e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 9 ( 2 0 1 5 ) 4 1 e4 7
Official Journal of the European Paediatric Neurology Society
Original article
Pediatric intramedullary spinal cord tumors: A single center experience Tezer Kutluk a,*, Ali Varan a, Candas‚ Kafalı a, Mutlu Hayran b, €ylemezog lu c, Faruk Zorlu d, Burc¸a Aydın a, Bilgehan Yalc¸ın a, Figen So a Canan Akyu¨z , Mu¨nevver Bu¨yu¨kpamukc¸u a a
Department of Pediatric Oncology, Hacettepe University, Institute of Oncology, 06100 Ankara, Turkey Department of Preventive Oncology, Hacettepe University, Institute of Oncology, 06100 Ankara, Turkey c Department of Pathology, Hacettepe University, Faculty of Medicine, 06100 Ankara, Turkey d Department of Radiation Oncology, Hacettepe University, Faculty of Medicine, 06100 Ankara, Turkey b
article info
abstract
Article history:
Aim: To evaluate clinical and radiological findings, pathological features and treatment
Received 24 May 2013
modalities in pediatric patients with intramedullary spinal cord tumors.
Received in revised form
Patients and methods: The medical records of 36 patients with intramedullary spinal tumors
24 September 2014
were reviewed for clinical, radiological and histopathological data, chemotherapy, radio-
Accepted 28 September 2014
therapy, surgical resection, treatment responses, events, and final outcome. Survival analyses were performed.
Keywords:
Results: The median age was 7.9 years (range: 1e16 years; male/female ratio:1.4). Ma-
Children
jority of the tumors were histopathologically diagnosed as astrocytomas (n ¼ 16, 44.4%)
Intramedullary spinal tumors
and ependymomas (n ¼ 19, 52.8%); whereas one was unclassified glioma. Overall, 94% of
Outcome
the astrocytomas and 84% of the ependymomas were low-grade, only three tumors
Treatment
were high-grade. In one patient with ependymoma, histopathological grade was undetermined. The primary tumor was commonly located in thoracic (47%) and cervical segments (28%). All patients had undergone surgery (gross-total resection, 33%; subtotal resection, 45%; biopsy, 22%). Radiotherapy was administered to 26 patients (72%) and chemotherapy to 15 patients (42%). The 3-, 5- and 10-year overall survival rates were 72%, 63% and 56%, respectively; and event-free survival rates were 43%, 40% and 40%. Survival did not significantly differ with gender, age groups, lag-time, neurologic status, histopathological tumor type, tumor location, extent of resection, treatment, or treatment responses in univariate survival analyses. Survival rates were significantly higher in patients with low-grade tumors and in ependymoma patients with resected tumors. Conclusions: Patients with low-grade tumors and those who underwent gross-total tumor resection had better prognosis. Surgery remains the main treatment in intramedullary
* Corresponding author. Tel.: þ90 312 3052990; fax: þ90 312 3107018. E-mail addresses: [email protected], [email protected] (T. Kutluk). http://dx.doi.org/10.1016/j.ejpn.2014.09.007 1090-3798/© 2014 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
42
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 9 ( 2 0 1 5 ) 4 1 e4 7
spinal tumors. The role of radiotherapy and chemotherapy is limited and even controversial in low-grade tumors. © 2014 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
1.
Introduction
Central nervous system tumors are the second most common type of tumors after leukemias in children. Medulla spinalis tumors, however, are rare and account for only 4e6% of all central nervous system tumors in children.1e3 Few series about intramedullary spinal cord tumors4e6 and large series including both intra- and extramedullary tumors have been reported; whereas some papers have been included retroperitoneal tumors that are presented with spinal cord compression.7,8 The treatment of intramedullary tumors is essentially surgery, which is supplemented with radiotherapy and chemotherapy, if warranted by the clinical and histopathological findings. Most patients with intramedullary tumors present with some neurological deficit at the time of the diagnosis may get these complications aggravated by surgery and radiotherapy.9 In this study, we have evaluated clinical and radiological findings, pathological features and treatment modalities in patients with intramedullary spinal cord tumors who were treated in our department during the last 40 years.
2.
Patients and methods
We identified 36 patients who were diagnosed with medulla spinalis tumors in our institution between January 1971 and December 2009. Our department, the reference center for pediatric oncology, serves half part of Turkey. The patients who were referred to our department were from neurosurgery clinic, pediatric neurology, and department of pediatrics of our hospital, and also from the other oncology and neurosurgery clinics. We excluded patients treated at other oncology centers, those who discontinued the therapy, and those who died soon after the surgery because of surgical complications. We retrospectively analyzed the clinical, epidemiological and histopathological characteristics, treatment modalities, survival rates and prognostic criteria in these patients. All patients underwent a complete physical and neurological examination. The interval between symptom onset and diagnosis was noted. Computed tomography (CT) and/or magnetic resonance imaging (MRI) were used to evaluate the primary tumor. Spinal extension was investigated using cervical, thoracic, and lumbar MRI in most patients. Surgical resection was performed in all patients. In cases earlier than 1984, the extent of resection was determined on the basis of surgeon's opinion and postoperative CT scans, whereas after 1984, it was determined using postoperative MRI findings.
