Chapter 10 Posterior Fossa and Brainstem Tumors in Children
• Presentation and Investigation
− Presentation of posterior fossa lesions is dictated by location, and aggressiveness of the lesion involved. The most common presenting symptom of a posterior fossa mass is headache related to mass effect, or obstruction of cerebrospinal fluid (CSF) pathways.
− Seizures from a posterior fossa mass are rare. If a patient with a posterior fossa tumor presents with seizures, consider the possibility of leptomeningeal spread.
− Magnetic resonance imaging (MRI) of the brain and spinal cord should be obtained to rule out disseminated disease. Occasionally lumbar puncture may be required for cytological examination.
− Pilocytic astrocytomas are the most common pediatric cerebellar neoplasm.
− The degree of mitotic activity, cellular atypia, and microvascular proliferation do not affect grade of pilocytic astrocytomas.
− Gross total resection of a pilocytic astrocytoma is considered curative. If the cyst wall enhances, it should be removed by the neurosurgeon.
− Desmoplastic medulloblastomas have a more favorable prognosis than classical medulloblastoma. Anaplastic/large cell histological finding has a poor prognosis and qualifies as high-risk medulloblastoma.
− The most common genetic anomaly in medulloblastoma is isochromosome 17q. In the near future, prognostic and risk stratification of medulloblastoma will be based on molecular profiling.
− “Second look” surgery should be considered when significant residual disease is evident on postoperative imaging.
− The current standard of care for average-risk medulloblastoma, age above 3 years, is gross total resection, postoperative craniospinal radiation of 23.4 Gy with a posterior fossa boost of 54 Gy, followed by 12 months of chemotherapy. Postoperative intensive chemotherapy can be used to delay radiation in children younger than 3 years of age.
− The 5-year survival rate for ependymoma is 60%.
− Classic histological features include ependymal rosettes and pseudorosettes.
− Ependymoma of the cerebellopontine (CP) angle can encase vital neurovascular structures.
− Extent of surgical resection is the only factor with significant prognostic value.
• Atypical Teratoid/Rhabdoid Tumor
− Loss of INI1 is found in 90% of atypical teratoid/rhabdoid tumors (AT/RTs).
− Owing to intermixed histopathological features, AT/RT can be confused with medulloblastoma or primitive neuroectodermal tumors (PNETs) if only small areas are biopsied.
− Gross total resection predicts for improved survival. Radiation therapy should not be used for children under 3 years of age. Intrathecal chemotherapy is being tested in recent clinical trials.
− Histologically, choroid plexus papillomas are difficult to distinguish from normal choroid epithelium.
− Choroid plexus tumors are more common in the very young.
− Choroid plexus tumors are extremely vascular and intraoperative blood loss can lead to morbidity and fatal outcome.
− Dermoids typically present in midline locations in association with a dermal sinus tract. The sinus tract should be completely excised to prevent recurrence.
− Epidermoid cysts occur laterally and are commonly found in the CP angle.
− High signal on diffusion-weighted imaging aids in differentiating an epidermoid from an arachnoid cyst.
− A third ventriculostomy prior to tumor resection in children over age 3 can be effective in eliminating CSF shunt requirements postoperatively.
− Not all brainstem tumors have an unfavorable prognosis. Subsets of focal brainstem gliomas are associated with long-term survival. Diffuse intrinsic pontine gliomas account for 60% to 80% of brainstem gliomas, with an average survival of 9 months. NF1 patients have brainstem tumors with a more favorable survival time.
− The use of neuronavigation and neurophysiological mapping and monitoring is essential for maximizing resection while minimizing harm to patients.
• Diffuse Intrinsic Pontine Glioma
− There is no current role for biopsy or surgical excision of these tumors.
− Palliative radiation will provide transient symptom relief in 75% of patients.
− More than 80% of these lesions have an indolent course.
− Large size (>2 cm), enhancement, and invasion of adjacent structures are signs of more aggressive tectal lesions.
− Benign tectal lesions in children older than 3 years can be managed with a third ventriculostomy and serial follow-up.
