Childs Nerv Syst (2012) 28:175–178 DOI 10.1007/s00381-011-1620-9
CASE REPORT
Gamma Knife radiosurgery as a treatment modality for low-grade pediatric brainstem gliomas: report of two cases Chih-Hsiang Liao & David Hung-Chi Pan & Huai-Che Yang & Hsiu-Mei Wu & Donald Ming-Tak Ho & Tai-Tong Wong & Yang-Hsin Shih
Received: 12 October 2011 / Accepted: 17 October 2011 / Published online: 30 October 2011 # Springer-Verlag 2011
Introduction Brainstem gliomas, accounting for only 2% of adult brain tumors, constitute 10% to 20% of central nervous system tumors in the pediatric group [3]. They are mainly located in the mesencephalon, the pons (including the cerebellar peduncles), and the medulla oblongata. In pediatric patients, a thorough neurological examination and magnetic resonance (MR) imaging are essential in the establishment of the C.-H. Liao : D. H.-C. Pan : H.-C. Yang : T.-T. Wong : Y.-H. Shih Department of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan, Republic of China H.-M. Wu Department of Radiology, Taipei Veterans General Hospital, Taipei, Taiwan, Republic of China D. M.-T. Ho Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, Republic of China D. H.-C. Pan : H.-C. Yang : H.-M. Wu : D. M.-T. Ho : T.-T. Wong : Y.-H. Shih National Yang Ming University School of Medicine, Taipei, Taiwan, Republic of China H.-C. Yang (*) Division of Functional Neurosurgery, Department of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, 201, Section 2, Shih-Pai Road, Taipei 112, Taiwan, Republic of China e-mail:
[email protected] H.-C. Yang e-mail:
[email protected]
diagnosis, treatment plans, and therapeutic approaches with or without biopsy [1, 12]. Some case series had proved the therapeutic effect of Gamma Knife radiosurgery (GKS) to brainstem gliomas [4, 8, 15]. For pediatric patients, however, long-term adverse effects caused by radiation injury are always the main concern. In this report, we reviewed our long-term follow-up experience of two pediatric cases with brainstem gliomas after GKS treatment.
Case reports Case 1 This 2.5-year-old girl was born at full term without perinatal insults. Weakness of her right limbs had been noticed since she learned to climb at 9 months old. When she started to walk at 11 months old, frequent falling episodes occurred. By the time of presentation in our hospital, progressive weakness of her right limbs had been noted for 4 months. The MR imaging of the brain revealed a well-circumscribed focal lesion in the lower pons (Fig. 1a, b). According to the indolent clinical course and the radiological findings, a low-grade focal pontine glioma was impressed. Due to the deep-seated location of the tumor and high risks of open surgery, microsurgical resection was not considered. The patient received stereotactic radiosurgery using Gamma Knife (Model 4C; Elekta Instruments, Stockholm, Sweden) under general anesthesia in 2007 (Table 1). No immediate neurologic deficits were noticed after GKS, and she was discharged from the hospital on the next day. About 6 months after GKS, the patient’s motor function improved. There were no adverse radiation effects (ARE) on follow-up MR
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Fig. 1 Case 1, image diagnosed focal glioma in the lower pons. a Before GKS, there was a well-circumscribed lesion in the lower pons, about 2.0×1.6×1.7 cm in size, with minimal central enhancement on postcontrast sagittal SE T1WI. b The lesion showed well-circumscribed high signal intensity on pre-GKS axial FSE T2WI. A low-grade glioma was diagnosed. c Axial FSE T2WI at 10 months after GKS demonstrated conspicuous tumor shrinkage. There was no ARE. Tumor volume was about 0.603 ml. d Further tumor regression without ARE was noted on T2 axial view at 42 months after GKS. The residual tumor volume was about 0.255 ml
impressed. The pure tone audiometry revealed left sensorineural hearing loss. The MR imaging of the brain revealed an enhanced intra-axial tumor in the left pontomedullary region, involving the left middle cerebellar peduncle with mild mass effect. The patient received a suboccipital craniotomy in 2001, and partial tumor removal was performed (Fig. 2a). Histopathology study showed a lowgrade astrocytoma (WHO grade II; Ki-67 labeling index, 3.9; Fig. 3). There were no new neurological deficits after the operation. In case of sampling bias, 3 months after the operation, the patient received external beam radiation of total 5,800 cGy in 30 fractions. Tumor progression was noticed in the follow-up MR imaging 1 year after the operation and fractionated radiotherapy (Fig. 2b). Therefore, the patient was further treated with stereotactic radiosurgery using Gamma Knife (Model B; Elekta Instruments) in 2002 (Table 1). There were no new neurological deficits after GKS, and the patient was discharged on the next day. In serial MR imaging follow-ups, gradual tumor regression was noted (Fig. 2c, d). His facial palsy improved (House–Brackmann grade II). Neither developmental delay nor learning disorder was noted. There was no tumor recurrence up to 8 years after GKS. The patient’s condition remains good and stable, and he has an average school performance.