Total or gross-total resection was defined as the absence of any visible disease on postoperative imaging studies. Subtotal resection was defined as removal of >50% of the total tumor mass, with visible residual tumor on postoperative imaging studies. Biopsy was defined as the surgical removal of 180 Present Present Low-grade High-grade Cervical Cervicothoracic Thoracic Thoracolumbar Lumbar Lumbosacral Holokordal Brain stem þ cervical None CCNU based regimen Others Performed Complete response Partial response No response Total resection Subtotal resection Biopsy
Astrocytoma (n ¼ 16)
Ependymoma (n ¼ 19)
All patientsa (n ¼ 36)
5.50 1.33 12.0 5 (31.3%) 10 (62.5%) 1 (6.3%) 8 (50.0%) 8 (50.0%) 11 (68.8%) 5 (31.3%) 13 (81.3%) 6 (37.5%) 15 (93.8%) 1 (6.3%) 4 (25.0%) 2 (12.5%) 3 (18.8%) 2 (12.5%) 2 (12.5%) 0 (0.0%) 2 (12.5%) 1 (6.3%) 13 (81.3%) 2 (12.5%) 1 (6.3%) 13 (81.3%) 2 (12.5%) 10 (62.5%) 4 (25.0%) 1 (6.3%) 9 (56.3%) 6 (37.5%)
12.0 1.25 16.0 4 (21.1%) 3 (15.8%) 12 (63.2%) 12 (63.2%) 7 (36.8%) 10 (52.6%) 9 (47.4%) 14 (73.7%) 9 (47.4%) 16 (88.9%) 2 (11.1%) 1 (5.3%) 2 (10.5%) 6 (31.6%) 8 (42.1%) 0 (0.0%) 1 (5.3%) 0 (0.0%) 1 (5.3%) 7 (36.8%) 10 (52.6%) 2 (10.5%) 13 (68.4%) 10 (52.6%) 7 (36.8%) 2 (10.5%) 10 (52.6%) 7 (36.8%) 2 (10.5%)
7.5 1.25 16.0 9 (25.0%) 13 (36.1%) 14 (38.9%) 21 (58.3%) 15 (41.7%) 22 (61.1%) 14 (38.9%) 28 (77.8%) 15 (41.7%) 32 (91.4%) 3 (8.6%) 6 (16.7%) 4 (11.1%) 9 (25.0%) 10 (27.8%) 2 (5.6%) 1 (2.8%) 2 (5.6%) 2 (5.6%) 21 (58.3%) 12 (33.3%) 3 (8.3%) 26 (72.2%) 13 (36.1%) 17 (47.2%) 6 (16.7%) 12 (33.3%) 16 (44.4%) 8 (22.2%)
Including 1 glial tumor.
The most common complaints were weakness/gait disturbances (83.3%) and pain (55.6%), the most frequent physical examination findings were deep tendon reflex changes (80%) and motor deficits (78%). The neurologic status at the time of diagnosis, as assessed using the modified McCormick scale was as follows: grades IeII (normal or mild deficit) in 14 patients (39%) and grades IIIeV (moderate to severe deficit) in 22 patients (61%). The histopathological diagnoses were astrocytomas (n ¼ 16, 44.4%), ependymomas (n ¼ 19, 52.8%), and unclassified glioma (n ¼ 1) (Table 1). All 15 patients with astrocytoma and 16 patients with ependymomas were low-grade. Three patients were highgrade including two ependymomas and one astrocytoma. One patient was ependymoma of undetermined grade. The median interval between symptom onset and diagnosis was 180 days (range: 10e1080 days). Moreover this interval did not differ with histopathological tumor type, but was longer in the case of low-grade tumors (6 months) than in the case of high-grade tumors (1.5 months, p ¼ 0.027). Surgery was performed in all patients for either diagnosis or treatment. Gross total resection was performed in 12 (33.3%) patients, subtotal resection in 16 (44.5%) patients, and biopsy in 8 (22.2%) patients. The rate of gross total resection was significantly higher in the case of ependymomas than in the case of astrocytomas (10 versus 1 patient).
We selected chemotherapy and/or radiotherapy protocols according to histopathological findings. Chemotherapy was administered to 3 patients with astrocytomas. Two of these patients had low-grade tumors and were treated with the PCV regimen; the third one had a high-grade tumor and was treated with the COPP regimen. All 12 patients with ependymomas underwent chemotherapy including two patients with high-grade tumors. All 10 patients with lowgrade tumors and one patient with high grade tumor were treated with the PCV regimen. The second patient with a highgrade tumor was treated using CDDP-based regimen. Radiotherapy was administered to 13 patients each from the astrocytoma (3750e5040 cGy) and ependymoma groups (1080e5000 cGy). The overall 3- and 5-year survival rates for all the patients were 71.7% and 62.8%, whereas event-free survival rates were 49.1% and 43.1%, respectively (Fig. 1). Median follow-up time was 7.75 years. The overall 5-year survival rate was 56% in the astrocytoma group and 68% in the ependymoma group (p ¼ 0.9) (Fig. 2). The factors significantly associated with overall and event-free survival are presented in Table 2. Patients with low-grade tumors had higher survival rates than the patients with high-grade tumors (Table 2). The overall survival rate did not differ with the extent of surgical resection in the astrocytoma group. In the ependymoma group, the overall survival was longer in patients who
44
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 9 ( 2 0 1 5 ) 4 1 e4 7
Fig. 1 e Overall and event-free survival rates of 36 patients with intramedullary spinal cord tumors.
