- Email: [email protected]
Spinal cord glioblastoma: 25 years of experience from a single institution
Journal of Clinical Neuroscience xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Clinical Study
Spinal cord glioblastoma: 25 years of experience from a single institution Vijay Yanamadala a,c,⇑, Robert M. Koffie a,c, Ganesh M. Shankar a,c, Jay I. Kumar a,c, Quinlan D. Buchlak a,c, Vidya Puthenpura a, Matthew P. Frosch b,c, Thomas M. Gudewicz b,c, Lawrence F. Borges a,c, John H. Shin a,c a
Department of Neurosurgery, Massachusetts General Hospital, 15 Parkman Street, WACC 021, Boston, MA 02115, USA Department of Pathology, Massachusetts General Hospital, Boston, MA, USA c Harvard Medical School, Boston, MA, USA b
a r t i c l e
i n f o
Article history: Received 11 November 2015 Accepted 21 November 2015 Available online xxxx Keywords: Glioblastoma Spinal cord Spinal cord glioblastoma
a b s t r a c t Accounting for less than 0.2% of all glioblastomas, high grade gliomas of the spinal cord are very rare. Here, we discuss our approach to managing patients with high grade spinal cord glioma and review the literature on the subject. Six patients with high grade spinal cord gliomas who presented to our institution between 1990 and 2015 were reviewed. Each patient underwent subtotal surgical resection, with a subset receiving adjuvant chemotherapy and radiation. Our primary outcomes of interest were preoperative and post-operative functional status. One year survival rate was 100%. All patients had stable or improved American Spine Injury Association score immediately after surgery, which was maintained at 3 months in 83.3% of patients. Karnofsky Performance Status (KPS) was stable at 3 month follow up in 50% of patients, but all had decreased KPS 1 year after surgery. A subset of patients received postoperative radiation and chemotherapy with 0% tumor recurrence rate at 3 months. We assessed the molecular profiles of tumors from two patients in our series and found that each had mutations in TP53, but had wildtype BRAF, IDH-1, and MGMT. Taken together, our data show that patients with high grade spinal cord gliomas have an excellent survival at 1 year, but with some decline in functional status within this period. Further studies are needed to elucidate the natural history of the disease and to explore the role of adjuvant targeted molecular therapies. Ó 2015 Elsevier Ltd. All rights reserved.
1. Introduction
2. Methods
High grade glioma of the spinal cord is an uncommon pathology. A survey of all patients (173 males and 294 females) registered with primary intraspinal neoplasms in the Norwegian Cancer Registry from 1955 through 1986 found that spinal glioblastomas (GBM) accounted for 0.2% of all GBM, and 1.4% of spinal gliomas [1]. A number of individual case reports [2–16] and a few small studies involving 3–15 patients [17–21] have been reported in the literature, totaling fewer than 200 cases [9,11]. Given the paucity of cases, conclusive evidence-based management of spinal high grade gliomas has yet to be defined. Herein, we discuss our experience with intrinsic spinal cord high grade gliomas over the past 25 years and review current treatment paradigms.
2.1. Patient selection Following Institutional Review Board approval, we retrospectively analyzed data gathered from patients undergoing laminectomy for resection of high grade intramedullary glioma between 1990 and 2015. Various faculty neurosurgeons performed the operations with the assistance of resident physicians at a tertiary care level, university affiliated teaching hospital. Patient and operative characteristics were recorded for all patients meeting study criteria, including age, sex, presenting symptoms, type of operation performed, and pre-operative and post-operative functional status.
2.2. Treatment characteristics
⇑ Corresponding author. Tel.: +1 617 726 3303; fax: +1 617 726 2424. E-mail address: [email protected] (V. Yanamadala).
Surgery was performed for all patients via a posterior approach with laminectomy overlying the involved spinal cord segments, primary dural opening, resection of the tumor in a subtotal fashion, and closure of the dural defect utilizing a dural graft.
http://dx.doi.org/10.1016/j.jocn.2015.11.011 0967-5868/Ó 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Yanamadala V et al. Spinal cord glioblastoma: 25 years of experience from a single institution. J Clin Neurosci (2015), http://dx.doi.org/10.1016/j.jocn.2015.11.011
2
V. Yanamadala et al. / Journal of Clinical Neuroscience xxx (2015) xxx–xxx
Table 1 Characteristics of six patients with spinal cord glioblastoma meeting study criteria Patient characteristic
Metric
Age mean [range], years Sex, male/female Spinal level Cervical Thoracic
40 [30–72] 2/4 3 3
Pre-operative ASIA score A B C D E
2 1 2 1 0
ASIA = American Spine Injury Association.