images. The follow-up MR imaging at 10th and 42nd months after GKS showed remarkable shrinkage of the tumor (Fig. 1c, d). There was no evidence of tumor recurrence, and the clinical condition remained stable up to 4 years of follow-up. Neither developmental delay nor learning disorder was noted. Currently, she attends normal kindergarten with good performance. Case 2 This 5.5-year-old boy had a history of progressive left facial palsy for more than 1 year. At the time of presentation, left central facial palsy (House–Brackmann grade III) was Table 1 GKS volumes and dosages in brainstem gliomas
Case 1 Case 2
TV (cm3)
RV (cm3)
MD (Gy)
DTP (Gy), % isodose volume
DTC (Gy)
Total isocenters
3.5 2.4
4.0 3.4
14.5 15.4
11 (57) 12 (63)
19.3 19.05
9 11
DTC dose at the target center, DTP dose at the target periphery, MD mean dose to the target, RV radiation volume, TV tumor volume
Fig. 2 Case 2, a surgically proved low-grade astrocytoma at left pontomedullary junction. a Preoperative, contrast-enhanced axial SE T1WI showed a lobulated, partially exophytic tumor at left side pontomedullary junction with heterogenous enhancement. b Tumor progression was noted 1 year after partial surgical resection and fractionated radiotherapy. c Conspicuous shrinkage of the enhancing tumor at 1 year after GKS. d Further regression of the tumor with no obvious enhancing component at 8 years after GKS
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Fig. 3 Histopathologic study of the tumor reveals a WHO grade II astrocytoma. a H&E stain shows an astrocytoma with modest hypercellularity and mild nuclear pleomorphism. Vascular proliferation and necrosis are not observed (original magnification ×200). b Presence of Rosenthal fibers indicates slow tumor growth (H&E, original magnification ×200). c Tumor cells are immunoreactive for glial fibrillary acidic protein (anti-GFAP, original magnification ×200). d The Ki-67 labeling index is 3.9 (anti-Ki-67, original magnification ×400)
Discussion The treatment of brainstem gliomas in children is a great challenge. In most cases, the natural history of the disease is a steady progression to death, with a median survival period of 4 to 15 months [2]. The 5-year survival rate for children with brainstem tumors ranges from 25% to 30%, regardless of histological characteristics [2, 12]. The simplest classification divides these tumors into two groups, either focal or diffuse. Diffuse brain stem gliomas are characterized by diffuse infiltration and swelling of the brain stem, and they constitute the majority (75–85%) of intrinsic brainstem tumors [5, 7]. Most children die within 18 months of diagnosis, which is similar to the clinical course for glioblastoma multiforme [7]. Neither surgery nor fractionated radiation therapy has a definitive role for such diffuse type tumor. Stereotactic radiosurgery is not an appropriate alternative either. On the other hand, focal brainstem gliomas are small in size and relatively circumscribed. They are often located in the tectum, cervicomedullary junction with dorsal exophytic growth. Infrequent locations include the tegmentum, pons, and medulla oblongata [2, 5, 7, 15]. They typically have indolent onsets, developing long tract signs, cranial nerve symptoms, or obstructive hydrocephalus. Multiple treatment modalities have been utilized to deal with focal brainstem gliomas. For cases of cervicomedullary tumors with dorsal exophytic growth, surgical resection is suitable. Because the decussation fibers in the cervicomedullary and pontomedullary junctions present as natural barriers for longitudinal tumor growth, the ependyma of the fourth ventricular