• Surgical Approaches to the Posterior Fossa
− The telovelar approach to the fourth ventricle offers an alternative to the midline approach in which the cerebellar vermis is split.
− Intraoperative mapping/monitoring helps the surgeon in identifying and preserving lower cranial nerves and the brainstem nuclei during surgery.
− Use corridors created by the lesion such as cysts, or presentation to the pial surface, as landmarks to begin the resection of posterior fossa tumors. Do not transgress the floor of the fourth ventricle when resecting brainstem tumors.
Pediatric brain tumors are the leading cause of solid cancer–related death in children. Approximately 60% of these tumors occur below the tentorium, including the brainstem, cerebellum, fourth ventricle, and cerebellopontine angle. In contrast, in the adult population the majority of these neoplasms occurs in the supratentorial compartment. The pathological features of these tumors are diverse, and prognosis ranges from excellent to dismal, depending on histopathological findings, extent of surgical resection, and use of adjunctive therapies (Table 10.1). Great technological strides have been made in regard to improving and understanding tumor biology, imaging, surgical techniques, and chemotherapeutic/radiation protocols, leading to increased survival time in these patients. For example, survival time for medulloblastoma in Cushing’s day in the 1920s averaged 17 months. The addition of craniospinal radiation in the 1950s yielded 3-year survival rates of 65% and in the modern era with combined surgery, radiation, and chemotherapy average-risk medulloblastoma patients can achieve a 5-year survival rate of 80% to 85%.1 However, these treatments can lead to significant morbidity to the developing brain and thus we still have more to learn from these complex and challenging tumors.
TABLE 10.1 Survival Data for Pediatric Posterior Fossa Tumors With Current Best Management
| Tumor Subtype | Survival with Current Best Management |
|---|---|
| Pilocytic astrocytoma | EFS > 90% at 5 years28 |
| Medulloblastoma | Average risk: EFS 80% at 5 years67 High risk: EFS 60% at 4 years71 |
| Ependymoma | GTR: 70-80% 5-year survival rate101 STR: 20-40% 5-year survival rate |
| AT/RT | 3-year EFS 50-78% with radiation122,123 3-year EFS 11% in young children with no radiation123 |
| Choroid plexus papilloma | OS 100% at 2 years132 Atypical tumor: OS 89% at 2 years132 |
| Choroid plexus carcinoma | OS 36% at 2 years132 |
| Diffuse pontine glioma | 9-month survival207, 228 |
| Focal brainstem glioma | 5-year survival rates 50-100%194, 226–228, 239 |
AT/RT, atypical teratoid/rhabdoid tumor; CPP, choroid plexus papilloma; EFS, event-free survival rate; GTR, gross total resection; OS, overall survival rate; STR, subtotal resection.
General Diagnostic Imaging Features
Once stabilized, patients with a posterior fossa lesion require magnetic resonance imaging (MRI) of both the brain and spinal cord to rule out leptomeningeal spread. Cerebrospinal fluid (CSF) may be acquired by lumbar puncture if deemed safe prior to surgery to look for malignant cells. If a metastatic workup cannot be performed prior to surgery, then a waiting period of 10 to 14 days prior to imaging or obtaining lumbar CSF should elapse after surgery to avoid false positive results from surgical intervention.2 MRI can also alert the surgeon to instances when the brainstem or floor of the fourth ventricle has been compromised by an invading tumor.