2.3. Outcomes Our primary outcomes of interest were pre-operative and postoperative functional status. Overall follow-up and survival were also assessed where possible. Neurological examination was assessed in the immediate post-operative period, at 3 month follow-up, and at 1 year follow-up. It was categorized according to the American Spine Injury Association (ASIA) grading system. Overall functional status was assessed at these same time points using the Karnofsky Performance Status (KPS) scale. Postoperative treatment details, including chemotherapy and radiation therapy, were also investigated in all cases. Tumor pathology underwent careful review. This included tumor genomics and mutational status where available. All complications were rigorously recorded including pulmonary embolism, urinary retention (requiring placement of temporary indwelling urinary catheter), durotomy (full thickness dural tear requiring primary suture closure), cerebrospinal fluid leak (post-operative transcutaneous cerebrospinal fluid drainage), surgical site infection, neurological deficit, pneumonia, urinary tract infection, and myocardial infarction. 2.4. Search strategy The review of recent literature was performed by employing the following search terms and appropriate combinations thereof: ‘‘spinal glioblastoma” and ‘‘spinal glioblastoma multiforme.” The primary literature database queried was PubMed. All 28 studies published during the past 5 years (2010–2014) were reviewed. A subset of 22 studies (involving a total of 33 patients) had outcome data pertinent to our focus and were included in the analysis. 3. Results 3.1. Patient characteristics In this retrospective study, six patients were identified who met the inclusion criteria of spinal cord high grade glioma over the study period of 25 years at our institution. The mean patient age was 40 years, with a median age of 33 years. The age range was 30 to 72 years. Of the six patients, two were men and four were women. Three patients had cervical tumors and three patients had thoracic tumors. Two patients presented with an ASIA A examination below the involved cord level, one patient with an ASIA B examination, two patients with an ASIA C examination, and the remaining patient with an ASIA D examination. All patients underwent laminectomy with subtotal resection and duraplasty as described in the Methods section. The patient characteristics are summarized in Table 1.
3.2. Patient outcomes All patients, at a minimum, were followed-up for 1 year. The 1 year survival rate was 100%. Unfortunately, two patients were lost to follow-up thereafter. The maximum follow-up period was 3 years. This was experienced by one patient. The mean followup period was 1.5 years. With regard to neurological status, all patients had a stable or improved ASIA score post-operatively. Five of these patients maintained a stable examination at 3 month follow-up. However, four of these patients had a decrement of at least one ASIA grade by their 1 year follow-up appointment. The KPS was used to assess functional status as described in the Methods. Three patients had a stable KPS at 3 month follow-up. However, all six patients had a decrement in their functional status by the time 1 year had passed. These outcomes are summarized in Table 2. Three patients, all of whom received surgery after 2003, received post-operative radiation and chemotherapy. These patients began fractionated radiation therapy with a total dose of 54 Gy in 30 fractions to the involved spinal cord 6 weeks after surgery and after a thorough wound assessment. They also started concurrent temozolomide (75 mg/m2) and bevacizumab (10 mg/ kg). These patients had follow-up imaging every 3 months, and all patients demonstrated no evidence of tumor recurrence. 3.3. Pathology Two of these patients had molecular pathology information available. Of these patients, TP53, BRAF, IDH-1, and MGMT methylation status were assessed. All patients had mutations in TP53 and demonstrated wildtype BRAF, IDH-1, and MGMT. These findings are summarized in Table 3. 3.4. Complications As described in the Methods section, all complications were rigorously assessed including pulmonary embolism, urinary retention (requiring placement of an indwelling urinary catheter), unintended durotomy (full thickness dural tear requiring primary suture closure), cerebrospinal fluid leak (post-operative transcutaneous cerebrospinal fluid drainage), surgical site infection, neurological deficit, pneumonia, urinary tract infection, and myocardial infarction. One patient had a pulmonary embolism within 3 months (at 2.5 months). Four patients required the placement of an indwelling urinary catheter post-operatively, and all of these patients required subsequent scheduled straight catheterization. No patients had an unintended durotomy or cerebrospinal fluid leak. No patients had surgical site infections or other complications. These findings are summarized in Table 4.
Table 2 Outcomes for six patients with spinal cord glioblastoma Patient outcomes
Metric
Follow-up mean [range], years Neurological status (stable or improved ASIA score) Immediate post-operative 3 months 1 year Functional status (stable or improved KPS) Immediate post-operative 3 months 1 year Post-operative radiation Post-operative chemotherapy 1 year survival
1.5 [1–3] 6 5 1 5 3 0 3 3 100% (6/6)
ASIA = American Spine Injury Association, KPS = Karnofsky Performance Status.
