Childs Nerv Syst (2010) 26:359–365 DOI 10.1007/s00381-009-0979-3
ORIGINAL PAPER
Neurological complications of neuroblastic tumors: experience of a single center G. Burca Aydin & M. Tezer Kutluk & Munevver Buyukpamukcu & Canan Akyuz & Bilgehan Yalcin & Ali Varan
Received: 20 May 2009 / Revised: 23 June 2009 / Published online: 28 August 2009 # Springer-Verlag 2009
Abstract Aim This study aims to evaluate the prevalence and clinical characteristics of neurological complications in patients with newly diagnosed neuroblastic tumors (NT). Patients and method Hospital file search was performed in patients with NT, and neurological complications, clinical, and treatment features were analyzed. Results Out of 523 patients with NT, 19 patients had Horner's syndrome, 9 patients had opsoclonus-myoclonusataxia syndrome (OMA), 11 patients had central nervous system (CNS) involvement, and 49 patients had spinal cord compression (SCC) at diagnosis. During follow-up, seven more patients had CNS metastases. Survival rates were poor in patients with CNS involvement; all died at a median of 7.9 months after diagnosis. The neurological symptoms and signs of patients with SCC were mild, moderate, and severe in 13, 9, and 22 patients, respectively. Sphincter deficiency and sensory loss were diagnosed in 52.3% and 43.2% of patients. The neurological deficits of 11/17 patients who had symptoms less than 4 weeks were G. B. Aydin Department of Pediatric Oncology, Ankara Oncology Research Hospital, 06070, Demetevler, Ankara, Turkey M. T. Kutluk : M. Buyukpamukcu : C. Akyuz : B. Yalcin : A. Varan Department of Pediatric Oncology, Hacettepe University Institute of Oncology, 06100, Yenisehir, Ankara, Turkey G. B. Aydin (*) : M. T. Kutluk (*) Angora evleri, Pusula sok. No:7, Beysukent, Ankara, Turkey e-mail:
[email protected] e-mail:
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completely resolved or improved. The incidence of sequelae after laminectomy, radiotherapy, and chemotherapy were 46.2%, 66.6%, and 13.6%, respectively. Conclusion The prevalence rates of Horner's syndrome, OMA, CNS metastasis, and SCC were found to be 3.6%, 1.8%, 2.2%, and 9.4%, respectively. Metastasis to the CNS indicated a very poor prognosis. No differences in neurological improvement in patients with SCC were found between those treated with radiotherapy, laminectomy, or chemotherapy alone, but laminectomy and radiotherapy caused significant late sequelae. Early diagnosis and proper management is critical to avoid long-term sequelae in patients with SCC. Keywords Neuroblastoma . CNS metastases . Horner's syndrome . OMA . Spinal cord compression . Neurological deficit . Brain metastases
Introduction Neuroblastic tumors have characteristic neurological manifestations, such as Horner's syndrome, opsoclonusmyoclonus-ataxia syndrome (OMA), and spinal cord compression (SCC). Horner's syndrome is a characteristic symptom of the infiltration of tumor into the cervical paraspinal ganglion; it is diagnosed by heterochromia, ptosis, myosis, and enophthalmus. OMA is a rare and special type of paraneoplastic syndrome of autoimmune origin, which manifests as ataxia and/or opsomyoclonus. The prevalence rates of OMA have been reported to be 2– 3% in patients with neuroblastoma (NBL) [1–4]. SCC is another presenting sign of NBL. Since these tumors may arise from anywhere along the paravertebral sympathetic chain, they may involve paraspinal ganglions and extend into the neural foramens of the vertebral bodies to grow as
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dumbbell tumors. The compression of nerve roots and the spinal cord by a dumbbell tumor may cause transverse myelitis [5–15]. Metastasis to the central nervous system (CNS) is the worst neurological complication of NBL. Involvement of CNS is not common among patients with neuroblastoma. The usual pattern of CNS involvement is found in progressive disease or relapse, and it is actually rare on admission [15–22]. Except CNS involvement, other conditions are not defined as poor prognostic factors, but usually cause morbidity. We aimed to present the neurological findings from our group of patients with neuroblastic tumors and their effects to the prognosis, as well as to increase the awareness of neurological features which are critical on quality of life.