Despite the classic imaging of each tumor type, it can be very difficult to differentiate these tumors based on MRI or CT alone. Classically, medulloblastoma has a higher cellularity than either pilocytic astrocytoma or ependymoma and as such has a higher density on CT or is hypointense on T1 MRI. The solid portion of a pilocytic astrocytoma is hyperintense to CSF on T2 sequences in 50% of cases.3 Ependymoma can typically be seen exiting laterally or inferiorly from the foramen of Luschka or Magendie, respectively. However, imaging characteristics often overlap or are atypical, and diagnosis based on traditional imaging alone is not reliable. Recently, studies have utilized diffusion-weighted imaging (DWI) and magnetic resonance spectroscopy (MRS) to enhance predictive values. DWI measures the microscopic diffusion of water in tissues. Highly cellular tumors such as medulloblastoma have restricted diffusion and higher signals on apparent diffusion coefficient (ADC) maps. Proton MRS analyzes the metabolic composition from tissues such as choline (high in tumors), N-acetylaspartate (reduced in tumors), lactate, taurine (high in medulloblastoma), glutamine, myoinositol, and alanine. Utilizing these two methods in conjunction may help increase predictive values of imaging for pediatric posterior fossa tumors or help distinguish relapse from radiation necrosis.4
Individual Posterior Fossa Tumor Types
Pilocytic Astrocytoma
Cerebellar astrocytomas were first described in a series of 76 tumors by Harvey Cushing.5,6 Pilocytic astrocytomas (PAs) are the most common pediatric cerebellar neoplasm and occur at a mean age of 7 to 8 years.7,8 There is no gender predilection. Pilocytic astrocytomas are WHO (World Health Organization) grade I lesions, indicating their slow growth, indolent behavior, and high survival rate. They can occur in any location of the neuraxis, but the cerebellar hemispheres (~50%), optic pathways, thalamus, and hypothalamus are the most common sites.7 There are case reports of pilocytic tumors occurring within the CPA.9,10 The vast majority of cerebellar astrocytomas are pilocytic (WHO I), as was found in 88% of patients in the Hospital for Sick Children series.11 However, distinctions between fibrillary and pilocytic tumors of the cerebellum have not been useful in predicting prognosis.
Imaging
Typically, cerebellar pilocytic astrocytomas appear as well-circumscribed cystic lesions with a solid enhancing nodule (Fig. 10.1). Computed tomography (CT) imaging reveals a well-demarcated lesion with cystlike features, very occasional calcifications, and intense enhancement of the solid component with contrast agent administration.12,13 A pilocytic astrocytoma can present on imaging in four patterns: (1) An enhancing mural nodule or mass accompanied by a nonenhancing cyst; (2) an enhancing mural nodule with an intensely enhancing cyst; (3) a predominantly solid mass with no cyst component; and (4) a necrotic mass with a central nonenhancing zone.14 Pilocytic tumors typically arise from the vermis and the cerebellar hemispheres but can extend into the ventricular system.15 Pilocytic astrocytomas are isointense to hypointense relative to normal brain on T1 images and hyperintense to normal brain in T2 images.7 However, diagnosing pilocytic astrocytomas, medulloblastomas, and ependymomas with complete accuracy is not possible based on traditional imaging. Next-generation MRS and DWI techniques (described earlier) may be helpful in the future.
Dissemination or leptomeningeal spread of pilocytic astrocytoma is rare and is more common in tumors arising from the hypothalamus, partially resected tumors, and tumors of the very young.16 In contrast with other more aggressive tumors, leptomeningeal dissemination of a pilocytic astrocytoma is not incompatible with long-term survival.17
Histology