Please cite this article in press as: Yanamadala V et al. Spinal cord glioblastoma: 25 years of experience from a single institution. J Clin Neurosci (2015), http://dx.doi.org/10.1016/j.jocn.2015.11.011
3
V. Yanamadala et al. / Journal of Clinical Neuroscience xxx (2015) xxx–xxx Table 3 Tumor molecular profiles were available for two patients with spinal cord glioblastoma Molecular profile IDH-1 mutation MGMT methylation BRAF mutation TP 53 mutation
Patients testing positive 0/2 0/2 0/2 2/2
Table 4 Complications of six patients with spinal cord glioblastoma Complications
Patient count
Pulmonary embolism within 3 months Urinary retention Unintentional durotomy or CSF leak Surgical site infection
1 4 0 0
Patient outcomes
Metric
Follow-up mean [range], months Neurological status (stable or improved ASIA score) Immediate post-operative 3 months 1 year Functional status (stable or improved KPS) Immediate post-operative 3 months 1 year Post-operative radiation Post-operative chemotherapy 1 year survival No resection performed
26.9 [2–144] 14 16 10 17 15 13 27 23 78.6% (22/28) 6
ASIA = American Spine Injury Association, KPS = Karnofsky Performance Status.
CSF = cerebrospinal fluid.
3.5. Literature review Where available, corresponding outcomes from 33 patients found in 22 articles were summarized in Table 5, 6. The average age of the 33 patients reviewed was 25 years and most (n = 19) were female. The majority of patients were diagnosed with thoracic (n = 12) and cervical (n = 9) GBM. Most patients fell into the C (n = 11) and D (n = 10) preoperative ASIA examination categories (Table 5). Patients completed follow-up at 26.9 months on average. Fourteen patients experienced a stable or improved ASIA score in the immediate post-operative period. Sixteen showed the same at 3 months and 10 at 1 year. Functional status was stable or had improved in 17 patients in the immediate post-operative period, 15 patients at 3 months and 13 patients at 1 year. Twenty-seven patients received post-operative radiation, 23 received post-operative chemotherapy and 78.6% of patients had survived 1 year later (Table 6). 4. Discussion As evidenced in the literature and corroborated by our institutional experience, spinal cord GBM is a rare diagnosis. The six patients identified within our database of patients with intramedullary spinal cord tumors represent less than 1% of patients with intramedullary neoplasms treated at our institution. However, despite the paucity of cases, some clear trends have emerged.
Table 5 Characteristics of 33 patients with spinal cord glioblastoma described in the recent literature [2–16,18,20,21,29,30] Patient characteristic
Metric
Age mean [range], years Sex, male/female/not recorded Spinal level Cervical Thoracic Cervicothoracic Conus Pre-operative ASIA score A B C D E N/A
25.1 [1–30] 13/19/1
ASIA = American Spine Injury Association, N/A = not available.
Table 6 Outcomes of 33 patients with spinal cord glioblastoma described in the recent literature [2–16,18,20,21,29,30]
9 12 6 6 1 0 11 10 0 11
These patients appear to have a good 1 year survival rate. However, functional status does appear to uniformly deteriorate over this period. Surgical resection in our series managed to preserve neurological status in the majority of patients at 3 month followup. While no direct natural history comparison can be made, all of these patients had a steadily deteriorating neurological examination status pre-operatively and would likely have deteriorated without surgery. Post-operative treatment has generally combined radiation and chemotherapy, in line with current treatment paradigms for intracranial GBM. At our institution, current treatment includes fractionated radiation and chemotherapy with temozolomide and bevacizumab, radiation treatment, and chemotherapy. Radiotherapy is almost always used [4], though optimal dosage remains uncertain and the relative value of radiation, chemotherapy, and surgical resection is controversial. Most of the available literature recommends some combination of these three approaches [4,24,25]. Several protocols have been reported. In one case, whole brain irradiation combined with focal irradiation of the spinal cord in addition to intrathecal administration of beta-interferon adjuvant therapy resulted in the longest known survival rate at the time of writing [26]. Chemotherapy is especially used for high grade gliomas and in cases where the disease is progressing substantially [13]. Both temozolomide and bevacizumab were shown to improve survival in a retrospective series of eight patients [28]. Bevacizumab is thought to be particularly suitable for spinal cord gliomas because it decreases peritumoral edema and mass effect [13]. A retrospective study of six patients for whom surgical treatment, temozolomide-based chemotherapy, and post-radiotherapy temozolomide had failed, had some response to bevacizumab as a salvage therapy [23]. Cordectomy or other surgical resection is recommended in cases where neurologic deficits expected from surgery already exist or the tumor occupies the lower lumbar