, Jallo G. Brainstem astroblastoma. Pediatr Neurosurg 2004;40:145–6. 35. Kim DS, Park SY, Lee SP. Astroblastoma: a case report. J Korean Med Sci 2004;19: 772–6. 36. Kubota T, Hirano A, Sato K, et al. The fine structure of astroblastoma. Cancer 1985;55:745–50. 37. Kubota T, Sato K, Arishima H, et al. Astroblastoma: immunohistochemical and ultrastructural study of distinctive epithelial and probable tanycytic differentiation. Neuropathology 2006;26:72–81. 38. Lau PP, Thomas TM, Lui PC, et al. ‘‘Low-grade’’ astroblastoma with rapid recurrence: a case report. Pathology 2006;38:78–80. 39. Lehman NL. Central nervous system tumors with ependymal features: a broadened spectrum of primarily ependymal differentiation? J Neuropathol Exp Neurol 2008;67:177–88. 40. Mangano FT, Bradford AC, Mittler MA, et al. Astroblastoma. Case report, review of the literature, and analysis of treatment strategies. J Neurosurg Sci 2007; 51:21–7. 41. Mierau GW, Tyson RW, McGavran L, et al. Astroblastoma: ultrastructural observations on a case of high-grade type. Ultrastruct Pathol 1999;23:325–32. 42. Miranda P, Lobato RD, Cabello A, et al. Complete surgical resection of highgrade astroblastoma with long time survival: case report and review of the literature. Neurocirugia (Astur) 2006;17:60–3. 43. Moritani S, Kushima R, Bamba M, et al. Highly anaplastic extraventricular ependymoma arising in an adult, mimicking metastatic adenocarcinoma with heavy stromal inflammation and emperiporesis. Pathol Int 2003;53:539–46. 44. Moulignier A, Mikol J, Pialoux G, et al. Cerebral glial tumors and human immunodeficiency virus-1 infection. More than a coincidental association. Cancer 1994;74:686–92. 45. Notarianni C, Akin M, Fowler M, et al. Brainstem astroblastoma: a case report and review of the literature. Surg Neurol 2008;69:201–5.
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46. Ortega-Aznar A, Romero-Vidal FJ, de la Torre J, et al. Neonatal tumors of the CNS: a report of 9 cases and a review. Clin Neuropathol 2001;20:181–9. 47. Pizer BL, Moss T, Oakhill A, et al. Congenital astroblastoma: an immunohistochemical study. Case report. J Neurosurg 1995;83:550–5. 48. Port JD, Brat DJ, Burger PC, et al. Astroblastoma: radiologic-pathologic correlation and distinction from ependymoma. AJNR Am J Neuroradiol 2002;23:243–7. 49. Ransom DT, Ritland SR, Moertel CA, et al. Correlation of cytogenetic analysis and loss of heterozygosity studies in human diffuse astrocytomas and mixed oligo-astrocytomas. Genes Chromosomes Cancer 1992;5:357–74. 50. Rubinstein LJ, Herman MM. The astroblastoma and its possible cytogenic relationship to the tanycyte. An electron microscopic, immunohistochemical, tissue- and organ-culture study. Acta Neuropathol 1989;78:472–83. 51. Sageshima M, Masuda H, Kawamura K, et al. Immature cerebellar astrocytoma in an infant. Acta Pathol Jpn 1987;37:1513–20. 52. Sener RN. Astroblastoma: diffusion MRI, and proton MR spectroscopy. Comput Med Imaging Graph 2002;26:187–91. 53. Shuangshoti S, Kasantikul V, Suwanwela N, et al. Solitary primary intracranial extracerebral glioma. Case report. J Neurosurg 1984;61:777–81. 54. Shuangshoti S, Mitphraphan W, Kanvisetsri S, et al. Astroblastoma: report of a case with microsatellite analysis. Neuropathology 2000;20:228–32. 55. Steinberg GK, Shuer LM, Conley FK, et al. Evolution and outcome in malignant astroglial neoplasms of the cerebellum. J Neurosurg 1985;62:9–17.