underwent gross total or subtotal resection than those who underwent tumor biopsy (Table 2). Again in the ependymoma group, overall survival was lower in patients aged 3e10 years than in those aged 3 years or >10 years. These associations observed for the extent of resection and age in the ependymoma patients was not observed with astrocytomas. Tumor
1,0
location, interval between symptom onset and diagnosis, chemotherapy, and radiotherapy did not have any effect on overall survival. The event-free survival rate (EFS) did not significantly differ between the astrocytoma group (5-year EFS: 43.8%) and the ependymoma group (5-year EFS: 42.1%, p ¼ 0.46) (Fig. 2),
____ Astrocytoma, overall survival _ _ _ _ _ Astrocytoma, event-free survival _ _ _ Ependymoma, overall survival _ _ _ _ _ _ Ependymoma, event-free survival
,9 ,8
Survival (%)
,7 ,6 ,5 ,4 ,3 ,2 ,1 0,0 0
1
2
3
4
5
6
7
8
9
10 11 12 13 14 15 16 17 18 19 20
Time (years)
Log-rank; overall survival, p=0.928 event-free survival, p=0.46
Fig. 2 e Overall and event-free survival rates according to histopathology.
45
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 9 ( 2 0 1 5 ) 4 1 e4 7
Table 2 e Significant factors associated with overall and event-free survival. Overall survival (OS) Grade (all patients) Age Group (ependymoma patients) Extent of resection (ependymoma patients)
5-year OS (SE) Low grade High grade [0e3] [3e10] 10þ Total Subtotal Biopsy
Event-free survival Grade (all patients) Extent of resection (all patients)
Low grade High grade Total Subtotal Biopsy
67.7% 33.3% 75.0% 0% 57.1% 80.0% 71.4% 0%
(8.4) (27.2) (21.7) () (17.2) (12.6) (17.1) ()
Median OS (years)
p-valuea
HR (95%CI)b
25þ 3.75 5.67 3.75 10.25þ 7.91 10.25þ 0.42
0.026
1 3.9 (1.1e14.3) 1 5.6 (0.7e40.8) 0.67 (0.12e3.7) 1 0.86 (0.19e3.9) 8.6 (1.3e56.7)
0.015
0.014
5-year EFS (SE)
Median EFS (years)
p-valuea
HR (95%CI)b
48.7% (9.0) 0% () 63.6% (14.5) 25.0% (10.8) 50.0% (17.7)
6.33 0.20 10.25þ 1.75 0.75
0.023
1 4.0 (1.1e14.9) 1 3.6 (1.2e11.0) 1.9 (0.48e7.8)
0.051
SE: standard error. a Log-rank test. b 95% confidence intervals (CI) and hazard ratio (HR) as calculated separately by the Cox regression model (a value of 1 for HR is used for the reference category).
but differed between patients with low- and high-grade tumors (Table 2). In addition, the event-free survival rate was higher in patients who underwent gross total resection than those who underwent subtotal resection or tumor biopsy (Table 2). However, event-free survival did not significantly differ with the age, tumor location, interval between symptom onset and diagnosis, chemotherapy, and radiotherapy. Functional outcomes were retrospectively examined from patient-files. Eight patients had motor deficits, 10 patients had neurogenic and bladder dysfunction, and sensorineural impairment, and 16 patients had spinal deformity (Table 3).
4.
Discussion
In our series, the overall and event-free survival rates of astrocytoma were similar with ependymoma, and survival was better in low grade tumors than the high grade tumors (p ¼ 0.02). Fortunately, most patients had low-grade tumors. Extent of the resection and age group were the other important factors. Total surgical resection has better survival rates.
Table 3 e Functional outcomes of 36 patients with intramedullary spinal cord tumors. Motor deficit Unable to walk Walking with support Ambulant independently Unknown Other deficits Neurogenic bladder Bowel dysfunction (constipation or incontinence) Somatosensory impairment No abnormality Unknown Spinal deformity:
2 6 27 1 7 2 1 25 1 16
Intramedullary spinal tumors accounted for only 4e6% of all CNS tumors.1e3 Most series in the literature have included paraspinal tumors such as neuroblastomas, lymphomas, rhabdomyosarcomas, and metastatic tumors along with primary medulla spinalis tumors.7,8 In a recent study from Munster that included 340 patients with brain tumors from seven centers, only 21 patients (6.17%) had primary medulla spinalis tumors.7 We included patients only with intramedullary spinal tumors excluding those with extramedullary or metastatic tumors. Our single-center study analyzed data from 38 years, which is one of the longest periods reported in the literature. Age distribution of our cases is similar to that reported by O'Sullivan et al.10 Scheinemann et al.11 reported the same age with 5.8 years in their study on spinal glioma patients, but most of their patients (41%) were under 4 years. The male/ female ratio in their study was 2.6. In our study, most of the astrocytoma patients (62%) were aged between 3 and 10 years. Most of the studies have reported male/female ratios between 1.2 and 1.4.10e14 The patients with intraspinal tumors have nonspecific complaints, which are occasionally