Histologically, pilocytic astrocytomas are characterized by a classic biphasic pattern of loose glial tissue and compacted piloid tissue (see Fig. 10.1). The piloid component comprises dense sheets of bipolar cells with fibrillary process containing Rosenthal fibers. The loose glial component contains protoplasmic astrocytes and eosinophilic granular bodies.18 Macroscopically pilocytic tumors appear well circumscribed; however, on the microscopic level 64% show infiltration of the surrounding brain, making surgical extirpation difficult.13 In the cerebellar pilocytic astrocytoma, invasion of the leptomeninges is common.18 However, this invasion does not correlate with a poor prognosis. Interestingly, the degree of mitotic index, cellular atypia, and microvascular proliferation has no effect on event-free survival. However, histopathological evidence of vascular hyalinization, calcification, necrosis, or oligodendroglioma-like features may predict a poorer clinical outcome.19 Very rarely, pilocytic astrocytomas undergo malignant transformation to an anaplastic pilocytic astrocytoma.7 The majority of malignant transformation has occurred after administration of radiotherapy.20,21
Contrary to the supratentorial and brainstem pilocytic tumors, cerebellar pilocytic astrocytomas are rare in the neurofibromatosis type 1 (NF1) population. Recently, genetic investigations have revealed gains at 7q34 resulting in the discovery of two important fusion proteins: KIA1546–BRAF and SRGAP3-RAF1. These fusion proteins lead to constitutive activation of the ERK/MAP kinase pathway.22–25
Management
Gross total resection of a pilocytic astrocytoma is considered curative.8,15,16,26,27 Resection of the mural nodule is key in the surgical extirpation of pilocytic astrocytomas. Surgeons debate the need for removal of the cystic wall, but no statistical difference in survival has been noted between patients with cyst wall removal and those without.14 Postoperative MRI is imperative to evaluate degree of resection because direct neurosurgical evaluation is unreliable. With gross total resection 10-year survival rates are in excess of 90%.28 Subtotal resection increases rate of recurrence (7% vs. 27%) but not overall survival.7,28 Spontaneous regression after partial resection as measured by MRI occurs more frequently than growth. Thus, a good argument can be made for observation of residual tumor in cases in which reoperation for total resection carries a high morbidity rate, such as when the tumor invades the fourth ventricle (~10%).28,29 No adjunctive therapy is required for the treatment of pilocytic astrocytoma unless leptomeningeal spread is evident. Leptomeningeal dissemination can then be treated with chemotherapy or radiation, although no standard protocol exists.16,17,30,31
Medulloblastoma
Medulloblastoma is the most common malignant solid neoplasm of childhood. Medulloblastomas are related to primitive neuroectodermal tumors (PNETs) and occur exclusively in the posterior fossa. The median age at presentation is 9 years in the entire population and 7.3 years in the pediatric population.32 There is a slight male predominance of 1.6:1.32
Histology and Genetics
The WHO classifies medulloblastoma as a grade IV lesion and recognizes five subtypes: classic, desmoplastic/nodular, medulloblastoma with extreme nodularity, anaplastic, and large cell.33 Desmoplastic/nodular lesions have a more favorable prognosis as opposed to large cell and anaplastic lesions, which have a poorer prognosis when compared to classic medulloblastoma.34–36 Classic medulloblastoma appears as a small blue cell tumor, composed of densely packed undifferentiated oval cells with hyperchromatic nuclei and scant cytoplasm (Fig. 10.2). As with other malignant lesions, there is marked nuclear pleomorphism and brisk mitotic activity.37 Homer-Wright rosettes composed of neoplastic cells concentrically arranged around fibrillary processes are a common histological feature. The desmoplastic type of medulloblastoma contains “pale islands” of reticulin fibers surrounding a nodular reticulin-free zone.37 The large cell and anaplastic subtypes are characterized by large nuclei with prominent nucleoli, and a lower nuclear-to-cytoplasmic ratio than classic medulloblastoma.38,39
Genetic insights into medulloblastoma were gained by studying the familial tumor predisposition syndromes: Gorlin’s syndrome (a mutation in the PTCH gene in the sonic hedgehog signaling pathway), Turcot’s syndrome (a mutation in the APC gene affecting the beta-catenin/Wnt signaling pathway, and Li-Fraumeni syndrome (a mutation in p53 tumor suppressor gene).40 However, these familial syndromes account for only a small percentage of medulloblastomas.