Patients and methods A retrospective search of previously untreated patients with neuroblastic tumors (neuroblastoma, ganglioneuroblastoma, and ganglioneuroma) was performed at the Hacettepe University Department of Pediatric Oncology between March 1972 and December 2004. Selection criteria were as follows: having radiological or clinical signs of SCC, Horner's syndrome, OMA, or CNS metastases. Reports of magnetic resonance images and/or computed tomographies of the patients were re-evaluated. Diagnosis of neuroblastoma was based upon tissue biopsy specimens or tumor cells in bone marrow with positive urinary vanillylmandelic acid. Since most of the patients were diagnosed and staged
before by the International Neuroblastoma Staging System (INSS), in first decades, all patients were staged according to the Evans staging system (Table 1) [23, 24]. Patient demographic and clinical characteristics, including age, sex, primary tumor site, stage, signs and symptoms of SCC, treatment modalities, and long-term sequelae were analyzed. For SCC, neurological deficits were grouped as mild (only motor deficit), moderate (motor and sphincter deficit), and severe (plegia). For the prevalence rates of Horner's syndrome and transverse myelitis, the patients with all neuroblastic tumors—NBL, ganglioneuroblastoma (GNBL), and ganglioneuroma (GN)—were selected. For the prevalence rates of OMA and CNS metastasis, only patients with NBL and GNBL were selected. The statistical significance between the treatment modalities and improvement of neurological symptoms and long-term sequelae was analyzed using the chi-square test. The mean lifespan for patients with CNS metastases on admission and at follow-up were compared using a oneway analysis of variance test. Event-free survivals (EFS) and overall survivals (OS) were calculated with the Kaplan–Meier method, and differences in survival were analyzed with the log rank test [25].
Results During 33 years, 523 patients with newly diagnosed neuroblastic tumors were treated: NBL was diagnosed in
Table 1 Evans and INSS staging systems Stage Evans staging system 1
2
3
4
4S
INSS staging system
Tumor confined to the organ or structure of origin
Localized tumor with complete gross excision, with or without microscopic residual disease; representative ipsilateral lymph nodes negative for tumor microscopically (nodes attached to and removed with the primary tumor may be positive) Tumors extending in continuity beyond the organ or structure 2A: localized tumor with incomplete gross excision; representative of origin but not crossing the midline. Regional lymph nodes ipsilateral nonadherent lymph nodes negative for tumor microscopically on the homolateral side may be involved 2B: localized tumor with or without complete gross excision, with ipsilateral nonadherent lymph nodes positive for tumor. Enlarged contralateral lymph nodes must be negative microscopically Tumors extending in continuity beyond the midline. Regional Unresectable unilateral tumor infiltrating across the midline, with or lymph nodes may be involved bilaterally without regional lymph node involvement; localized unilateral tumor with contralateral regional lymph node involvement; or midline tumor with bilateral extension by infiltration (unresectable) or by lymph node involvement Remote disease involving skeleton, organs, soft tissues, or distant lymph node groups, etc.