or sacral segments [24]. In such cases, cordectomy is expected to enhance long-term survival by limiting or delaying intracranial dissemination of spinal GBM [27]. In one report, cordectomy, along with radiation and chemotherapy, resulted in a lengthy 12 year survival [5]. As the molecular profiles of these tumors are investigated more thoroughly, it is likely that targeted therapies may become a reality in the future. We reported the molecular profiles of two patients in our series. The literature has begun to characterize infratentorial and spinal GBM by molecular profile, predominantly in the pediatric literature. Pediatric infratentorial GBM have been shown to have a distinct molecular signature from their adult counterparts [22]. Unique genotypic abnormalities resembling those of pediatric
Please cite this article in press as: Yanamadala V et al. Spinal cord glioblastoma: 25 years of experience from a single institution. J Clin Neurosci (2015), http://dx.doi.org/10.1016/j.jocn.2015.11.011
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V. Yanamadala et al. / Journal of Clinical Neuroscience xxx (2015) xxx–xxx
embryonal tumors have been demonstrated in one case of pediatric spinal GBM [21]. In the literature, in one case of spinal GBM in an infant, a targeted pharmacologic approach, which involved combining sorafenib with valproic acid, resulted in size reduction of the tumor, and improvement in symptoms [10]. Continued investigation into targeted therapies may yield such results for other patients with unique tumor molecular profiles in the future. While the challenges of treating rare diseases such as spinal cord GBM remain real, progress is being made in this arena. The evolution of treatment paradigms targeting molecular genomics and combining multimodal therapies is one such notable marker of progress. As we continue to investigate these treatment avenues, it is likely that the efficacy of therapies will continually improve for these patients. Conflicts of Interest/Disclosures The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication. References [1] Helseth A, Mørk SJ. Primary intraspinal neoplasms in Norway, 1955 to 1986. A population-based survey of 467 patients. J Neurosurg 1989;71:842–5. [2] O’Halloran PJ, Farrell M, Caird J, et al. Paediatric spinal glioblastoma: case report and review of therapeutic strategies. Childs Nerv Syst 2013;29:367–74. [3] Salem A, Alshorbaji A, Almousa A. Spinal glioblastoma multiforme. Hematol Oncol Stem Cell Ther 2014;7:56–7. [4] Randakevicˇiene˙ G, Gleizniene˙ R, Basevicˇius A, et al. An extremely rare case of glioblastoma multiforme of the spinal cord. Medicina (Kaunas) 2013;49:242–5. [5] Viljoen S, Hitchon PW, Ahmed R, et al. Cordectomy for intramedullary spinal cord glioblastoma with a 12-year survival. Surg Neurol Int 2014;25:101. [6] Liu X, Germin BI, Ekholm S. A case of cervical spinal cord glioblastoma diagnosed with MR diffusion tensor and perfusion imaging. J Neuroimag 2011;21:292–6. [7] Andrews AA, Enriques L, Renaudin J, et al. Spinal intramedullary glioblastoma with intracranial seeding. Report of a case. Arch Neurol 1978;35:244–5. [8] Kikkawa Y, Suzuki SO, Nakamizo A, et al. Radiation-induced spinal cord glioblastoma with cerebrospinal fluid dissemination subsequent to treatment of lymphoblastic lymphoma. Surg Neurol Int 2013;4:27. [9] Morais N, Mascarenhas L, Soares-Fernandes JP, et al. Primary spinal glioblastoma: a case report and review of the literature. Oncol Lett 2013;5:992–6. [10] Rokes CA, Remke M, Guha-Thakurta N, et al. Sorafenib plus valproic acid for infant spinal glioblastoma. J Pediatr Hematol Oncol 2010;32:511–4.
[11] Gee TS, Ghani AR, Idris B, et al. Case report: a rare case of pediatric conus medularis glioblastoma multiforme. Med J Malaysia 2012;67:438–41. [12] Yeung YF, Wong GK, Zhu XL, et al. Radiation-induced spinal glioblastoma multiforme. Acta Oncol 2006;45:87–90. [13] Varghese SS, Sebastian P, Joseph V, et al. An unusually long survival of a patient with glioblastoma of spinal cord: a case report. J Clin Diagn Res 2014;8: QD01–3. [14] Mayer RR, Warmouth GM, Troxell M, et al. Glioblastoma multiforme of the conus medullaris in a 28-year-old female: a case report and review of the literature. Clin Neurol Neurosurg 2012;114:275–7. [15] Mori K, Imai S, Shimizu J, et al. Spinal glioblastoma multiforme of the conus medullaris with holocordal and intracranial spread in a child: a case report and review of the literature. Spine J 2012;12:e1–6. [16] Ahn SJ, Kim IO. Spinal cord glioblastoma induced by radiation therapy of nasopharyngeal rhabdomyosarcoma with MRI findings: case report. Korean J Radiol. 