floor forms a weak point for tumor extrusion [2]. Hence, a surgical corridor is created by the tumor itself. For tectal tumors leading to hydrocephalus, the shunting surgery with open-ended follow-up by neuroimaging could serve as the initial management [11]. Fractionated radiotherapy or brachytherapy can also be a primary or adjuvant therapy for focal brainstem gliomas [9]. Although better disease-free survival has been reported, the long-term adverse effects of radiation therapy in children raise concerns, including memory loss, diminished cognitive abilities, learning disabilities, progressive deterioration in intelligence, impairment of fine motor/visual motor skills, and endocrinopathies [6]. In recent years, GKS has become an effective alternative in the treatment of focal brainstem gliomas, which avoids the drawbacks of traditional radiation therapy. In 2007, Yen et al. reported 20 cases (13 cases under 18 years old) of brainstem gliomas treated with GKS in the University of Virginia [15]. The tumor progression-free survival rate was 84% after 5 years. In his series, 13 cases were tectal gliomas, which implied that shunting and open-ended follow-up with neuroimaging might be suitable as well in some of his cases. In contrast, neither of our cases belonged to tectal gliomas, and both of them remained tumor progression free after GKS. In most cases, brainstem tumors can be distinguished from nontumorous lesions without direct histological examination when all diagnostic criteria, such as clinical history, signs and symptoms, and laboratory data (CSF analysis, infectious parameters, immunological findings), as well as the results of MR studies, are taken into account. In Schumacher’s study [12], MR imaging could differentiate
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tumorous or nontumorous in 96.5% of the cases. Of note, however, signal heterogeneity and patterns of gadolinium enhancement on MR imaging are extremely variable and correlate poorly with histological grade if gliomas are suspected [2, 12]. Open biopsy can provide histologic diagnosis, but the shortcomings of biopsy include the possibility of sampling error, the risk of morbidity, and the limited relevance to the choice of therapy [1, 12, 14]. In light of these considerations, biopsy should be critically assessed and reserved for atypical cases in pediatric population. In our patients, open surgery is not considered in case 1 in order to avoid surgical damage to the brainstem. For case 2, surgery and partial tumor removal could be accomplished without further neurological deficits due to dorsal lateral extension of the tumor. However, the recurrent tumor within the pons in case 2 needed further radiotherapy. Conventional radiotherapy might be deleterious to the developing brain of these small children. Therefore, both of our two patients were ideal candidates for radiosurgery. GKS can provide a sufficient radiation dose to the tumor while sparing the normal brain tissue any radiation damage. In these cases, remarkable shrinkage of the tumor was demonstrated in the sequential MR images up to 4 and 8 years of follow-up, respectively. In our patients, postGKS ARE were not observed in follow-up images. In Sharma’s study [13], despite with small patient number, it appeared that the development of post-GKS ARE was associated with transient neurological deficits in more than half of the patients. Such deficits tend to resolve over time after the ARE has regressed. The radiation tolerance of the brainstem may be the same as that of normal cerebral parenchyma [13]. In the early data by Kihlstrom et al. [8], the tumor control of tectal gliomas was achieved in six of seven patients treated with GKS, using the radiation doses that ranged from 14 to 35 Gy. However, the incidence of radiationinduced changes or necrosis accompanied by neurological deficits was high. In the series reported by Fuchs and colleagues [4], a peripheral dose of GKS ranging from 9 to 20 Gy (mean 12 Gy) produced good outcomes without complications. In Yen’s study [15], the peripheral dose ranged from 10 to 18 Gy, which appeared to be a safe dose range that yielded reasonable results, although a higher peripheral dose seemed to be more effective. In our cases, we used multiple isocenters to achieve both good conformal and gradient indexes during dose planning [10], with the peripheral doses of 11 and 12 Gy, respectively. The mean doses to the tumor in our patients were 14.5 and 15.4 Gy, respectively. Our experience suggests that the mean tumor dose of 14–16 Gy is probably optimal for good tumor control without significant complications.