Any primary tumor with dissemination to distant lymph nodes, bone, bone marrow, liver, skin, and/or other organs (except as defined for stage 4S) Patients who would otherwise be stage 1 or 2 but who have Localized primary tumor (as defined for stage 1, 2A, or 2B), with remote disease confined only to one or more of the following dissemination limited to skin, liver, and/or bone marrow (limited to sites: liver, skin, or bone marrow (without bone metastases) infants 0.05). Sixty-three percent (31 of the 49) of the patients with SCC were older children (>18 months), and the rest (18 patients, 37%) were 18 months or younger. The duration of symptoms in the infant group was shorter than in the older children group (p= 0.03). However, clinical neurological improvement was not statistically different between age groups (p=0.3). On admission, motor dysfunction was noted to varying degrees in 44 patients with SCC (Table 4). The neurological symptoms and signs were mild in 13 patients (29.5%), moderate in 9 patients (20.5%), and severe in 22 (50%) patients. Sphincter deficiency and sensory loss were diagnosed in 23 (52.3%) and 19 (43.2%) patients, respectively. Sixteen patients with urinary incontinence also had
anal sphincter dysfunction. The neurological deficits of 11/ 17 patients who had symptoms less than 4 weeks were completely resolved or improved, while 8/27 patients who had symptoms longer than 4 weeks were not resolved or improved (64.7% vs 29.6%; p=0.02). In the first decade of the study period, nine of the 14 (64.3%) patients had severe neurological deficit, while during the last decade, eight of the 21 (47%) had severe neurological deficit. But, the improvement of symptoms did not change during decades (p=0.4). The prevalence of late sequelae was similar in the 1970s, 1980s, 1990s, and after (23.8%, 28.6%, and 21.4%, respectively). Treatment options included chemotherapy in 47 patients, RT in 14 patients, and laminectomy in 13 patients. Laminectomy was mostly preferred in nonmetastatic disease and in patients with mild and moderate neurological deficits in early years. However, laminectomy did not reduce the neurological deficits (p=0.3). Only six patients (46.1%) who had laminectomy recovered or improved. Among the 14 patients treated with RT, nine improved (64.3%). Twenty-two patients were treated with only chemotherapy, mostly during last decade. The rate of the improvement of symptoms was 45.5%. In 23 patients, a full recovery was observed or only minor deficits were noted. Most of the patients with mild deficits recovered or improved (76.9%). The rate of recovery or improvement was significantly lower in patients with severe deficits (18.2%) than in patients with mild deficits
Table 4 Neurological signs and symptoms of 49 patients with spinal cord compression Neurological abnormality
Number
Percentage
None Mild (only motor deficit) Moderate (motor and sphincter deficit) Severe (plegia) Sensory loss
5 13 9 22 19
10.2 26.5 18.4 44.9 38.8
Anal sphincter deficit Urinary sphincter deficit Treatment Chemotherapy Radiotherapy Laminectomy Improvement Complete or partial No improvement Long-term sequelae Scoliosis Neurogenic bladder Both
16 23
32.7 46.9
47 14 13
95.9 28.6 26.5
23 26 12 6 8 2
46.9 53.1 24.5 12.2 16.3
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(p=0.002). Twelve patients had long-term sequelae of scoliosis (six patients) and neurogenic bladder (eight patients). Six of these patients were managed with laminectomy on admission, and eight were given RT. For the patients who had laminectomy and were treated with RT, late sequelae rates were 46.2% and 66.6%, respectively. Only three of 22 patients treated with chemotherapy alone had late sequelae (13.6%). Central nervous system involvement Eleven patients had CNS metastases on admission. The prevalence rate was 2.2% among 500 newly diagnosed patients with neuroblastoma. All had advanced diseases (stage 4) on admission, giving the prevalence of 4.3% among the 257 patients with stage 4 disease. The median age of eight boys and three girls with CNS disease was 4.6 years (0.6–12 years). Six of these patients presented with mass lesions in the brain parenchyma, and three had leptomeningeal involvement. Two patients had parasellar mass lesion extending from the retro-orbital tumor and posterior fossa mass from the cervical tumor. The 2-year overall survival rate for 11 patients with CNS metastasis at diagnosis was 9.1%. All patients died 0.3–37.9 months after the time of diagnosis (median 7.9 months). Six patients progressed with newly developed CNS findings: four patients with diffuse meningeal infiltration, one with tumor mass in cerebral parenchyma, and one with both conditions. Seven patients, who did not have CNS involvement on admission, progressed or relapsed with CNS disease on follow-up (2.8%). All but one patients were diagnosed after 1990s. Four patients had isolated CNS relapse, remaining three patients had also bone and bone marrow involvement. Three patients had mass lesions in the brain parenchyma, three had leptomeningeal involvement, and one had multiple nodular dural metastases. The last patient relapsed with multiple dural metastases and bone marrow involvement 7.3 years after diagnosis. He was given an intensive chemotherapy protocol and craniospinal radiotherapy and was followed up with slow progressive disease until he died at 10 years of age. All of the patients relapsed or progressed and eventually died from the disease. Bone metastases (including calvarium) were diagnosed in 13 patients and periorbital metastases were diagnosed in four patients on admission. The median time to CNS disease onset was 17.8 months (5.8–87.8 months) for the patients who did not have CNS metastasis on admission. These patients died after a median of 18.3 months from time of diagnosis (7.2– 119.4 months) and a median of 3.2 months (0–31.5 months) from the onset of CNS metastasis. The 2-year overall survival rate for the patients with and without CNS metastasis on admission was 9% and 28.6%, respectively. The overall survival rates of the patients with or without CNS disease on admission were not statistically different (p=0.06).