The largest genetic analysis on sporadic medulloblastoma comes from a study by Northcott and associates in which they analyzed 212 medulloblastomas with high-resolution SNP (single nucleotide polymorphism) genotyping. Isochromosome 17q was confirmed as the most common genetic alteration in medulloblastomas, found in 28% of specimens.41 This large data set corroborated other genes associated with medulloblastoma such as amplification of MYC oncogenes, OTX2, TERT, PDGFRA, and CDK.41 Interestingly, this paper identified a novel pathway of medulloblastoma pathogenesis including histone lysine methylation genes, which regulate gene expression during development.41
The cell of origin in medulloblastoma remains elusive. Some groups have proposed medulloblastoma to arise from the external granule layer of the developing cerebellum and others have proposed that the cell of origin arises from a subventricular progenitor zone. Recent genetic subgroup analysis has classified medulloblastoma into one of four or five distinct genetic groups.42,43 In a series of over 400 patients which was linked to patient prognostic data, medulloblastomas could be segregated into one of four subgroups: group A (characterized by defects in WNT pathway signaling), group B (characterized by defects in SHH signaling), group C, and group D. Prognosis was correlated with subgroup and revealed that patients with group B medulloblastoma were at the extremes of age (infant or adult), have a desmoplastic phenotype, and have a more favorable prognosis. Group A medulloblastoma behaved in a similar fashion to classic medulloblastoma, whereas group C and D tumors had a poorer prognosis, and presented with disseminated disease. Of greatest interest, however, was the ability to predict genetic subgroup based on immunohistochemistry alone (Table 10.2). These distinct genetic and prognostic subgroups argue for a multiple cell of origin for medulloblastoma, but what is more important, they may change the way we risk stratify and treat patients with medulloblastoma in the future.
TABLE 10.2 Novel Stratification of Medulloblastoma Based on Genetic Subgroup Analysis
| Subtype | Genetic Background | Immunohistochemical Stain |
|---|---|---|
| A | WNT tumors | DKK1 |
| B | Sonic Hedgehog (SHH) tumors | SFRP1 |
| C | NPR3 | |
| D | KCNA1 |
Data from Northcott PA, Korshunov A, Witt H, et al. Medulloblastoma comprises four distinct molecular variants. J Clin Oncol 2011;29(11):1408-1414.
Imaging
Medulloblastomas are typically midline cerebellar lesions arising from the vermis; however, in older children and adults they can arise from the cerebellar hemispheres.44 Classic CT imaging of medulloblastoma is a hyperdense lesion in the cerebellar vermis with surrounding vasogenic edema.45,46 Calcification (22%) and cyst formation (59%) may be observed in some cases.47 There is a high degree of variability of MR appearances of medulloblastoma. T1 sequences are usually iso-hypointense to white matter and hyperintense on T2 sequences (see Fig. 10.2). Tumor enhancement can be both homogeneous or heterogeneous.46 Similar to ependymoma, approximately14% of medulloblastomas may show foraminal extension.48 Leptomeningeal seeding on MRI is found in approximately 33% of patients. The spinal canal is the most common location of seeding; however, the supratentorial compartment may also be involved. Nodular or diffuse enhancement along the leptomeninges, nerve roots in the spinal canal, or cranial nerves in the CPA are common findings of CSF seeding (Fig. 10.3).46,49–51 Interestingly only 15% to 60% of patients with evidence of metastasis by MRI have positive CSF by cytological examination and only 70% of patients with positive cytological findings have evidence of metastasis by MRI. This highlights the importance of CSF cytological examination, especially in cases in which the MRI imaging is negative.52,53 Rare cases of extraneural spread have been reported to bone, lymph nodes, liver, and lung.54
Management
With combined surgical resection, radiation, and high-dose chemotherapy, 5-year progression-free survival rate in average-risk medulloblastoma is approximately 80%. Currently risk stratification is based on age (less than 3 years of age), presence of disseminated disease, and extent of surgical resection (Table 10.3). However, this stratification system fails to take into consideration the biology of medulloblastoma tumors, and a system based on molecular markers and genetic subgroup analysis may provide a better way of categorizing patients in the future. Current treatment studies are including favorable molecular markers such as nuclear beta-catenin and TrkC expression and unfavorable markers such as Myc genes and ERBB2 in their stratification paradigms.55
| Average-Risk Medulloblastoma | High-Risk Medulloblastoma |
|---|---|
| Age < 3 years ≤1.5 cm2 residual disease M0—no dissemination of tumor |
Age ≥ 3 years >1.5 cm2 residual disease M1—positive lumbar CSF cytological findings, negative MRI of brain and spine M2—macroscopic dissemination on MRI of brain and negative MRI of spine M3—macroscopic spinal dissemination on MRI M4—extraneural spread Anaplastic histological pattern |
CSF, cerebrospinal fluid; M0-M4, distant metastasis (staging); MRI, magnetic resonance imaging.
