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REVIEW ARTICLE |
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| Year : 2006 | Volume
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| Issue : 1 | Page : 5-10 |
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Primer on pediatric intracranial ependymomas
KK Bansal
Department of Neurosurgery, Himalayan Institute of Medical Sciences, Dehradun, UA, India
Correspondence Address:
K K Bansal
Department of Neurosurgery, Himalayan Institute of Medical Sciences, Dehradun, UA
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/1817-1745.22940
Aims and Objectives: To review the clinical features and current understanding of the biology and management of pediatric ependymoma, critically analysing the different treatment modalities. Materials and Methods: The MEDLINE database, bibliographies of selected articles, and current English-language texts on the subject were reviewed. A Pubmed search was made with keywords pediatric, intracranial, ependymoma, surgery, chemotherapy, and radiotherapy. Most recent articles and also significant older articles having all above said words were selected and their results were compared in detail. Results: Almost all articles stress the complete or near total resection of the tumor at first surgery followed by radiotherapy in patients older than 3 years of age and chemotherapy in younger children. Conformal radiation therapy (CRT) is a technique which has promising results. Conclusion: Local tumor control is single most important prognostic factor. This is best achieved through gross total tumor resection wherever possible. Radiotherapy should be offered to all patients (>3-years age) with focused dose (CRT) to tumor bed. Chemotherapy with the current agents does not appear to hold much promise. However, it may be useful in the context of providing the surgeon with an opportunity to do further surgery on a tumor that is less vascularized.
Keywords: Pediatric, intracranial, ependymoma, surgery, chemotherapy, and radiotherapy
How to cite this article:
Bansal K K. Primer on pediatric intracranial ependymomas. J Pediatr Neurosci 2006;1:5-10 |
| Incidence and Natural History | |  |
Ependymomas are one of the most common primary brain tumors of children younger than 5 year of age, accounting for 10-12% of all brain tumors in the pediatric population and 2.5% of all intracranial gliomas. Ependymomas develop from the oncogenetic event that transforms cells of ependymal lineage,[1] which line the ventricles of the brain and central canal of the spinal cord. Location of these tumors typically shows preference based on age, with supratentorial and spinal compartments more often affected in adults and fourth ventricular involvement more in children. Ninety percent of these tumors occur intracranially, two thirds of which are infratentorial. The mean age at the time of diagnosis is between 3-6 years and more then one fourth of them are diagnosed at younger than 3-years.[2]
Sixty percent of supratentorial tumors may arise from lateral or third ventricle but 40% arise from extra-ventricular cerebral parenchyma even without ventricular proximity.[3],[4] There is no sex preference for ependymoma and it occurs with equal frequency in both the sexes.
Infratentorial ependymomas typically arise from one of the three specific sites in the fourth ventricle: 60% from the floor, 30% the lateral aspect and 10% from roof.[5],[6] Usually occurring sporadically, they can be associated with Neurofibromatosis Type-II. There are no known definite causative agents although there are suggestions that certain viruses may play a role. [7],[8],[9] Epidemiological studies lately have suggested geographical (common in northern India) or racial (rare in migrant ethnic Chinese) distribution in its occurrence but the extent and importance of this is presently inconclusive.
The younger the child the worse the prognosis; it is uncertain whether this is due to tumors being more malignant at an early age or delayed administration of radiation therapy or chemotherapy in younger children. [10],[11],[12] Posterior fossa tumors usually occupy and grow within the fourth ventricle but they can extend through the foramen of Magendie inferiorly, foramen of Luschka laterally and into the cerebellopontine CP angle. These tumors may spread along the CSF axis before, during or after the surgery. Ependymomas developing in the supratentorial compartment usually to be low-grade tumors and a have better prognosis.[13],[14] The 5-year progression free survival after treatment in ependymoma is ranging from 23% to 45% and the 5-year survival estimate is 50% to 60% in various major series.[10],[11], [15],[16],[17] The median time to local recurrence is within the first 2 years.[10],[11],[15],[16],[18],[19]
Clinical presentation
Age at the time of diagnosis has been considered an important prognostic factor.[10] Ependymomas of the fourth ventricle frequently produces hydrocephalus due to hindrance of the CSF outflow and initially present with general signs of increased intracranial tension.[20] Intractable paroxysmal vomiting not related to particular time of the day or posture is more pronounced and often it is the first symptom, perhaps due to their attachment with floor of the fourth ventricle. Neonates may present with macromania, lethargy and failure to thrive. Papilloedema is an indirect sign of hydrocephalus while a bulging fontanelle is a direct sign. Enlarging head circumference is seen in children those who present prior to closure of cranial sutures. Due to direct involvement of local neural structures, there may be signs of cerebellar and brainstem compression, along with long tract signs and lower cranial nerve involvement.[11] Ataxia, nystagmus and 6th nerve involvement are seen in posterior fossa tumors; less common is torticollis indicating tonsillar impaction.