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Discussion Neurological symptoms in cancer patients can occur at any time: at diagnosis, during treatment, or at progression, mostly due to direct tumor invasion. In childhood, some special neurological syndromes can be noted at diagnosis. Neuroblastic tumors are special group of childhood tumor family, which may cause various neurological complications at diagnosis. Opsoclonus-myoclonus-ataxia syndrome is a rare neurological syndrome of neuroblastoma. In our group, 1.8% of the patients were diagnosed with OMA. The prevalence rate and clinical characteristics were similar to previous reports. The prevalence in the literature was reported to be approximately 2–3% of patients, and most of them were younger than 3 years of age [2–4]. Patients with OMA were reported to have longer survival in NBL. Most of the patients were reported to have localized disease. In our series of patients, two patients with stage 4 disease and one patient with stage 3 disease died with progressive disease. Six of nine patients (66.7%) were alive at the time of the analysis. The survival rate of this group was much better than that of the entire group, consistent with literature [1– 4]. The neurological findings for six patients were improved significantly and two patients recovered completely after chemotherapy without any immune suppressive therapy. In only one patient, late neurological sequelae were severe. He had severe mental retardation, persisting opsoclonus, myoclonus, and ataxia. There are conflicting reports in literature. Some authors suggested that chemotherapy helps immune suppression and improves neurological outcome [2–4], but some children worsen after surgery. In literature, most of the patients with OMA and localized disease were treated only with surgery. But in our series of patients, all were given chemotherapy either. Immune suppressive side effect of chemotherapy might explain why most of our patients had no major sequelae. Since OMA is one of the rare paraneoplastic syndromes of NBL, world-wide registry of these patients and review of treatment choices will be helpful for standardizing treatment and improving quality of life. Spinal cord compression is one of the emergency situations in pediatric oncology practice. Quick diagnosis and management is needed to shrink the tumor and regain neurological functions. Our group of patients with SCC and neuroblastoma is one of the largest series from a single center. Demographic findings, such as predominance of thoracic location and prevalence of paraplegia, bladder, and/or bowel dysfunction, were similar to literature. The duration of the symptoms was an important determinant for late sequelae. The patients, experiencing symptoms less than 4 weeks, were more likely to improve, while others who had longer periods of symptoms experienced more
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sequelae. These findings were similar to the results from previous studies [5–14]. The severity of symptoms was another important determinant of neurological recovery [5, 7, 10]. In most of the patients with mild deficit, symptoms improved either completely or significantly. However, the rate of recovery or improvement was low among patients with severe deficits. The management of SCC in NBL has been debated in previous reports [5–15]. In some reports, laminectomy and radiotherapy were the main treatment choices [6, 12]. In our study group, six patients were managed with laminectomy on admission and eight were given RT. For these patients, the rates of late sequelae were 46.2% and 66.6%, respectively. Laminectomy was mostly preferred in patients with local disease, when the objective was both obtaining tissue diagnosis and emergency decompression. Most of our patients with disseminated disease were treated with chemotherapy first. Only 13.6% of the patients who were treated with only chemotherapy had late sequelae. Later reports also suggest that chemotherapy should be considered as the initial treatment [5, 7, 8, 10]. Radiotherapy during the acute phase did not help the recovery or improvement of symptoms. Laminectomy added no benefit to prevent permanent neurological disability. In addition, laminectomy or radiotherapy of the growing vertebral column caused vertebral instability and asymmetrical growth, leading to