Surgery for Medulloblastoma
The goal of surgery in medulloblastoma is complete resection without causing neurological injuries. Several clinical trials have shown that extent of surgical resection correlates with recurrence-free survival.56–59 Postoperative imaging should be obtained 24 to 48 hours after surgery and compared to preoperative scans to determine extent of resection. In cases in which there is greater than 1.5 cm2 of residual tumor, a repeat procedure should be considered, if safe and anatomically feasible, to place the patient in the best prognostic category.
Treatment of Children Over Age 3 with Average-Risk Medulloblastoma
Management of medulloblastoma has evolved over time as new clinical trials are published on risk stratification and treatment paradigms. Medulloblastoma is a radiosensitive tumor and incorporation of radiotherapy has become a standard of care in treatment of children older than 3 years of age. The original radiation dose of 36 Gy to the neuroaxis and 54 Gy to the posterior fossa resulted in numerous detrimental side effects including cognitive decline, endocrine insufficiency, hearing loss, vascular complications, and secondary malignancies.60–65 Because of these detrimental effects of craniospinal radiation, efforts began to reduce the degree of craniospinal radiation in average-risk patients aimed at preserving neurological function. This was accomplished by increasing the intensity of chemotherapy. Chemotherapy had already proved an effective adjunct to radiation and surgery in earlier studies.66,67 Packer and colleagues reduced the degree of cranial spinal radiation to 23.4 Gy by adding chemotherapy during and after radiotherapy and still maintained excellent control with event-free-survival (EFS) of greater than 80% in nondisseminated medulloblastoma.68 Typical chemotherapeutics used in medulloblastoma include cisplatin, CCNU, vincristine, cyclophosphamide, and etoposide. There is some evidence to support a further reduction of craniospinal radiation to 18 Gy and the Children’s Oncology Group is currently examining this possibility.69 The current standard of care for average-risk medulloblastoma is gross total resection, postoperative craniospinal radiation of 23.4 Gy with a posterior fossa boost of 54 Gy, followed by 12 months of chemotherapy.
Treatment of Children Over Age 3 with High-Risk Medulloblastoma
The 5-year event-free survival rate across studies in high-risk medulloblastoma ranges from 30% to 70%.70 The best outcomes to date involve surgery, craniospinal radiation with 36 to 39.6 Gy, with a posterior fossa boost followed by intense cyclophosphamide, vincristine, cisplatin, and peripheral stem cell rescue. This regimen yielded a 5-year EFS rate of 70%.71 A 4-year EFS rate of 66% was reached by the Children’s Oncology Group (COG 99701) with surgery, concomitant daily vincristine/carboplatin and craniospinal radiation (36 Gy), and a posterior fossa boost followed by monthly cyclophosphamide and vincristine.72 These studies highlight the intensive regimens required to treat high-risk medulloblastoma. The adverse effects associated with these intensive treatments must be taken into consideration when one considers the enhanced survival rates for these patients.