Those occurring in the supratentorial compartment generally present with focal neurological deficits, seizures, and raised intracranial pressure from mass effect. Headaches are usually intermittent and may be worse in the morning. Though uncommon, CSF dissemination can occur with patients presenting with signs of meningismus or nerve root involvement.
Histopathology/biology/molecular characterization
Grossly, ependymomas are grayish-red tumors that frequently appear well circumscribed. Histologically, they are characterized by the presence of perivascular pseudo-rosettes and true ependymal rosettes (Homer-Wright). Several different subtypes have been identified that tend to occur at particular locations and ages. Classic and anaplastic ependymomas generally occur in children and young adults in the cerebral hemispheres and cerebellum, myxo-papillary ependymomas occur in the conus-medullaris of young adults and sub-ependymomas tend to arise in the fourth ventricle of the elderly.
The World Health Organization (WHO) divides ependymomas into three grades: WHO grade-I (sub-ependymoma and myxo-papillary ependymoma), WHO grade-II, which has four variants (cellular, papillary, clear and tanycytic) and grade-III (anaplastic ependymoma).[21]
The diagnosis of WHO grade-II is based on infrequent or absent mitoses, occasional non-palisading foci of necrosis and nodules with better cellularity and mitotic activity present.[21] Anaplastic ependymoma includes tumors with clearly defined ependymal differentiation showing perivascular pseudorosettes and increased cellularity, cytological atypia, and micro-vascular proliferation.
Ependymomas characteristically have homogeneous cells, infrequent mitoses and little necrosis. The nuclei of ependymal cells are oval and have dense clumps of chromatin as seen in other glial cells. Microscopic examination demonstrates a predominant glial pattern, studded with islands of cells with epithelial features, which makes the diagnosis of ependymoma. Pseudorosettes are the most common epithelial features; they appear as eosinophilic zones surrounding blood vessels. A tanycyte is an immature, bipolar, glial fibrillary acidic protein (GFAP)-positive cell that may symbolize an intermediate phase in the development of an ependymal cell. Clear cell ependymomas have the same "fried egg" appearance of Oligodendrogliomas. Papillary ependymomas may be superficially difficult to distinguish from choroid plexus papilloma but the fronds of a papillary ependymoma contain ependymal cells.
Ependymomas may spread by local invasion or CSF dissemination. Up to one fifth of the patients will show evidence of CSF spread at the time of diagnosis by positive CSF cytology or contrast enhanced MRI suggestive of metastatic spread. [22],[23],[24]
The oncogenic simian virus 40 (SV40) has been identified in a significant proportion of sporadic ependymoma specimens.[25],[26] Its large T-antigen viral protein binds to and neutralizes both p53 and retinoblastoma protein leading to disordered DNA repair mechanisms and cell-cycle regulation, respectively.[27] Rats inoculated intracerebrally with SV40 virus develop ependymomas.[28],[29]
Genetic aberrations in ependymomas include loss of chromosome 6q, 22q, and the X-chromosome and the gains of 1q or 9q. The frequency of 22q abnormality is much higher in spinal ependymomas.[30],[31] The gain of 1q seen in childhood anaplastic ependymomas appears to be associated with posterior fossa tumor.