scoliosis and loss of vertebral growth plates and to shorter stature [5, 7, 10, 11]. The most important problem in treating a child with paravertebral mass is the differential diagnosis. It should be noted that benign lesions such as vascular lesions, benign bone tumors, plexiform neurofibroma, tuberculosis, or ganglioneuroma can cause SCC as well as malignant tumors. And some malignant tumors might have long symptom period as can be expected with a benign tumor. The differential diagnosis also differs in adulthood and childhood. After detailed clinical and radiological evaluation, tru-cut biopsy might help obtaining tissue for histopathological diagnosis and biological risk determinants of a neuroblastic tumor. The decision of priority treatment choice should be discussed by treatment team, consisting pediatric oncologist, pediatric neurosurgeon or pediatric surgeon, and radiologist. Emergency surgery can be avoided in most of the patients. Laminectomy should be reserved for patients with acute and severe deficits that are unresponsive after several days of chemotherapy. Considering the side effects on a growing child, RT, like laminectomy, should be recommended conservatively. Chemotherapy should be the first choice of treatment for patients with SCC. Treatment strategies have changed over the years, but late sequelae have been constant over decades, mostly due to increased symptom duration. It seems that early access to medical care and increased
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awareness of SCC findings have major role to help reducing neurological morbidity. Metastasis to the central nervous system is not a frequent finding in neuroblastoma, but it has been reported as distinct finding in recent years and seems to be reported more frequently in the future. In some centers, the prevalence rate was reported to be 2.3% to 25% on admission [15–22] and up to 16% in relapse [17, 19, 20]. Of all our neuroblastoma patients, 2.2% were diagnosed with CNS metastases on admission. The prevalence rate among newly diagnosed stage 4 patients was 4.3%, and incidence of CNS relapse among patients who relapsed was 2.8%. The actual prevalence rate of CNS involvement in disease progression might be higher than it has been reported in patients with advanced disease. In the early decades, CNS disease might not have been accurately diagnosed due to technical limitations. Some patients with progressive disease refused further treatment, and CNS metastases (that would be occurred during follow-up) might have been missed. Given the wide range of prevalence of CNS metastasis, patients with unexplained neurological symptoms or deterioration should undergo detailed radiological CNS evaluation. CNS involvement or metastasis should be highly suspected among these patients with disseminated neuroblastoma. Metastasis to the CNS should be regarded as a poor prognostic sign. In our study group, the median time to death was 7.9 months for patients with CNS involvement on admission. The median time to death was even shorter (3.2 months) for patients who had newly developed CNS involvement after disease progression. One patient with CNS disease on admission lived 3 years, and another one who had progressive CNS disease lived for 10 years. Patients with CNS metastasis had lower survival rates in literature; usually, times of death were reported very short. Extended survival time for these patients was extremely unusual. Rarely, long-term survival may occur [15–22]. With the improved outcome of neuroblastoma and sophisticated radiological diagnostic techniques, it can be expected that more patients will be diagnosed with CNS disease in the future. Intensive chemotherapies provide more effective disease control in NBL. In patients with calvarium or periorbital metastases on admission, CNS may become a sanctuary site for tumor cells, like leukemia. All patients with CNS metastases should be treated vigorously. The fatal outcome of this group of patients necessitates the use of more or selectively intensive schema for the prevention and treatment of CNS disease. In stage 4 patients with calvarium or periorbital metastases, CNSdirected therapy might be discussed. Neurological complications whether they cause lifethreatening problems, like CNS metastases, or life-long morbidity, like OMA and SCC, need special approach.