Treatment of Infants and Young Children with Medulloblastoma
Treating infants and young children with medulloblastoma remains challenging and suboptimal. The developing brain is particularly susceptible to the toxicity of treatment regimes. These patients suffer from severe neurocognitive decline secondary to craniospinal irradiation. Thus, recent neuro-oncology clinical trials have promoted the use of chemotherapeutic strategies to delay or avoid craniospinal radiation. The Pediatric Oncology Group (POG) initiated a trial in the 1980s (the Baby POG study) treating infants with prolonged postoperative chemotherapy in an attempt to delay radiation until 3 years of age. The overall 5-year progression-free survival (PFS) rate was 31.8% but increased to 69% in those children with gross total resection.73 This study showed that craniospinal radiation could be delayed.73 The best results, to date, come from the Head Start 1 and 2 trials using induction chemotherapy of cisplatin, vincristine, etoposide, and cyclophosphamide followed by myeloablative chemotherapy and autologous stem cell rescue (methotrexate was added for disseminated disease). The 5-year PFS rates for infants was 64% in those with localized disease and 45% for disseminated disease. Interestingly, 50% of survivors never received radiation.74
Novel Therapeutics
As we begin to understand the molecular biology of medulloblastoma we have come to recognize and identify possible therapeutic targets. One such example is the use of a sonic hedgehog (SHH) pathway inhibitor GDC-0449. A 26-year-old man with recurrent resistant medulloblastoma with aberrant activation of SHH signaling was treated with the inhibitor and showed rapid (albeit transient) response.75
Proton beam therapy is a type of radiation therapy that utilizes charged beams that have a finite range in tissues and potentially allows sparing of normal tissues compared to conventional types of radiotherapy. To date, only a few patients with medulloblastoma have been treated with proton beam therapy; however, there is currently a phase II trial being undertaken at this time.76
Intrathecal (IT) chemotherapy to delay radiation threapy, salvage recurrent disease, or treat leptomeningeal seeding is being used now in several trials. IT chemotherapeutic regimens have been successfully used to avoid craniospinal radiation in the pediatric leukemia population.77 Case reports have shown moderate success and phase I and II trials for pediatric medulloblastoma are currently ongoing.78,79
Ependymoma
Ependymomas are the third most frequent brain tumor in the pediatric population. First described in 1926 by Cushing and Bailey, they account for 6.4% of primary brain tumors in children aged 0 to 14 years and for 30% of tumors in children less than 3 years of age.80 The mean age of presentation is 3.7 years.11 Unlike medulloblastoma, 5-year survival rates for ependymoma are approximately 60%.81
Imaging
The classic infratentorial ependymoma fills the fourth ventricle and extends laterally through the foramina of Luschka (15%) and inferiorly through the foramen of Magendie (60%). Typically, ependymoma demonstrates low T1, high T2, and intermediate to high fluid attenuated inversion recovery (FLAIR) signal intensity (Fig. 10.4).82 However, the lesions can be heterogeneous owing to cystic areas, calcifications (50%), and hemorrhage. Postcontrast imaging shows a heterogeneous enhancing tumor with areas of avid enhancement mixed with poorly enhancing regions. Diffusion-weighted imaging (DWI) is intermediate between pilocytic astrocytomas (low) and primitive neuroectodermal tumors (PNETs) (high).83 Ependymomas often encase neurovascular structures in the CPA, thus making surgical removal difficult without causing cranial nerve or vascular injury. Ikezaki and co-workers, classified posterior fossa ependymomas into three groups based on location: (1) the lateral type presenting in the CPA characterized by a poor prognosis secondary to involvement of cranial nerves and brainstem; (2) ependymomas localized to the floor of the fourth ventricle with an intermediate prognosis; and (3) those localized to the roof of the fourth ventricle with the most favorable outcome.84 Leptomeningeal dissemination occurs in 8% to 12% of patients by CSF cytological findings and occurs more frequently with anaplastic grades.85 Leptomeningeal disease with drop metastasis is most common in the lumbosacral region.
Histology
The WHO recognizes three grades of ependymoma and four histological variants (Table 10.4).33,80 The classic histological features of ependymoma are perivascular and ependymal rosettes. The former corresponds to ependymal cell processes radially arranged around a cell-free perivascular zone. The latter, ependymal rosettes, comprise tumor cells concentrically arranged to form a lumen.80 Ependymomas are given an anaplastic grade when there is evidence of (1) brisk mitotic activity; (2) increased cellularity; (3) microvascular proliferation; or (4) pseuodopalisading necrosis. However, there is debate in the literature as to the precise definition of anaplastic criteria. In part, this controversy has called into question whether or not histological grade predicts for survival.86–95
| WHO Grade | Histological Subtype(s) |
|---|---|
| Grade I (subependymoma and myxopapillary) | Cellular ependymoma (grade II) |
| Grade II (ependymoma) | Papillary ependymoma (grade II or III) |
| Grade III (anaplastic ependymoma) | Clear cell ependymoma (grade II or III) |
| Tanycytic ependymoma (grade II or III) |
WHO, World Health Organization.