While there is still much to discover, the molecular cell-biology of this tumor is becoming better known. Cytogenetically, i n situ hybridization studies have demonstrated several non-random chromosomal imbalances in sporadic ependymoma, the most common of which is loss of chromosome 22q.[32],[33] Though both cranial and spinal ependymomas occur in patients with NF2, the locus involved in sporadic tumors seems to be different from the NF2 gene locus as sporadic tumors harboring 22q loss occur almost exclusively in the spine. [34],[35],[36] Gain of 1q is seen frequently in ependymomas of the fourth ventricle and has been linked with a more anaplastic phenotype and may thus contain genes necessary for tumor progression.[30],[37],[38],[39] Recently, co-over-expression of certain receptor tyrosine kinases, ERBB2 and ERBB4, has been demonstrated to correlate with proliferative indices and worsened patient prognosis.[40] Although no specific tumor suppressor gene has been identified for ependymomas, CDKN2A, CDKN2B and p14ARF expression are frequently silenced by aberrant methylation.[41],[42]
Neuro imaging
Ependymomas typically appear as isodense to heterogeneously enhancing midline cerebellar or hemispheric tumors on both CT and MRI [Figure - 1]a, b. In the posterior fossa, they typically take origin on the floor of the fourth ventricle and grow to take up it completely. On non-contrast computed tomography scan the tumor is heterogeneous, seen in midline posterior fossa with varying amount of cysts, necrosis and calcification, and the solid portion enhances well after contrast injection. The imaging modality of choice is a bi/tri-planar gadolinium-enhanced MRI, which, because of its better anatomical resolution, demonstrates the extent of the tumor and its relationship to the brainstem and spinal cord. MRI with all available sequences, including enhanced, un-enhanced T1 and T2 weighted imaging, proton density, and fluid attenuated inversion recovery (FLAIR) are capable of water suppression to clearly differentiate the tumor borders. MR spectroscopy can be used as an adjunct to MRI in the evaluation of ependymomas, but there is limited data available of its usefulness. In addition to cranial imaging, an MRI of the spine should be performed pre-operatively to assess the presence of possible CSF metastases in the nerve roots, as their presence significantly worsens prognosis and likely nullifies the benefits that might have otherwise be gained by complete resection. Neuro-navigation or Intra-operative ultrasound can be useful for defining the relationship of tumors to the surface of the brain prior to entering the nervous system as well as potentially increasing the chances of total resection by demonstrating possible residual tumor.[43] Post surgical MR examination should be done within 48-72 hrs of surgery, which minimizes post-surgical changes and demonstrate residual tumor if any.
Treatment
These are comparatively slow growing tumors but have a tendency for local invasion or local recurrence.[44] For ependymomas, the ultimate goal of treatment should be total micro-surgical resection [Figure - 2]. The extent of surgical resection has been considered the most significant determinant with increased survival in almost every large series of pediatric ependymoma.[16],[18],[45],[46],[47] This is achieved by aggressive primary resection, immediate second look surgery if a post-operative residual tumor is identified and re-surgery at time of recurrence. Unfortunately, the ability to totally resect these tumors differs based on their location. Overall, between 35-50% of posterior fossa ependymomas can be resected completely but only 23-40% of those occurring adjacent to the brainstem in the fourth ventricle can be completely resected safely.[16],[48],[49] Complete resection is more easily achieved for supratentorial tumors, between 60-85% of these ependymomas can be completely removed.[49] Aggressive attempts to remove tumors in other locations, including those involving lower cranial nerves, are associated with increased morbidity.
Sutton reported 5-year progression free survival of 80% for patients who underwent gross total resections of the tumor but this reduced to 48%, 22%, and 0% for near-total resections, partial resections and biopsies, respectively.[50] Pollack's series showed a sudden drop in 5-year progression free survivals from 80% to 8.9% with total and subtotal tumor removal, respectively.[11] Perilongo et al[19] retrospectively analyzed 92 children with ependymoma who participated in the Italian pediatric Neuro-oncology Group. For patients who underwent gross total resection, the 10-year survival estimate was 70%, and the progression free survival was 57%; for patients who had undergone subtotal resection, the 10-year survival estimate was 32%, and the 10-year progression free survival estimate was 11% only. Finally, Robertson et al[16] prospectively treated 32 patients and they notice that 5-year progression free survival was 66% for patients with residual tumor measuring 1.5 cm 2sub or less and 11% for those with residual tumor measuring more than 1.5 cm 2sub , all of whom were treated with post-operative radiation.
The outcomes for this tumor also depend on the age of the patient and the location. Children have a more guarded prognosis as compared to adults, with the worst outcomes in patients under the age of two. Spinal ependymomas and supratentorial ependymomas usually have a better outcome than those in the infratentorial compartment, probably because they are more amenable to gross-total resection. Successful treatment of intracranial ependymoma by resection alone has been reported by different groups.[13],[14] Their patients with supratentorial ependymoma had prolonged recurrence free survival after gross total resection only. These findings signify that some patients with low-grade supratentorial ependymoma require resection only. Dhellemmes et al[50] recently reported the results of re-surgery and achieved total resection in recurrences and had more than 50% survival at 74.7 months follow-up after re-operation. Because maximal surgical extirpation is so critical to long-term outcome, it is now advocated that a post-operative enhanced MRI be obtained within 48 hours of surgery with the view of a second operation should operable tumor be evident on the imaging. Up to 71% of patients with partial resections had evidence of CSF dissemination whereas 83% of patients who had total tumor removal were free of CSF spread.[51]
There is much debate currently on the role of adjuvant treatment for ependymoma. It is commonly recommended that post-operative radiation be used following resection. Multiple resections may be required as palliative therapy during the course of the disease. The role of chemotherapy is less well demonstrated. However, patients under 3 are generally treated with chemotherapy as a method of delaying radiotherapy until the brain further matures.