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Especially for patients in low or intermediate risk groups, late sequelae are of great importance. Growing young children with neurological morbidity will have lots of social, physiological, and economic costs. Early diagnosis and proper management is critical to avoid long-term sequelae in patients with neurological complications.
References 1. Russo C, Cohn SL, Petruzzi MJ, de Alarcon PA (1997) Long-term neurologic outcome in children with opsoclonus-myoclonus associated with neuroblastoma: a report from the Pediatric Oncology Group. Med Pediatr Oncol 28(4):284–288 2. Pranzatelli MR (1992) The neurobiology of the opsoclonusmyoclonus syndrome. Clin Neuropharmacol 15(3):186–228 3. Rudnick E, Khakoo Y, Antunes NL, Seeger RC, Brodeur GM, Shimada H, Gerbing RB, Stram DO, Matthay KK (2001) Opsoclonus-myoclonus-ataxia syndrome in neuroblastoma: clinical outcome and antineuronal antibodies—a report from the Children’s Cancer Group Study. Med Pediatr Oncol 36(6):612–622 4. Matthay KK, Blaes F, Hero B, Plantaz D, De Alarcon P, Mitchell WG, Pike M, Pistoia V (2005) Opsoclonus myoclonus syndrome in neuroblastoma a report from a workshop on the dancing eyes syndrome at the advances in neuroblastoma meeting in Genoa, Italy, 2004. Cancer Lett 228(1–2):275–282 5. De Bernardi B, Balwierz W, Bejent J, Cohn SL, Garre ML, Iehara T, Plantaz D, Simon T, Angelini P, Cama A, London WB, Kramer K, Katzenstein HM, Tortori-Donati P, Rossi A, D’Angio GJ, Evans AE (2005) Epidural compression in neuroblastoma: diagnostic and therapeutic aspects. Cancer Lett 228(1–2):283–299 6. Sundaresan N, Sachdev VP, Holland JF, Moore F, Sung M, Paciucci PA, Wu L, Kelligher K, Hough L et al (1995) Surgical treatment of spinal cord compression from epidural metastasis. J Clin Oncol 13(9):2330–2335 7. Katzenstein HM, Kent PM, London WB, Cohn SL (2001) Treatment and outcome of 83 children with intraspinal neuroblastoma: the Pediatric Oncology Group experience. J Clin Oncol 19 (4):1047–1055 8. Sandberg DI, Bilsky MH, Kushner BH, Souweidane MM, Kramer K, Laquaglia MP, Panageas KS, Cheung NK (2003) Treatment of spinal involvement in neuroblastoma patients. Pediatr Neurosurg 39(6):291–298 9. Plantaz D, Rubie H, Michon J, Mechinaud F, Coze C, Chastagner P, Frappaz D, Gigaud M, Passagia JG, Hartmann O (1996) The treatment of neuroblastoma with intraspinal extension with chemotherapy followed by surgical removal of residual disease. A prospective study of 42 patients—results of the NBL 90 Study of the French Society of Pediatric Oncology. Cancer 78(2):311–319 10. Hoover M, Bowman LC, Crawford SE, Stack C, Donaldson JS, Grayhack JJ, Tomita T, Cohn SL (1999) Long-term outcome of patients with intraspinal neuroblastoma. Med Pediatr Oncol 32 (5):353–359 11. Paulino AC, Fowler BZ (2005) Risk factors for scoliosis in children with neuroblastoma. Int J Radiat Oncol Biol Phys 61(3):865–869 12. Punt J, Pritchard J, Pincott JR, Till K (1980) Neuroblastoma: a review of 21 cases presenting with spinal cord compression. Cancer 45(12):3095–3101