2012;13:652–7. [17] Prasad GL, Borkar SA, Subbarao KC, et al. Primary spinal cord glioblastoma multiforme: a report of two cases. Neurol India 2012;60:333–5. [18] Ozgiray E, Akay A, Ertan Y, et al. Primary glioblastoma of the medulla spinalis: a report of three cases and review of the literature. Turk Neurosurg 2013;23:828–34. [19] Ciappetta P, Salvati M, Capoccia G, et al. Spinal glioblastomas: report of seven cases and review of the literature. Neurosurgery 1991;28:302–6. [20] Ononiwu C, Mehta V, Bettegowda C, et al. Pediatric spinal glioblastoma multiforme: current treatment strategies and possible predictors of survival. Childs Nerv Syst 2012;28:715–20. [21] Lober R, Sharma S, Bell B, et al. Pediatric primary intramedullary spinal cord glioblastoma. Rare Tumor 2010;2:e48. [22] Sharma S, Free A, Mei Y, et al. Distinct molecular signatures in pediatric infratentorial glioblastomas defined by aCGH. Exp Mol Pathol 2010;89:169–74. [23] Chamberlain MC, Johnston SK. Recurrent spinal cord glioblastoma: salvage therapy with bevacizumab. J Neurooncol 2011;102:427–32. [24] Singh PK, Singh VK, Tomar J, et al. Spinal glioblastoma multiforme: unusual cause of post-traumatic tetraparesis. J Spinal Cord Med 2009;32:583–6. [25] Cohen AR, Wisoff JH, Allen JC, et al. Malignant astrocytomas of the spinal cord. J Neurosurg 1989;70:50–4. [26] Asano N, Kitamura K, Seo Y, et al. Spinal cord glioblastoma multiforme with intracranial dissemination–case report. Neurol Med Chir (Tokyo) 1990;30:489–94. [27] Marchan EM, Sekula Jr RF, Jannetta PJ, et al. Long-term survival enhanced by cordectomy in a patient with a spinal glioblastoma multiforme and paraplegia. Case report. J Neurosurg Spine 2007;7:656–9. [28] Kaley TJ, Mondesire-Crump I, Gavrilovic IT. Temozolomide or bevacizumab for spinal cord high-grade gliomas. J Neurooncol 2012;109:385–9. [29] Tseng HM, Kuo LT, Lien HC, et al. Prolonged survival of a patient with cervical intramedullary glioblastoma multiforme treated with total resection, radiation therapy, and temozolomide. Anticancer Drug 2010;21:963–7. [30] Kim WH, Yoon SH, Kim CY, et al. Temozolomide for malignant primary spinal cord glioma: an experience of six cases and a literature review. J Neurooncol 2011;101:247–54.
Please cite this article in press as: Yanamadala V et al. Spinal cord glioblastoma: 25 years of experience from a single institution. J Clin Neurosci (2015), http://dx.doi.org/10.1016/j.jocn.2015.11.011
Contents lists available at ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Clinical Study
Spinal cord glioblastoma: 25 years of experience from a single institution Vijay Yanamadala a,c,⇑, Robert M. Koffie a,c, Ganesh M. Shankar a,c, Jay I. Kumar a,c, Quinlan D. Buchlak a,c, Vidya Puthenpura a, Matthew P. Frosch b,c, Thomas M. Gudewicz b,c, Lawrence F. Borges a,c, John H. Shin a,c a
Department of Neurosurgery, Massachusetts General Hospital, 15 Parkman Street, WACC 021, Boston, MA 02115, USA Department of Pathology, Massachusetts General Hospital, Boston, MA, USA c Harvard Medical School, Boston, MA, USA b
a r t i c l e
i n f o
Article history: Received 11 November 2015 Accepted 21 November 2015 Available online xxxx Keywords: Glioblastoma Spinal cord Spinal cord glioblastoma
a b s t r a c t Accounting for less than 0.2% of all glioblastomas, high grade gliomas of the spinal cord are very rare. Here, we discuss our approach to managing patients with high grade spinal cord glioma and review the literature on the subject. Six patients with high grade spinal cord gliomas who presented to our institution between 1990 and 2015 were reviewed. Each patient underwent subtotal surgical resection, with a subset receiving adjuvant chemotherapy and radiation. Our primary outcomes of interest were preoperative and post-operative functional status. One year survival rate was 100%. All patients had stable or improved American Spine Injury Association score immediately after surgery, which was maintained at 3 months in 83.3% of patients. Karnofsky Performance Status (KPS) was stable at 3 month follow up in 50% of patients, but all had decreased KPS 1 year after surgery. A subset of patients received postoperative radiation and chemotherapy with 0% tumor recurrence rate at 3 months. We assessed the molecular profiles of tumors from two patients in our series and found that each had mutations in TP53, but had wildtype BRAF, IDH-1, and MGMT. Taken together, our data show that patients with high grade spinal cord gliomas have an excellent survival at 1 year, but with some decline in functional status within this period. Further studies are needed to elucidate the natural history of the disease and to explore the role of adjuvant targeted molecular therapies. Ó 2015 Elsevier Ltd. All rights reserved.
1. Introduction
2. Methods
High grade glioma of the spinal cord is an uncommon pathology. A survey of all patients (173 males and 294 females) registered with primary intraspinal neoplasms in the Norwegian Cancer Registry from 1955 through 1986 found that spinal glioblastomas (GBM) accounted for 0.2% of all GBM, and 1.4% of spinal gliomas [1]. A number of individual case reports [2–16] and a few small studies involving 3–15 patients [17–21] have been reported in the literature, totaling fewer than 200 cases [9,11]. Given the paucity of cases, conclusive evidence-based management of spinal high grade gliomas has yet to be defined. Herein, we discuss our experience with intrinsic spinal cord high grade gliomas over the past 25 years and review current treatment paradigms.