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Conclusion GKS represents as a reasonable treatment alternative, either primary or adjuvant, in selective pediatric cases with low-grade brainstem gliomas. More patient numbers and longer follow-up periods are crucial in the assessment of the efficacy of GKS in the future. References 1. Albright AL, Packer RJ, Zimmerman R, Rorke LB, Boyett J, Hammond GD (1993) Magnetic resonance scans should replace biopsies for the diagnosis of diffuse brain stem gliomas: a report from the Children's Cancer Group. Neurosurgery 33(6):1026– 1029, discussion 1029–1030 2. Epstein FJ, Farmer JP (1993) Brain-stem glioma growth patterns. J Neurosurg 78(3):408–412. doi:10.3171/jns.1993.78.3.0408 3. Freeman CR, Bourgouin PM, Sanford RA, Cohen ME, Friedman HS, Kun LE (1996) Long term survivors of childhood brain stem gliomas treated with hyperfractionated radiotherapy. Clinical characteristics and treatment related toxicities. The Pediatric Oncology Group. Cancer 77(3):555–562. doi:10.1002/(SICI)1097-0142 (19960201)77:33.0.CO;2-3 4. Fuchs I, Kreil W, Sutter B, Papaethymiou G, Pendl G (2002) Gamma Knife radiosurgery of brainstem gliomas. Acta Neurochir Suppl 84:85–90 5. Guillamo JS, Doz F, Delattre JY (2001) Brain stem gliomas. Curr Opin Neurol 14(6):711–715 6. Hadjipanayis CG, Kondziolka D, Gardner P, Niranjan A, Dagam S, Flickinger JC, Lunsford LD (2002) Stereotactic radiosurgery for pilocytic astrocytomas when multimodal therapy is necessary. J Neurosurg 97(1):56–64. doi:10.3171/jns.2002.97.1.0056 7. Jallo GI, Biser-Rohrbaugh A, Freed D (2004) Brainstem gliomas. Childs Nerv Syst 20(3):143–153. doi:10.1007/s00381-003-0870-6 8. Kihlstrom L, Lindquist C, Lindquist M, Karlsson B (1994) Stereotactic radiosurgery for tectal low-grade gliomas. Acta Neurochir Suppl 62:55–57 9. Mundinger F, Braus DF, Krauss JK, Birg W (1991) Long-term outcome of 89 low-grade brain-stem gliomas after interstitial radiation therapy. J Neurosurg 75(5):740–746. doi:10.3171/jns.1991.75.5.0740 10. Paddick I, Lippitz B (2006) A simple dose gradient measurement tool to complement the conformity index. J Neurosurg 105 (Suppl):194–201. doi:10.3171/sup.2006.105.7.194 11. Pollack IF, Pang D, Albright AL (1994) The long-term outcome in children with late-onset aqueductal stenosis resulting from benign intrinsic tectal tumors. J Neurosurg 80(4):681–688. doi:10.3171/ jns.1994.80.4.0681 12. Schumacher M, Schulte-Monting J, Stoeter P, Warmuth-Metz M, Solymosi L (2007) Magnetic resonance imaging compared with biopsy in the diagnosis of brainstem diseases of childhood: a multicenter review. J Neurosurg 106(2 Suppl):111–119. doi:10.3171/ ped.2007.106.2.111 13. Sharma MS, Kondziolka D, Khan A, Kano H, Niranjan A, Flickinger JC, Lunsford LD (2008) Radiation tolerance limits of the brainstem. Neurosurgery 63(4):728–732. doi:10.1227/01. NEU.0000325726.72815.22, discussion 732–723 14. Tilgner J, Herr M, Ostertag C, Volk B (2005) Validation of intraoperative diagnoses using smear preparations from stereotactic brain biopsies: intraoperative versus final diagnosis—influence of clinical factors. Neurosurgery 56(2):257–265, discussion 257–265 15. Yen CP, Sheehan J, Steiner M, Patterson G, Steiner L (2007) Gamma Knife surgery for focal brainstem gliomas. J Neurosurg 106(1):8–17. doi:10.3171/jns.2007.106.1.8