365 13. De Bernardi B, Pianca C, Pistamiglio P, Veneselli E, Viscardi E, Pession A, Alvisi P, Carli M, Donfrancesco A, Casale F, Giuliano MG, di Montezemolo LC, Di Cataldo A, Lo Curto M, Bagnulo S, Schumacher RF, Tamburini A, Garaventa A, Clemente L, Bruzzi P (2001) Neuroblastoma with symptomatic spinal cord compression at diagnosis: treatment and results with 76 cases. J Clin Oncol 19(1):183–190 14. Gunes D, Uysal KM, Cetinkaya H, Gazeteci Tekin H, Yuceer N, Sarialioglu F, Olgun N (2009) Paravertebral malignant tumors of childhood: analysis of 28 pediatric patients. Childs Nerv Syst 25:63–69 15. Tasdemiroglu E, Ayan I, Kebudi R (1998) Extracranial neuroblastomas and neurological complications. Childs Nerv Syst 14 (12):713–718 16. Matthay KK, Brisse H, Couanet D et al (2003) Central nervous system metastases in neuroblastoma: radiologic, clinical, and biologic features in 23 patients. Cancer 98(1):155–65 17. Kramer K, Kushner B, Heller G, Cheung NK (2001) Neuroblastoma metastatic to the central nervous system. The memorial sloan-kettering cancer center experience and a literature review. Cancer 91(8):1510–1519 18. DuBois SG, Kalika Y, Lukens JN, Brodeur GM, Seeger RC, Atkinson JB, Haase GM, Black CT, Perez C, Shimada H, Gerbing R, Stram DO, Matthay KK (1999) Metastatic sites in stage IV and IVS neuroblastoma correlate with age, tumor biology, and survival. J Pediatr Hematol Oncol 21(3):181–189 19. Shaw PJ, Eden T (1992) Neuroblastoma with intracranial involvement: an ENSG Study. Med Pediatr Oncol 20(2):149– 155 20. Kellie SJ, Hayes FA, Bowman L, Kovnar EH, Langston J, Jenkins JJ 3rd, Pao WJ, Ducos R, Green AA (1991) Primary extracranial neuroblastoma with central nervous system metastases characterization by clinicopathologic findings and neuroimaging. Cancer 68(9):1999–2006 21. Paulino AC, Nguyen TX, Barker JL Jr (2003) Brain metastasis in children with sarcoma, neuroblastoma, and Wilms' tumor. Int J Radiat Oncol Biol Phys 57(1):177–183 22. Jaing TH, Yang CP, Hung IJ, Wang HS, Tseng CK, Hsueh C (2003) Brain metastases in children with neuroblastoma—a single-institution experience. Med Pediatr Oncol 41(6):570–571 23. Evans AE, D’Angio GJ, Randolph J (1971) A proposed staging for children with neuroblastoma. Children’s cancer study group A. Cancer 27(2):374–378 24. Brodeur GM, Pritchard J, Berthold F, Carlsen NL, Castel V, Castelberry RP, De Bernardi B, Evans AE, Favrot M, Hedborg F et al (1993) Revisions of the international criteria for neuroblastoma diagnosis, staging, and response to treatment. J Clin Oncol 11(8):1466–1477 25. Peto R, Pike MC, Armitage P, Breslow NE, Cox DR, Howard SV, Mantel N, McPherson K, Peto J, Smith PG (1977) Design and analysis of randomized clinical trials requiring prolonged observation of each patient. II. Analysis and examples. Br J Cancer 35 (1):1–39 26. Aydin GB, Kutluk MT, Büyükpamukçu M, Akyüz C, Kale G, Şenocak ME, Yalçın B, Varan A (2009) Neuroblastoma in Turkish children: experience of a single center. J Pediatr Hematol Oncol 31(7):471–480 27. Emir S, Akyüz C, Büyükpamukçu M (2003) Correspondence: treatment of the neuroblastoma-associated opsoclonus-myoclonusataxia (OMA) syndrome with high-dose methylprednisolone. Med Pediatr Oncol 40(2):139