56. Sugita Y, Terasaki M, Shigemori M, et al. Astroblastoma with unusual signetring-like cell components: a case report and literature review. Neuropathology 2002;22:200–5. 57. Thiessen B, Finlay J, Kulkarni R, et al. Astroblastoma: does histology predict biologic behavior? J Neurooncol 1998;40:59–65. 58. Tsuchida T, Kamata K, Kawamata M, et al. Brain tumors in tuberous sclerosis. Report of 4 cases. Childs Brain 1981;8:271–83. 59. Tumialan LM, Brat DJ, Fountain AJ, et al. An astroblastoma mimicking a cavernous malformation: case report. Neurosurgery 2007;60:E569–70. 60. Unal E, Koksal Y, Vajtai I, et al. Astroblastoma in a child. Childs Nerv Syst 2008;24:165–8. 61. Velasco ME, Dahl D, Roessmann U, et al. Immunohistochemical localization of glial fibrillary acidic protein in human glial neoplasms. Cancer 1980;45:484–94. 62. Whittle IR, Viswanathan R. Acute intraoperative brain herniation during elective neurosurgery: pathophysiology and management considerations. J Neurol Neurosurg Psychiatry 1996;61:584–90. 63. Yamashita J, Handa H, Yamagami T, et al. Astroblastoma of pure type. Surg Neurol 1985;24:218–22. 64. Yunten N, Ersahin Y, Demirtas E, et al. Cerebral astroblastoma resembling an extra-axial neoplasm. J Neuroradiol 1996;23:38–40. 65. Fuller GN, Scheithauer BW. The 2007 revised World Health Organization (WHO) classification of tumours of the central nervous system: newly codified entities. Brain Pathol 2007;17:304–7.
Contents lists available at ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Review
Clinical features and post-surgical outcome of patients with astroblastoma Michael E. Sughrue , Jay Choi , Martin J. Rutkowski, Derick Aranda, Ari J. Kane, Igor J. Barani, Andrew T. Parsa ⇑ Department of Neurological Surgery, University of California, San Francisco, 505 Parnassus Avenue, California 94117, USA
a r t i c l e
i n f o
Article history: Received 28 September 2010 Accepted 2 November 2010
Keywords: Astroblastoma Surgery Gross total resection Radiotherapy Tumor control
a b s t r a c t Astroblastoma is a rare tumor, and thus experience with these lesions is very limited. The prognosis and appropriate treatment is not well understood, as few individual centers have enough experience with astroblastoma to guide treatment recommendations. We performed a systematic comprehensive search of the published English language literature on patients undergoing surgery for astroblastoma to summarize what is known about these tumors, and to provide some framework for future efforts in this area. A total of 62 references met our inclusion criteria, and contained individual patient data on 116 patients with astroblastoma. Determination of overall survival rates was performed using Kaplan–Meier analysis. This analysis suggests that the distribution is bimodal, with a prominent peak in young adulthood. Astroblastomas are generally amenable to complete tumor resection, even when very large, with gross total resection (GTR) achieved in 71/85 (84%) of reported patients, including both 9 cm tumors reported. Patients undergoing GTR experienced a significant improvement in survival compared to patients who underwent subtotal resection (STR) (5-year progression-free survival: GTR 83% versus [vs.] STR 55%, log rank p = 0.011). Although patients receiving external beam radiotherapy or fractionated threedimensional conformal radiotherapy (XRT) seemed to have lower survival rates, this was not statistically significant (5-year survival: GTR 94% vs. GTR + XRT 73%, log rank p = 0.463). Thus, we have reported the results of a summary of the literature on astroblastomas and have accurately described outcome characteristics using a data set that would be difficult to accumulate at a single center treating this tumor. Ó 2010 Published by Elsevier Ltd.