asymptomatic. Intraspinal tumors in children are low-grade and progress slowly, and therefore their diagnosis can be delayed. The interval between symptom onset and diagnosis was approximately 10 months in the case of low-grade tumors11,13 and 2e7 months in the case of high-grade tumors.14e16 The high rate of severe deficit was probably due to delays in admission to our center. Other studies have reported similar symptoms as in our study, but with a better neurological status (McCormick grade II).9,11,13,17 Radiotherapy has been successfully used to treat both ependymomas and astrocytomas10,18e21 in some series. O'Sullivan et al.10 used radiotherapy in cases who had uncomplete resection. Besides Kopelson et al.22 suggested radiotherapy to all patients either totally resected or unresected. However, contradictory results have been reported in other studies.2,23 Another reason for avoiding radiotherapy is that, radiotherapy can cause secondary malignancy and
46
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 9 ( 2 0 1 5 ) 4 1 e4 7
growth retardation. In present study, radiotherapy was not used in low-grade spinal tumors unless there was a recurrent disease. Chemotherapy has been used to treat spinal tumors in a few studies. Procarbazine þ CCNU þ vincristine, eightdrugs-in-one day, and carboplatin and vincristine regimens have all been used, with similar results.15,24e29 United Kingdom Children's Cancer Study Group have successfully used carboplatin, vincristine, cyclophosphamide, methotrexate protocol in high grade astrocytoma,30 Packer et al.25 reported that, carboplatin plus vincristine has resulted in survival rates of 52% and 62% in recurrent and newly diagnosed low grade astrocytoma, respectively. Oppositely, carboplatin and vincristine have not improved the disease in a patient reported by Foreman et al26. Although some papers have mentioned that chemotherapy and radiotherapy can be used for both low- and high-grade tumors, it is generally accepted that low-grade spinal tumors should be followed up without these treatments, if total or subtotal resection has been performed.31e34 Our series is one of the largest series of intramedullary spinal tumors from a single center. We found that histopathological tumor grade was the most important prognostic factor. It can be conclude that, although we treated our patients with both radiotherapy and/or chemotherapy, patients with low-grade spinal tumors can be followed up without these treatments, if total or subtotal surgical resection has been performed.
Conflict of interest We have no conflict of interest.
references
1. Constantini S, Epstein F. Intraspinal tumors in children and infants. In: Youmans J, editor. Neurological surgery. 4th ed. Philadelphia: Saunders; 1996. p. 3123e33. 2. Houten JK, Weiner HL. Pediatric inramedullary spinal cord tumors: special considerations. J Neurooncol 2000;47:225e30. 3. Auguste KI, Gupta N. Pediatric intramedullary spinal cord tumors. Neurosurg Clin N Am 2006;17(1):51e61. 4. Bowers DC, Weprin BE. Intramedullary spinal cord tumors. Curr Treat Options Neurol 2003;5:207e12. 5. Constantini S, Houten J, Miller DC, Freed D, Ozek MM, Rorke LB, et al. Intramedullary spinal cord tumors in children under the age of 3 years. J Neurosurg 1996;85:1036e43. 6. Cooper PR. Outcome after operative treatment of intramedullary spinal cord tumors in adults: intermediate and longterm results in 51 patients. Neurosurgery 1989;25:855e9. 7. Rickert CH, Paulus W. Epidemiology of central nervous system tumors in childhood and adolescence based on the new WHO classification. Child's Nerv Syst 2001;17:503e11. 8. Wilne S, Collier J, Kennedy C, Koller K, Grundy R, Walker D. Presentation of childhood CNS tumors: a systematic review and meta-analysis. Lancet Oncol 2007;8:685e95. 9. McGirt MJ, Chaichana KL, Atiba A, Attenello F, Yao KC, Jallo GI. Resection of intramedullary spinal cord tumors in children: assessment of long-term motor and sensory deficits. J Neurosurg Pediatr 2008;1:63e7.
10. O'Sullivan C, Jenkin RD, Doherty MA, Hoffman HJ, Greenberg ML. Spinal cord tumors in children: long trem results of combined surgical and radiation treatment. J Neurosurg 1994;81:507e12. 11. Scheinemann K, Bartels U, Huang A, Hawkins C, Kulkarni AV, Bouffet E, et al. Survival and functional outcome of childhood spinal cord low-grade gliomas. J Neurosurg Pediatr 2009;4:254e61. 12. Innocenzi G, Raco A, Cantore G, Raimondi AJ. Intramedullary astrocytomas and ependymomas in the pediatric age group: a retrospective study. Childs Nerv Syst 1996;12:776e80. 13. Constantini S, Miller DC, Allen JC, Rorke LB, Freed D, Epstein FJ. Radical excision of intramedullay spinal cord tumors: surgical morbidity and long term follow-up evaluation in 164 children and young adults. J Neurosurg (Spine 2) 2000;93:183e93. 