Radiation therapy
Mork et al[52] were the first to show that post-operative radiation improves outcome in ependymoma. Since then, post-operative radiation therapy has been considered customary treatment for patients operated for ependymoma. They reported a survival estimate of 17% for patients who underwent resection alone versus 40% for those who received cranial radiation in addition. Radiation therapy may be recommended for patients older than 3, although there remains a risk for neuro-cognitive sequelae.
The pediatric oncology group study has shown that children with completely resected ependymoma in whom radiation therapy (RT) was delayed for 2 years experienced a worse outcome than those in whom therapy was delayed for 1 year (5-year survival 38% versus 88%).[45] Pediatric oncology group presented data on standard radiotherapy and Hyper-fractionated radiation therapy (HFRT) dose did not show any difference in the outcome.[53] A phase II trial of conformal radiation therapy (CRT) has shown that 3-year progression free survival was 74.7 ± 5.7% after median follow-up of 38.2 months.[54] They have treated with 59.4 Gy CRT to 80% of their patients, localized to gross tumor volume and a margin of 10 mm. The incidence of local failure at 3 year was 14.8 ± 4.0%.
Radiation dose is another controversial issue in ependymoma. Various studies have shown a dose-dependent response level for ependymoma, indicating a dose threshold of 45 to 50 Gy.[55],[56] Recent studies have proven that dose escalation in sub-totally resected tumors is favorable in posterior fossa ependymoma, 50%, 4-year event free survival with 69.6 Gy (POG 9132) in comparison to 24%, 4-year survival (POG 8532) after using lower dose of radiation.[57] This has also been shown by retrospective analyses that increase in radiation dose to the primary site appears to improve local control.[58],[59] Stereotactic radiosurgery is now increasingly becoming used in patients with residual, unresectable or recurrent tumor. [60],[61],[62],[63]
Adjuvant chemotherapy
Although the role of chemotherapy is not yet convincingly established, in younger children it may be given until the child's brain becomes mature enough to tolerate cranial radiation, usually at 3 years of age. Various retrospective and prospective trials have been published showing minimal benefit in terms of improving long-term disease free survival.[49],[64] At least four cycles of combination of multiagent drugs has been tried. The main chemotherapeutic agents used were vincristine, ifosfomide, etoposide and carboplatine in a variety of schedules.[65] Their patients received vincristine at same time during radiation but combination chemotherapy was started 4-6 weeks after completion of RT. Myelosupression is the major toxicity noticed during combination chemotherapy. They found 5-year progression free survival (PFS) of 74%, which is a bit better than RT alone in completely resected tumor. The PFS for children with postoperative residual tumor treated with RT and chemotherapy in this study was higher than literature for RT alone.[65]
Regardless of some combinations showing marginal effectiveness in the adjuvant treatment, childhood intracranial ependymomas may, in general, be considered as chemo-resistant. The over-expression of the multi-drug resistance-1 gene and the 06-methylguanine-DNA methyl transferase has been blamed as possible mechanisms for this phenomenon.[66] Cisplatin is the only agent that has reproducibly shown some worth in ependymoma with a cumulative response rate of 34%.[66] The children cancer group (CCG) 942 is the only randomized trial, which compared survival after radiation alone, and survival after combination of radiotherapy with chemotherapy, did not show improved outcome.[2]
| Conclusion | | |
Utmost local control of the tumor is single most important prognostic factor. This is achieved by gross total, if feasible, or near total surgical resection, which can offer long-term disease free survival. Radiotherapy should be offered to all patients (>3 years age) with focused dose (CRT) to tumor bed. Second look surgery in immediate post-operative period for residual tumor if any or surgery for recurrences is reasonable. In an attempt to facilitate the second surgery, chemotherapy may be given but as such chemotherapy has failed to improve overall survival.
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Figures
[Figure - 1], [Figure - 2]
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