2.1. Patient selection Following Institutional Review Board approval, we retrospectively analyzed data gathered from patients undergoing laminectomy for resection of high grade intramedullary glioma between 1990 and 2015. Various faculty neurosurgeons performed the operations with the assistance of resident physicians at a tertiary care level, university affiliated teaching hospital. Patient and operative characteristics were recorded for all patients meeting study criteria, including age, sex, presenting symptoms, type of operation performed, and pre-operative and post-operative functional status.
2.2. Treatment characteristics
⇑ Corresponding author. Tel.: +1 617 726 3303; fax: +1 617 726 2424. E-mail address: [email protected] (V. Yanamadala).
Surgery was performed for all patients via a posterior approach with laminectomy overlying the involved spinal cord segments, primary dural opening, resection of the tumor in a subtotal fashion, and closure of the dural defect utilizing a dural graft.
http://dx.doi.org/10.1016/j.jocn.2015.11.011 0967-5868/Ó 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Yanamadala V et al. Spinal cord glioblastoma: 25 years of experience from a single institution. J Clin Neurosci (2015), http://dx.doi.org/10.1016/j.jocn.2015.11.011
2
V. Yanamadala et al. / Journal of Clinical Neuroscience xxx (2015) xxx–xxx
Table 1 Characteristics of six patients with spinal cord glioblastoma meeting study criteria Patient characteristic
Metric
Age mean [range], years Sex, male/female Spinal level Cervical Thoracic
40 [30–72] 2/4 3 3
Pre-operative ASIA score A B C D E
2 1 2 1 0
ASIA = American Spine Injury Association.
2.3. Outcomes Our primary outcomes of interest were pre-operative and postoperative functional status. Overall follow-up and survival were also assessed where possible. Neurological examination was assessed in the immediate post-operative period, at 3 month follow-up, and at 1 year follow-up. It was categorized according to the American Spine Injury Association (ASIA) grading system. Overall functional status was assessed at these same time points using the Karnofsky Performance Status (KPS) scale. Postoperative treatment details, including chemotherapy and radiation therapy, were also investigated in all cases. Tumor pathology underwent careful review. This included tumor genomics and mutational status where available. All complications were rigorously recorded including pulmonary embolism, urinary retention (requiring placement of temporary indwelling urinary catheter), durotomy (full thickness dural tear requiring primary suture closure), cerebrospinal fluid leak (post-operative transcutaneous cerebrospinal fluid drainage), surgical site infection, neurological deficit, pneumonia, urinary tract infection, and myocardial infarction. 2.4. Search strategy The review of recent literature was performed by employing the following search terms and appropriate combinations thereof: ‘‘spinal glioblastoma” and ‘‘spinal glioblastoma multiforme.” The primary literature database queried was PubMed. All 28 studies published during the past 5 years (2010–2014) were reviewed. A subset of 22 studies (involving a total of 33 patients) had outcome data pertinent to our focus and were included in the analysis. 3. Results 3.1. Patient characteristics In this retrospective study, six patients were identified who met the inclusion criteria of spinal cord high grade glioma over the study period of 25 years at our institution. The mean patient age was 40 years, with a median age of 33 years. The age range was 30 to 72 years. Of the six patients, two were men and four were women. Three patients had cervical tumors and three patients had thoracic tumors. Two patients presented with an ASIA A examination below the involved cord level, one patient with an ASIA B examination, two patients with an ASIA C examination, and the remaining patient with an ASIA D examination. All patients underwent laminectomy with subtotal resection and duraplasty as described in the Methods section. The patient characteristics are summarized in Table 1.
3.2. Patient outcomes All patients, at a minimum, were followed-up for 1 year. The 1 year survival rate was 100%. Unfortunately, two patients were lost to follow-up thereafter. The maximum follow-up period was 3 years. This was experienced by one patient. The mean followup period was 1.5 years. With regard to neurological status, all patients had a stable or improved ASIA score post-operatively. Five of these patients maintained a stable examination at 3 month follow-up. However, four of these patients had a decrement of at least one ASIA grade by their 1 year follow-up appointment. The KPS was used to assess functional status as described in the Methods. Three patients had a stable KPS at 3 month follow-up. However, all six patients had a decrement in their functional status by the time 1 year had passed. These outcomes are summarized in Table 2. Three patients, all of whom received surgery after 2003, received post-operative radiation and chemotherapy. These patients began fractionated radiation therapy with a total dose of 54 Gy in 30 fractions to the involved spinal cord 6 weeks after surgery and after a thorough wound assessment. They also started concurrent temozolomide (75 mg/m2) and bevacizumab (10 mg/ kg). These patients had follow-up imaging every 3 months, and all patients demonstrated no evidence of tumor recurrence. 3.3. Pathology Two of these patients had molecular pathology information available. Of these patients, TP53, BRAF, IDH-1, and MGMT methylation status were assessed. All patients had mutations in TP53 and demonstrated wildtype BRAF, IDH-1, and MGMT. These findings are summarized in Table 3. 3.4. Complications As described in the Methods section, all complications were rigorously assessed including pulmonary embolism, urinary retention (requiring placement of an indwelling urinary catheter), unintended durotomy (full thickness dural tear requiring primary suture closure), cerebrospinal fluid leak (post-operative transcutaneous cerebrospinal fluid drainage), surgical site infection, neurological deficit, pneumonia, urinary tract infection, and myocardial infarction. One patient had a pulmonary embolism within 3 months (at 2.5 months). Four patients required the placement of an indwelling urinary catheter post-operatively, and all of these patients required subsequent scheduled straight catheterization. No patients had an unintended durotomy or cerebrospinal fluid leak. No patients had surgical site infections or other complications. These findings are summarized in Table 4.