14. Crawford JR, Zaninovic A, Santi M, Rushing EJ, Olsen CH, Keating RF, et al. Primary spinal cord tumors of childhood: effects of clinical presentation, radiographic features, and pathology on survival. J Neurooncol 2009;95(2):259e69. 15. McCormick PC, Torres R, Post KD, Stein BM. Intramedullary ependymoma of the spinal cord. J Neurosurg 1990;72: 523e32. 16. Cohen AR, Wisoff JH, Allen JC, Epstein F. Malignant astrocytomas of the spinal cord. J Neurosurg 1989;70:50e4. 17. Rossitch Jr E, Zeidman SM, Burger PC, Curnes JT, Harsh C, Anscher M, et al. Clinical and pathological analysis of spinal cord astrocytomas in children. Neurosurgery 1990;27:193e6. 18. Minehan KJ, Brown PD, Scheithauer BW, Krauss WE, Wright MP. Prognosis and treatment of spinal cord astrocytoma. Int J Radiat Oncol Biol Phys 2009;73(3):727e33. 19. McLaughlin MP, Marcus Jr RB, Buatti JM, McCollough WM, Mickle JP, Kedar A, et al. Ependymoma: result, prognostic factors and treatment recommendations. Int J Radiat Oncol Bil Phys 1998;40:845e50. 20. Garcia DM. Primary spinal cord tumors treated with surgery and postoperative irradiation. Int J Radiat Oncol Biol Phys 1985;11:1933e9. 21. Huddart R, Traish D, Ashley S, Moore A, Brada M. Management of spinal astrocytoma with conservative surgery and radiotherapy. Br J Neurosurg 1993;7:473e81. 22. Kopelson G, Linggood RM, Kleinman GM, Doucette J, Wang CC. Management of intramedullary spinal cord tumors. Radiology 1980;135:473e9. 23. Isaacson SR. Radiation therapy and the management of intramedullary spinal cord tumors. J Neurooncol 2000;47:231e8. 24. Allen JC, Aviner S, Yates AJ, Boyett JM, Cherlow JM, Turski PA, et al. Treatment of high-grade spinal cord astrocytoma of childhood with “8-in-1” chemotherapy and radiotherapy: a pilot study of CCG-945.Children's Cancer Group. J Neurosurg 1998;88:215e20. 25. Packer RJ, Lange B, Ater J, Nicholson HS, Allen J, Walker J, et al. Carboplatin and vincristine for recurrent and newlydiagnosed low grade gliomas of childhood. J Clin Oncol 1993;11:850e6. 26. Foreman NK, Hay TC, Handler M. Chemotherapy for spinal cord astrocytoma. Med Pediatr Oncol 1998;30:311e2. 27. Fort DW, Packer RJ, Kirkpatric GB, Kuttesch JF, Ater JL. Carboplatin and vincristine for pediatric primary spinal cord astrocytomas. Child's Nerv Syst 1998;14:484. 28. Weiss E, Klingebiel T, Kortmann R-D, Hess CF, Bamber M. Intraspinal high-grade astrocytoma in a child-rationale for chemotherapy and more intensive radiotherapy? Child's Nerv Syst 1997;13:108e12. 29. Mora J, Cruz O, Gala S, Navarro R. Successful treatment of childhood intramedullary spinal cord astrocytomas with irinotecan and cisplatin. Neuro Oncol 2007;9:39e46.
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30. Lashford LS, Campbell RH, Gattamaneni HR, Robinson K, Walker D, Bailey C. An intensive multiagent chemotherapy regimen for brain tumors occurring in very young children. Arch Dis Child 1996;74:219e23. 31. Traul DE, Shaffrey ME, Schiff D. Spinal-cord neoplasmsintradural neoplasms. Lancet Oncol 2007;8:35e45. 32. Balmaceda C. Chemotherapy for intramedullary spinal cord tumors. J Neurooncol 2000;47:293e307.
33. Lowis SP, Pizer BL, Coakham H, Nelson RJ, Bouffet E. Chemotherapy for spinal cord astrocytoma: can natural history be modified? Childs Nerv Syst 1998;14:317e21. 34. Mottl H, Koutecky J. Treatment of spinal cord tumors in children. Med Pediatr Oncol 1997;29:293e5.
47
Official Journal of the European Paediatric Neurology Society
Original article
Pediatric intramedullary spinal cord tumors: A single center experience Tezer Kutluk a,*, Ali Varan a, Candas‚ Kafalı a, Mutlu Hayran b, €ylemezog lu c, Faruk Zorlu d, Burc¸a Aydın a, Bilgehan Yalc¸ın a, Figen So a Canan Akyu¨z , Mu¨nevver Bu¨yu¨kpamukc¸u a a
Department of Pediatric Oncology, Hacettepe University, Institute of Oncology, 06100 Ankara, Turkey Department of Preventive Oncology, Hacettepe University, Institute of Oncology, 06100 Ankara, Turkey c Department of Pathology, Hacettepe University, Faculty of Medicine, 06100 Ankara, Turkey d Department of Radiation Oncology, Hacettepe University, Faculty of Medicine, 06100 Ankara, Turkey b
article info
abstract
Article history:
Aim: To evaluate clinical and radiological findings, pathological features and treatment
Received 24 May 2013
modalities in pediatric patients with intramedullary spinal cord tumors.
Received in revised form
Patients and methods: The medical records of 36 patients with intramedullary spinal tumors
24 September 2014
were reviewed for clinical, radiological and histopathological data, chemotherapy, radio-
Accepted 28 September 2014
therapy, surgical resection, treatment responses, events, and final outcome. Survival analyses were performed.