1. Introduction While the concept of the astroblastoma has been with us since the work of Bailey in the early 20th century, due to the exceeding rarity of this tumor, little is known about its biologic behavior, its prognosis, and the appropriate course of treatment.1 It is generally considered a pediatric tumor, and has been estimated to represent between 0.48% and 2.8% of all pediatric brain tumors.1 There are few sources from which to gain significant insight about the clinical behavior of these tumors, and there is no consensus regarding the best treatment goals for patients with astroblastoma. Management approaches described in the literature include surgery with a goal of gross total resection (GTR) when possible,2 subtotal resection (STR) alone, with or without radiotherapy3 and/or chemotherapy.3,4 Given the lack of detailed knowledge of the potential benefit of aggressive surgical resection, the risk-to-benefit ratio of these efforts is unclear. In an attempt to provide a comprehensive reference on astroblastoma, we systematically reviewed the published literature to ⇑ Corresponding author. Tel.: +1 415 353 9308.
E-mail address: [email protected] (A.T. Parsa). These two authors contributed equally to this article.
0967-5868/$ - see front matter Ó 2010 Published by Elsevier Ltd. doi:10.1016/j.jocn.2010.11.007
summarize what is known about the presentation and clinical course of patients with astroblastoma. Where possible, we make statistical determinations regarding the efficacy of various treatment approaches using the existing body of published individual patient data found in these reports. 2. Materials and methods 2.1. Article selection A comprehensive systematic review of the literature was conducted on tumor control and progression-free survival after treatment of astroblastoma, pooling data from the existing English language literature. Articles were identified via a Pubmed search with key words ‘‘astroblastoma’’ alone and in combination with ‘‘treatment,’’ ‘‘mortality,’’ and ‘‘morbidity.’’ After reviewing these articles, a thorough review of all referenced sources was also performed. All references that contained disaggregated data specifically addressing clinical behavior with adequate follow up in patients who had undergone surgery (biopsy or resection) of histologically confirmed astroblastoma were included in our analysis. Any paper that did not provide some follow-up data on these patients with
M.E. Sughrue et al. / Journal of Clinical Neuroscience 18 (2011) 750–754
imaging was excluded from survival comparisons, as these would not facilitate Kaplan–Meier analysis.
2.2. Data extraction We extracted all data presented in all manuscripts, which were entered into a database and cross-checked for accuracy. Because not all studies published all types of data, often the relevant analysis was performed on a subset of the whole cohort. Overall survival was determined from survival curves at the 5-year time points. Studies that did not present patient data in a way that variables could be reliably determined were excluded from survival analysis.
2.3. Statistical analysis Survival analysis was performed using Kaplan–Meier analysis with between-group differences being determined by the logrank test. Statistically significant between-group differences were subsequently analyzed using Cox regression analysis in which the covariates – the use of adjuvant radiotherapy, and histological tumor grade, which we hypothesized might be potential confounders – were forced into the regression model to ensure that the apparent between-group differences were not falsely created by confounding variables. Cox regression analysis of between-group survival comparisons were performed using Kendall’s tau.5 We also tested interaction terms between each of the variables. The statistical significance of the interactions was assessed with the use of backward conditional stepwise regression, in which statistical significance was estimated by means of the likelihood-ratio test to assess the effect of removing interaction terms for all strata of the given variable.6 After finding that none of the interaction terms would significantly (unadjusted p > 0.2 for all terms) alter the log likelihood of the regression model if removed, we calculated the adjusted hazard ratios (HR) (without adjusting for interactions). Pearson’s chi-squared (v2) test was used to analyze for differences in pre-operative categorical factors. Fisher’s exact test was used if there were fewer than five values per group. Analysis of variance (ANOVA) was used to evaluate for statistical differences in pre-operative continuous factors, including age. Kaplan–Meier estimates were used to generate time-to-progression curves. Differences in time to progression were analyzed by the log-rank test. Analyses were carried out using Statistical Package for the Social Sciences version 16.0 (SPSS, Chicago, IL, USA).