Table 2 Outcomes for six patients with spinal cord glioblastoma Patient outcomes
Metric
Follow-up mean [range], years Neurological status (stable or improved ASIA score) Immediate post-operative 3 months 1 year Functional status (stable or improved KPS) Immediate post-operative 3 months 1 year Post-operative radiation Post-operative chemotherapy 1 year survival
1.5 [1–3] 6 5 1 5 3 0 3 3 100% (6/6)
ASIA = American Spine Injury Association, KPS = Karnofsky Performance Status.
Please cite this article in press as: Yanamadala V et al. Spinal cord glioblastoma: 25 years of experience from a single institution. J Clin Neurosci (2015), http://dx.doi.org/10.1016/j.jocn.2015.11.011
3
V. Yanamadala et al. / Journal of Clinical Neuroscience xxx (2015) xxx–xxx Table 3 Tumor molecular profiles were available for two patients with spinal cord glioblastoma Molecular profile IDH-1 mutation MGMT methylation BRAF mutation TP 53 mutation
Patients testing positive 0/2 0/2 0/2 2/2
Table 4 Complications of six patients with spinal cord glioblastoma Complications
Patient count
Pulmonary embolism within 3 months Urinary retention Unintentional durotomy or CSF leak Surgical site infection
1 4 0 0
Patient outcomes
Metric
Follow-up mean [range], months Neurological status (stable or improved ASIA score) Immediate post-operative 3 months 1 year Functional status (stable or improved KPS) Immediate post-operative 3 months 1 year Post-operative radiation Post-operative chemotherapy 1 year survival No resection performed
26.9 [2–144] 14 16 10 17 15 13 27 23 78.6% (22/28) 6
ASIA = American Spine Injury Association, KPS = Karnofsky Performance Status.
CSF = cerebrospinal fluid.
3.5. Literature review Where available, corresponding outcomes from 33 patients found in 22 articles were summarized in Table 5, 6. The average age of the 33 patients reviewed was 25 years and most (n = 19) were female. The majority of patients were diagnosed with thoracic (n = 12) and cervical (n = 9) GBM. Most patients fell into the C (n = 11) and D (n = 10) preoperative ASIA examination categories (Table 5). Patients completed follow-up at 26.9 months on average. Fourteen patients experienced a stable or improved ASIA score in the immediate post-operative period. Sixteen showed the same at 3 months and 10 at 1 year. Functional status was stable or had improved in 17 patients in the immediate post-operative period, 15 patients at 3 months and 13 patients at 1 year. Twenty-seven patients received post-operative radiation, 23 received post-operative chemotherapy and 78.6% of patients had survived 1 year later (Table 6). 4. Discussion As evidenced in the literature and corroborated by our institutional experience, spinal cord GBM is a rare diagnosis. The six patients identified within our database of patients with intramedullary spinal cord tumors represent less than 1% of patients with intramedullary neoplasms treated at our institution. However, despite the paucity of cases, some clear trends have emerged.
Table 5 Characteristics of 33 patients with spinal cord glioblastoma described in the recent literature [2–16,18,20,21,29,30] Patient characteristic
Metric
Age mean [range], years Sex, male/female/not recorded Spinal level Cervical Thoracic Cervicothoracic Conus Pre-operative ASIA score A B C D E N/A
25.1 [1–30] 13/19/1
ASIA = American Spine Injury Association, N/A = not available.