Keywords:
Results: The median age was 7.9 years (range: 1e16 years; male/female ratio:1.4). Ma-
Children
jority of the tumors were histopathologically diagnosed as astrocytomas (n ¼ 16, 44.4%)
Intramedullary spinal tumors
and ependymomas (n ¼ 19, 52.8%); whereas one was unclassified glioma. Overall, 94% of
Outcome
the astrocytomas and 84% of the ependymomas were low-grade, only three tumors
Treatment
were high-grade. In one patient with ependymoma, histopathological grade was undetermined. The primary tumor was commonly located in thoracic (47%) and cervical segments (28%). All patients had undergone surgery (gross-total resection, 33%; subtotal resection, 45%; biopsy, 22%). Radiotherapy was administered to 26 patients (72%) and chemotherapy to 15 patients (42%). The 3-, 5- and 10-year overall survival rates were 72%, 63% and 56%, respectively; and event-free survival rates were 43%, 40% and 40%. Survival did not significantly differ with gender, age groups, lag-time, neurologic status, histopathological tumor type, tumor location, extent of resection, treatment, or treatment responses in univariate survival analyses. Survival rates were significantly higher in patients with low-grade tumors and in ependymoma patients with resected tumors. Conclusions: Patients with low-grade tumors and those who underwent gross-total tumor resection had better prognosis. Surgery remains the main treatment in intramedullary
* Corresponding author. Tel.: þ90 312 3052990; fax: þ90 312 3107018. E-mail addresses: [email protected], [email protected] (T. Kutluk). http://dx.doi.org/10.1016/j.ejpn.2014.09.007 1090-3798/© 2014 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
42
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 9 ( 2 0 1 5 ) 4 1 e4 7
spinal tumors. The role of radiotherapy and chemotherapy is limited and even controversial in low-grade tumors. © 2014 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
1.
Introduction
Central nervous system tumors are the second most common type of tumors after leukemias in children. Medulla spinalis tumors, however, are rare and account for only 4e6% of all central nervous system tumors in children.1e3 Few series about intramedullary spinal cord tumors4e6 and large series including both intra- and extramedullary tumors have been reported; whereas some papers have been included retroperitoneal tumors that are presented with spinal cord compression.7,8 The treatment of intramedullary tumors is essentially surgery, which is supplemented with radiotherapy and chemotherapy, if warranted by the clinical and histopathological findings. Most patients with intramedullary tumors present with some neurological deficit at the time of the diagnosis may get these complications aggravated by surgery and radiotherapy.9 In this study, we have evaluated clinical and radiological findings, pathological features and treatment modalities in patients with intramedullary spinal cord tumors who were treated in our department during the last 40 years.
2.
Patients and methods
We identified 36 patients who were diagnosed with medulla spinalis tumors in our institution between January 1971 and December 2009. Our department, the reference center for pediatric oncology, serves half part of Turkey. The patients who were referred to our department were from neurosurgery clinic, pediatric neurology, and department of pediatrics of our hospital, and also from the other oncology and neurosurgery clinics. We excluded patients treated at other oncology centers, those who discontinued the therapy, and those who died soon after the surgery because of surgical complications. We retrospectively analyzed the clinical, epidemiological and histopathological characteristics, treatment modalities, survival rates and prognostic criteria in these patients. All patients underwent a complete physical and neurological examination. The interval between symptom onset and diagnosis was noted. Computed tomography (CT) and/or magnetic resonance imaging (MRI) were used to evaluate the primary tumor. Spinal extension was investigated using cervical, thoracic, and lumbar MRI in most patients. Surgical resection was performed in all patients. In cases earlier than 1984, the extent of resection was determined on the basis of surgeon's opinion and postoperative CT scans, whereas after 1984, it was determined using postoperative MRI findings.
Total or gross-total resection was defined as the absence of any visible disease on postoperative imaging studies. Subtotal resection was defined as removal of >50% of the total tumor mass, with visible residual tumor on postoperative imaging studies. Biopsy was defined as the surgical removal of 180 Present Present Low-grade High-grade Cervical Cervicothoracic Thoracic Thoracolumbar Lumbar Lumbosacral Holokordal Brain stem þ cervical None CCNU based regimen Others Performed Complete response Partial response No response Total resection Subtotal resection Biopsy
Astrocytoma (n ¼ 16)
Ependymoma (n ¼ 19)
All patientsa (n ¼ 36)
5.50 1.33 12.0 5 (31.3%) 10 (62.5%) 1 (6.3%) 8 (50.0%) 8 (50.0%) 11 (68.8%) 5 (31.3%) 13 (81.3%) 6 (37.5%) 15 (93.8%) 1 (6.3%) 4 (25.0%) 2 (12.5%) 3 (18.8%) 2 (12.5%) 2 (12.5%) 0 (0.0%) 2 (12.5%) 1 (6.3%) 13 (81.3%) 2 (12.5%) 1 (6.3%) 13 (81.3%) 2 (12.5%) 10 (62.5%) 4 (25.0%) 1 (6.3%) 9 (56.3%) 6 (37.5%)
12.0 1.25 16.0 4 (21.1%) 3 (15.8%) 12 (63.2%) 12 (63.2%) 7 (36.8%) 10 (52.6%) 9 (47.4%) 14 (73.7%) 9 (47.4%) 16 (88.9%) 2 (11.1%) 1 (5.3%) 2 (10.5%) 6 (31.6%) 8 (42.1%) 0 (0.0%) 1 (5.3%) 0 (0.0%) 1 (5.3%) 7 (36.8%) 10 (52.6%) 2 (10.5%) 13 (68.4%) 10 (52.6%) 7 (36.8%) 2 (10.5%) 10 (52.6%) 7 (36.8%) 2 (10.5%)
7.5 1.25 16.0 9 (25.0%) 13 (36.1%) 14 (38.9%) 21 (58.3%) 15 (41.7%) 22 (61.1%) 14 (38.9%) 28 (77.8%) 15 (41.7%) 32 (91.4%) 3 (8.6%) 6 (16.7%) 4 (11.1%) 9 (25.0%) 10 (27.8%) 2 (5.6%) 1 (2.8%) 2 (5.6%) 2 (5.6%) 21 (58.3%) 12 (33.3%) 3 (8.3%) 26 (72.2%) 13 (36.1%) 17 (47.2%) 6 (16.7%) 12 (33.3%) 16 (44.4%) 8 (22.2%)
Including 1 glial tumor.