The most common genetic alteration in ependymoma is loss of chromosome 22; however, in posterior fossa ependymoma the putative tumor suppressor at this locus remains elusive.96 Other genetic events common in posterior fossa ependymomas are 9q and 1q gain, loss of 6q, and monosomy 17p.96 Interestingly, DNA identical to portions of the SV40 virus has been isolated from ependymoma, and SV40 is capable of inducing ependymoma in rodents.
Surgical Management
The key to treatment of ependymoma remains complete macroscopic surgical resection, as it is known that the degree of resection is the most significant predictor of survival. The goals of surgery are tissue diagnosis, management of hydrocephalus, and cyotoreduction. Complete surgical resection leads to 5-year survival rates ranging around 70% to 80%,80 whereas patients with subtotal resection have significantly poorer outcomes with 5-year survival rates around 20% to 40%.91,97 Given the predictive value of resection on survival, patients should undergo a postoperative MRI within 48 hours to ensure macroscopic resection. “Second look” surgery is warranted in cases in which bulky residual disease is found after initial surgery.91,98–100 It should be stressed here that gross total resection can be made difficult with large ependymomas extending into the CPA encasing cranial nerves and vascular structures or when invasion of the floor of the fourth ventricle occurs. The morbidity of complete resection in these cases may be high (10-30%).101
Adjunctive Therapies
Postoperative radiation treatment is an established standard of care for patients with ependymoma because it is a radiosensitive tumor. A recent study from St. Jude Children’s Research Hospital showed a 7-year EFS rate and overall survival (OS) rate of 69% and 81%, respectively, with maximal surgical resection and local conformational radiation therapy. Craniospinal radiation was reserved for those cases with evidence of CSF dissemination by imaging or cytological appearance.102 Interestingly, baseline and longitudinal testing of cognitive outcome demonstrate most survivors within normal range despite a large portion of patients being 3 years or less at treatment.102
Currently, there are no proven established protocols for chemotherapy in the treatment of ependymoma. There has been moderate success in using chemotherapy to delay radiation therapy in young children with ependymoma.73,103,104 Current studies are being undertaken to evaluate molecularly targeted therapy such as the small molecule tyrosine kinase inhibitors (geftinib, erlotinib, baevacizumab).105
The rate of relapse following treatment ranges from 30% to 72%.97,102,104,,106,107 The vast majority of relapses occurs locally, and median survival time after relapse varies from 8.4 to 24 months.108 The literature supports reoperation for recurrence of ependymoma.98,107 For children who have not received radiation therapy, radiation therapy should be given. Re-irradiation is an option for children previously treated with radiotherapy, but morbidity rate from radiation necrosis may be high.109–111
Atypical Teratoid/Rhabdoid Tumor
Malignant rhabdoid tumors (MRTs) were first described as a highly malignant subtype of Wilms’ tumor.112 It is now recognized that MRTs occur throughout the body. Biggs and associates first described an intracranial MRT in 1987.113 These tumors were first termed atypical teratoid/rhabdoid tumors (AT/RTs) in a landmark paper in 1995 because of their histological characteristics, which showed neuroepithelial, peripheral epithelial, and mesenchymal elements.114 The WHO first recognized AT/RT as a separate tumor entity in 2000. It is predominantly a tumor of infants and young children with a median age of diagnosis at 26 months with a slight male predominance.114,115 Approximately 30% of AT/RTs occur infratentorially (CPA and cerebellum), and 22% have CSF dissemination at diagnosis.115 The overall survival time is 18 months; however, in patients presenting with signs of metastasis the prognosis is significantly worse at 8 months.115