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3.2. Clinical presentation of astroblastoma While astroblastoma has typically been considered by many to be a pediatric brain tumor, an analysis of published reports suggests that the distribution is bimodal, with a prominent peak in young adulthood (Fig. 1). Of the 100 patients for which patient gender was clearly stated, there seemed to be a clear female predominance (70 females, 30 males) and this relationship seemed to persist in all age groups. Although tumor dimensions were inconsistently presented (detailed information was provided for only 20 patients), the available data suggest that astroblastomas can grow quite large prior to diagnosis. In 16/20 patients (80%) the largest diameter of the astroblastoma at the time of diagnosis was >3 cm; in 10/20 (50%) the largest diameter was >5 cm, and in 2/20 (10%), the largest diameter was >9 cm. Based on the data presented for 95 patients, astroblastoma location is overwhelmingly supratentorial (87 supratentorial, eight infratentorial) (Table 1). Although astroblastoma can occur in the brainstem (three patients), cerebellum (one patient), and intraventricularly (six patients), most patients present with a cerebral mass (85 patients), with a frontal lobe predominance (frontal 38 patients, parietal 22, temporal 16, and occipital four) (Table 1). Presenting symptoms were provided for 52 patients, and the symptom occurrence is summarized in Table 2. Many patients presented with non-localizing features suggestive of elevated intracranial pressure, such as headache (31 patients) and nausea/ vomiting (15 patients). Focal neurologic deficits occurred in 18 of 52 patients. There was one report of a preoperative hemorrhage into an astroblastoma.
3.3. Surgical resectability and post-surgical prognosis of astroblastoma patients Based on the data from 85 patients that included the extent of resection, astroblastomas are generally amenable to complete tumor resection, even when very large. Gross total resection (GTR) was achieved in 71/85 patients (84%), which included both of the 9-cm tumors. Survival analysis suggested that patients who underwent GTR had a significant improvement in survival compared to those receiving a subtotal resection (STR) (5-year survival: GTR 83% versus [vs.] STR 55%, log rank p = 0.011) (Fig. 2).
3. Results 3.1. Clinical characteristics of included patients The literature search yielded a total of 62 references that met our inclusion criteria,1–4,7–64 and contained individual patient data on 116 patients with astroblastoma. These reports were published from 1975 to 2009, and included eight case series of varying sizes (2, 2, 3, 6, 7, 8, 13, and 20 patients respectively), as well as 54 case reports (48/62 reports were published after 1990). Due to the small number of multiple patient series, comparison of interinstitutional variability, and statistical correction for the effects of this source heterogeneity, was not possible. The length of post-operative follow-up was stated for 76 patients in these studies and ranged from 3 months to 244 months (median, 24 months). All survival data were provided in reports since 1990.
Fig. 1. Bar graphs depicting the patient age at time of diagnosis for all reported patients with astroblastoma showing a bimodal distribution, with a prominent peak in young adulthood.
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Table 1 Tumor location in published reports of patients with astroblastoma Supratentorial Infratentorial
87 8
Frontal Parietal Temporal Occipital Brainstem/cerebellum Intraventricular
38 22 16 4 5 6
Table 2 Presenting symptoms in published reports of 52 patients with astroblastoma Headache Focal deficits Nausea/vomiting Non-specified visual disturbance Seizure Hemorrhage Altered mental status
31 18 15 13 11 1 1
Fig. 3. Comparison of progression-free survival between patients treated with gross total resection (GTR) versus GTR plus external beam radiotherapy or fractionated three-dimensional conformal radiotherapy, XRT) (GTR + XRT) showing no significant difference in survival rates between the groups (log-rank p = 0.463; NS = not significant).
94% vs. GTR + XRT 73%, log rank p = 0.463) (Fig. 3). We identified only two patients who received STR without radiation; thus, this was not a meaningful subgroup comparison for the effect of XTR.
4. Discussion
Fig. 2. Comparison of progression-free survival between patients treated with gross total resection (GTR) compared to subtotal resection (STR) and post-operative radiotherapy showing significant difference in survival rates between the groups (log-rank p = 0.011).