The most common complaints were weakness/gait disturbances (83.3%) and pain (55.6%), the most frequent physical examination findings were deep tendon reflex changes (80%) and motor deficits (78%). The neurologic status at the time of diagnosis, as assessed using the modified McCormick scale was as follows: grades IeII (normal or mild deficit) in 14 patients (39%) and grades IIIeV (moderate to severe deficit) in 22 patients (61%). The histopathological diagnoses were astrocytomas (n ¼ 16, 44.4%), ependymomas (n ¼ 19, 52.8%), and unclassified glioma (n ¼ 1) (Table 1). All 15 patients with astrocytoma and 16 patients with ependymomas were low-grade. Three patients were highgrade including two ependymomas and one astrocytoma. One patient was ependymoma of undetermined grade. The median interval between symptom onset and diagnosis was 180 days (range: 10e1080 days). Moreover this interval did not differ with histopathological tumor type, but was longer in the case of low-grade tumors (6 months) than in the case of high-grade tumors (1.5 months, p ¼ 0.027). Surgery was performed in all patients for either diagnosis or treatment. Gross total resection was performed in 12 (33.3%) patients, subtotal resection in 16 (44.5%) patients, and biopsy in 8 (22.2%) patients. The rate of gross total resection was significantly higher in the case of ependymomas than in the case of astrocytomas (10 versus 1 patient).
We selected chemotherapy and/or radiotherapy protocols according to histopathological findings. Chemotherapy was administered to 3 patients with astrocytomas. Two of these patients had low-grade tumors and were treated with the PCV regimen; the third one had a high-grade tumor and was treated with the COPP regimen. All 12 patients with ependymomas underwent chemotherapy including two patients with high-grade tumors. All 10 patients with lowgrade tumors and one patient with high grade tumor were treated with the PCV regimen. The second patient with a highgrade tumor was treated using CDDP-based regimen. Radiotherapy was administered to 13 patients each from the astrocytoma (3750e5040 cGy) and ependymoma groups (1080e5000 cGy). The overall 3- and 5-year survival rates for all the patients were 71.7% and 62.8%, whereas event-free survival rates were 49.1% and 43.1%, respectively (Fig. 1). Median follow-up time was 7.75 years. The overall 5-year survival rate was 56% in the astrocytoma group and 68% in the ependymoma group (p ¼ 0.9) (Fig. 2). The factors significantly associated with overall and event-free survival are presented in Table 2. Patients with low-grade tumors had higher survival rates than the patients with high-grade tumors (Table 2). The overall survival rate did not differ with the extent of surgical resection in the astrocytoma group. In the ependymoma group, the overall survival was longer in patients who
44
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 9 ( 2 0 1 5 ) 4 1 e4 7
Fig. 1 e Overall and event-free survival rates of 36 patients with intramedullary spinal cord tumors.
underwent gross total or subtotal resection than those who underwent tumor biopsy (Table 2). Again in the ependymoma group, overall survival was lower in patients aged 3e10 years than in those aged 3 years or >10 years. These associations observed for the extent of resection and age in the ependymoma patients was not observed with astrocytomas. Tumor
1,0
location, interval between symptom onset and diagnosis, chemotherapy, and radiotherapy did not have any effect on overall survival. The event-free survival rate (EFS) did not significantly differ between the astrocytoma group (5-year EFS: 43.8%) and the ependymoma group (5-year EFS: 42.1%, p ¼ 0.46) (Fig. 2),
____ Astrocytoma, overall survival _ _ _ _ _ Astrocytoma, event-free survival _ _ _ Ependymoma, overall survival _ _ _ _ _ _ Ependymoma, event-free survival
,9 ,8
Survival (%)
,7 ,6 ,5 ,4 ,3 ,2 ,1 0,0 0
1
2
3
4
5
6
7
8
9
10 11 12 13 14 15 16 17 18 19 20
Time (years)
Log-rank; overall survival, p=0.928 event-free survival, p=0.46
Fig. 2 e Overall and event-free survival rates according to histopathology.