Table 6 Outcomes of 33 patients with spinal cord glioblastoma described in the recent literature [2–16,18,20,21,29,30]
9 12 6 6 1 0 11 10 0 11
These patients appear to have a good 1 year survival rate. However, functional status does appear to uniformly deteriorate over this period. Surgical resection in our series managed to preserve neurological status in the majority of patients at 3 month followup. While no direct natural history comparison can be made, all of these patients had a steadily deteriorating neurological examination status pre-operatively and would likely have deteriorated without surgery. Post-operative treatment has generally combined radiation and chemotherapy, in line with current treatment paradigms for intracranial GBM. At our institution, current treatment includes fractionated radiation and chemotherapy with temozolomide and bevacizumab, radiation treatment, and chemotherapy. Radiotherapy is almost always used [4], though optimal dosage remains uncertain and the relative value of radiation, chemotherapy, and surgical resection is controversial. Most of the available literature recommends some combination of these three approaches [4,24,25]. Several protocols have been reported. In one case, whole brain irradiation combined with focal irradiation of the spinal cord in addition to intrathecal administration of beta-interferon adjuvant therapy resulted in the longest known survival rate at the time of writing [26]. Chemotherapy is especially used for high grade gliomas and in cases where the disease is progressing substantially [13]. Both temozolomide and bevacizumab were shown to improve survival in a retrospective series of eight patients [28]. Bevacizumab is thought to be particularly suitable for spinal cord gliomas because it decreases peritumoral edema and mass effect [13]. A retrospective study of six patients for whom surgical treatment, temozolomide-based chemotherapy, and post-radiotherapy temozolomide had failed, had some response to bevacizumab as a salvage therapy [23]. Cordectomy or other surgical resection is recommended in cases where neurologic deficits expected from surgery already exist or the tumor occupies the lower lumbar or sacral segments [24]. In such cases, cordectomy is expected to enhance long-term survival by limiting or delaying intracranial dissemination of spinal GBM [27]. In one report, cordectomy, along with radiation and chemotherapy, resulted in a lengthy 12 year survival [5]. As the molecular profiles of these tumors are investigated more thoroughly, it is likely that targeted therapies may become a reality in the future. We reported the molecular profiles of two patients in our series. The literature has begun to characterize infratentorial and spinal GBM by molecular profile, predominantly in the pediatric literature. Pediatric infratentorial GBM have been shown to have a distinct molecular signature from their adult counterparts [22]. Unique genotypic abnormalities resembling those of pediatric
Please cite this article in press as: Yanamadala V et al. Spinal cord glioblastoma: 25 years of experience from a single institution. J Clin Neurosci (2015), http://dx.doi.org/10.1016/j.jocn.2015.11.011
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embryonal tumors have been demonstrated in one case of pediatric spinal GBM [21]. In the literature, in one case of spinal GBM in an infant, a targeted pharmacologic approach, which involved combining sorafenib with valproic acid, resulted in size reduction of the tumor, and improvement in symptoms [10]. Continued investigation into targeted therapies may yield such results for other patients with unique tumor molecular profiles in the future. While the challenges of treating rare diseases such as spinal cord GBM remain real, progress is being made in this arena. The evolution of treatment paradigms targeting molecular genomics and combining multimodal therapies is one such notable marker of progress. As we continue to investigate these treatment avenues, it is likely that the efficacy of therapies will continually improve for these patients. Conflicts of Interest/Disclosures The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication. References [1] Helseth A, Mørk SJ. Primary intraspinal neoplasms in Norway, 1955 to 1986. A population-based survey of 467 patients. J Neurosurg 1989;71:842–5. [2] O’Halloran PJ, Farrell M, Caird J, et al. Paediatric spinal glioblastoma: case report and review of therapeutic strategies. Childs Nerv Syst 2013;29:367–74. [3] Salem A, Alshorbaji A, Almousa A. Spinal glioblastoma multiforme. Hematol Oncol Stem Cell Ther 2014;7:56–7. [4] Randakevicˇiene˙ G, Gleizniene˙ R, Basevicˇius A, et al. An extremely rare case of glioblastoma multiforme of the spinal cord. Medicina (Kaunas) 2013;49:242–5. [5] Viljoen S, Hitchon PW, Ahmed R, et al. Cordectomy for intramedullary spinal cord glioblastoma with a 12-year survival. Surg Neurol Int 2014;25:101. [6] Liu X, Germin BI, Ekholm S. A case of cervical spinal cord glioblastoma diagnosed with MR diffusion tensor and perfusion imaging. J Neuroimag 2011;21:292–6. [7] Andrews AA, Enriques L, Renaudin J, et al. Spinal intramedullary glioblastoma with intracranial seeding. Report of a case. Arch Neurol 1978;35:244–5. [8] Kikkawa Y, Suzuki SO, Nakamizo A, et al. Radiation-induced spinal cord glioblastoma with cerebrospinal fluid dissemination subsequent to treatment of lymphoblastic lymphoma. Surg Neurol Int 2013;4:27. [9] Morais N, Mascarenhas L, Soares-Fernandes JP, et al. Primary spinal glioblastoma: a case report and review of the literature. Oncol Lett 2013;5:992–6. [10] Rokes CA, Remke M, Guha-Thakurta N, et al. Sorafenib plus valproic acid for infant spinal glioblastoma. J Pediatr Hematol Oncol 2010;32:511–4.
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Please cite this article in press as: Yanamadala V et al. Spinal cord glioblastoma: 25 years of experience from a single institution. J Clin Neurosci (2015), http://dx.doi.org/10.1016/j.jocn.2015.11.011