To address the possibility that between-group differences in histologic grades in the use of adjuvant radiotherapy might be artificially creating the appearance of a survival benefit, we performed a Cox regression analysis, which demonstrated a significant survival benefit for patients who underwent GTR compared to STR, even after controlling for stated histologic tumor grade (HR for GTR = 0.25, 95% confidence interval = 0.07–0.86, p = 0.028). 3.4. Does the use of adjuvant radiation improve survival in patients with astroblastoma? Our analysis of the published data identified survival statistics for 36 patients who received adjuvant focal radiation (either external beam radiotherapy or fractionated three-dimensional conformal radiotherapy) (XRT), and 23 patients who did not. Although patients who received XRT seemed to experienced worse survival rates, this was not statistically significant (5-year survival: GTR
Astroblastoma is a rare central nervous system (CNS) lesion about which little is known to guide clinical management. In this study, we systematically reviewed the published literature in English on astroblastoma in an attempt to better understand expected outcomes after surgery for astroblastoma, with or without postoperative radiotherapy. Our principle goal was to identify features of these tumors not described thoroughly by isolated case reports (the predominant source of information in the published literature). According to the latest World Health Organization (WHO) classification of CNS tumors,65 astroblastoma is considered a high grade glial neoplasm. However, an analysis of the published data does not support this premise as we found 5-year survival rates for patients receiving GTR at around 95%, with reports of survival exceeding 10 and even 20 years. Furthermore, these tumors often can grow to a large size prior to causing symptoms that prompt a diagnostic imaging study. In our experience, we have seen very few patients with WHO grade III or IV brain tumors reach such a large size without causing death, or serious symptoms far sooner. Together, we feel these observations support the view that astroblastoma is a low grade glial neoplasm, and should be reclassified as such.29 Another aim of this study was to characterize the clinical presentation and behavior of astroblastoma, which is not well understood. We found that astroblastoma is overwhelmingly a supratentorial, intracerebral tumor, which can be intraventricular, and that it is rare in the occipital lobes and posterior fossa. Symptoms are non-specific and related to elevated intracranial pressure, with focal deficits occurring less commonly. Additionally, we found that while astroblastoma is generally considered a pediatric brain tumor, the incidence of this tumor is bimodal with many young adult patients. The appropriate management of these tumors is not clear, as there is no Class 1 or 2 data. Based on what is known, GTR alone provides excellent tumor control rates, and STR should be avoided,
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if possible. Furthermore, the addition of adjuvant focal radiotherapy after STR does not appear to provide equivalent outcomes to GTR. There are few data as to whether functional white matter tracts are displaced by these lesions, or whether these tumors are infiltrative, and have tracts running through them. Astroblastomas are usually not histologically infiltrative lesions,39 but until this is better elaborated upon, given the importance of GTR, we would recommend the use of intraoperative mapping in these instances, including subcortical motor mapping, if functional brain is potentially involved. Adjuvant external beam radiotherapy has been tried for astroblastoma with variable results. While the data are not definitive, we cannot recommend empirically administering radiotherapy after the first operation for patients with astroblastoma who have undergone GTR, given the lack of evidence supporting the efficacy of this approach, and the good results obtained with GTR alone. Where patients have undergone STR, adjuvant radiotherapy has been administered to most patients, but lacking a control group, it is impossible to assess whether this approach truly benefits these patients. 4.1. Study limitations It is impossible for us to control for the quality of the data reported in the literature and an overly stringent definition of ‘‘tumor recurrence’’ in some studies may contribute to variability in rates of tumor control. Furthermore, subjectively defined variables, such as histologic grade, extent of resection, and the adequacy of radiation therapy likely vary between studies, and we cannot independently confirm the validity of these definitions in other groups’ publications. Also, as the astroblastoma literature largely consists of case reports, it is impossible to use statistical meta-analysis methods to assess the effects of between-center heterogeneity on patient outcomes, and to control for this heterogeneity.
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