45
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 9 ( 2 0 1 5 ) 4 1 e4 7
Table 2 e Significant factors associated with overall and event-free survival. Overall survival (OS) Grade (all patients) Age Group (ependymoma patients) Extent of resection (ependymoma patients)
5-year OS (SE) Low grade High grade [0e3] [3e10] 10þ Total Subtotal Biopsy
Event-free survival Grade (all patients) Extent of resection (all patients)
Low grade High grade Total Subtotal Biopsy
67.7% 33.3% 75.0% 0% 57.1% 80.0% 71.4% 0%
(8.4) (27.2) (21.7) () (17.2) (12.6) (17.1) ()
Median OS (years)
p-valuea
HR (95%CI)b
25þ 3.75 5.67 3.75 10.25þ 7.91 10.25þ 0.42
0.026
1 3.9 (1.1e14.3) 1 5.6 (0.7e40.8) 0.67 (0.12e3.7) 1 0.86 (0.19e3.9) 8.6 (1.3e56.7)
0.015
0.014
5-year EFS (SE)
Median EFS (years)
p-valuea
HR (95%CI)b
48.7% (9.0) 0% () 63.6% (14.5) 25.0% (10.8) 50.0% (17.7)
6.33 0.20 10.25þ 1.75 0.75
0.023
1 4.0 (1.1e14.9) 1 3.6 (1.2e11.0) 1.9 (0.48e7.8)
0.051
SE: standard error. a Log-rank test. b 95% confidence intervals (CI) and hazard ratio (HR) as calculated separately by the Cox regression model (a value of 1 for HR is used for the reference category).
but differed between patients with low- and high-grade tumors (Table 2). In addition, the event-free survival rate was higher in patients who underwent gross total resection than those who underwent subtotal resection or tumor biopsy (Table 2). However, event-free survival did not significantly differ with the age, tumor location, interval between symptom onset and diagnosis, chemotherapy, and radiotherapy. Functional outcomes were retrospectively examined from patient-files. Eight patients had motor deficits, 10 patients had neurogenic and bladder dysfunction, and sensorineural impairment, and 16 patients had spinal deformity (Table 3).
4.
Discussion
In our series, the overall and event-free survival rates of astrocytoma were similar with ependymoma, and survival was better in low grade tumors than the high grade tumors (p ¼ 0.02). Fortunately, most patients had low-grade tumors. Extent of the resection and age group were the other important factors. Total surgical resection has better survival rates.
Table 3 e Functional outcomes of 36 patients with intramedullary spinal cord tumors. Motor deficit Unable to walk Walking with support Ambulant independently Unknown Other deficits Neurogenic bladder Bowel dysfunction (constipation or incontinence) Somatosensory impairment No abnormality Unknown Spinal deformity:
2 6 27 1 7 2 1 25 1 16
Intramedullary spinal tumors accounted for only 4e6% of all CNS tumors.1e3 Most series in the literature have included paraspinal tumors such as neuroblastomas, lymphomas, rhabdomyosarcomas, and metastatic tumors along with primary medulla spinalis tumors.7,8 In a recent study from Munster that included 340 patients with brain tumors from seven centers, only 21 patients (6.17%) had primary medulla spinalis tumors.7 We included patients only with intramedullary spinal tumors excluding those with extramedullary or metastatic tumors. Our single-center study analyzed data from 38 years, which is one of the longest periods reported in the literature. Age distribution of our cases is similar to that reported by O'Sullivan et al.10 Scheinemann et al.11 reported the same age with 5.8 years in their study on spinal glioma patients, but most of their patients (41%) were under 4 years. The male/ female ratio in their study was 2.6. In our study, most of the astrocytoma patients (62%) were aged between 3 and 10 years. Most of the studies have reported male/female ratios between 1.2 and 1.4.10e14 The patients with intraspinal tumors have nonspecific complaints, which are occasionally asymptomatic. Intraspinal tumors in children are low-grade and progress slowly, and therefore their diagnosis can be delayed. The interval between symptom onset and diagnosis was approximately 10 months in the case of low-grade tumors11,13 and 2e7 months in the case of high-grade tumors.14e16 The high rate of severe deficit was probably due to delays in admission to our center. Other studies have reported similar symptoms as in our study, but with a better neurological status (McCormick grade II).9,11,13,17 Radiotherapy has been successfully used to treat both ependymomas and astrocytomas10,18e21 in some series. O'Sullivan et al.10 used radiotherapy in cases who had uncomplete resection. Besides Kopelson et al.22 suggested radiotherapy to all patients either totally resected or unresected. However, contradictory results have been reported in other studies.2,23 Another reason for avoiding radiotherapy is that, radiotherapy can cause secondary malignancy and
46
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 9 ( 2 0 1 5 ) 4 1 e4 7
growth retardation. In present study, radiotherapy was not used in low-grade spinal tumors unless there was a recurrent disease. Chemotherapy has been used to treat spinal tumors in a few studies. Procarbazine þ CCNU þ vincristine, eightdrugs-in-one day, and carboplatin and vincristine regimens have all been used, with similar results.15,24e29 United Kingdom Children's Cancer Study Group have successfully used carboplatin, vincristine, cyclophosphamide, methotrexate protocol in high grade astrocytoma,30 Packer et al.25 reported that, carboplatin plus vincristine has resulted in survival rates of 52% and 62% in recurrent and newly diagnosed low grade astrocytoma, respectively. Oppositely, carboplatin and vincristine have not improved the disease in a patient reported by Foreman et al26. Although some papers have mentioned that chemotherapy and radiotherapy can be used for both low- and high-grade tumors, it is generally accepted that low-grade spinal tumors should be followed up without these treatments, if total or subtotal resection has been performed.31e34 Our series is one of the largest series of intramedullary spinal tumors from a single center. We found that histopathological tumor grade was the most important prognostic factor. It can be conclude that, although we treated our patients with both radiotherapy and/or chemotherapy, patients with low-grade spinal tumors can be followed up without these treatments, if total or subtotal surgical resection has been performed.
Conflict of interest We have no conflict of interest.
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