CHAPTER 124 Primitive Neuroectodermal Tumors
History
Through the years, many different names have been applied to the tumors that are now known as medulloblastomas or primitive neuroectodermal tumors (PNETs). First described by Bailey and Cushing in 1925,1 they were initially called spongioblastoma cerebelli, subsequently termed spongioblastomas, and eventually named medulloblastoma cerebelli, as they were thought to arise in the cerebellum from medulloblasts. Medulloblasts were thought to be pluripotential cells that eventually gave rise to these tumors in the cerebellum. Present terminology refers to medulloblastomas specifically as PNETs located in the posterior fossa, but it should be noted that although we will limit our discussion to tumors within the brain, PNETs may also occur outside the brain throughout the body, particularly as peripheral neuroblastomas and Ewing sarcomas.
Incidence
PNETs are found in both children and adults, although they are more common in children. Posterior fossa PNETs (medulloblastomas) are the most common malignant solid tumor and the most common malignant brain tumor diagnosed in children. Medulloblastomas constitute about 20% of childhood brain tumors and about 30% of all posterior fossa tumors. Medulloblastomas account for 1% of all adult brain tumors. The incidence of childhood brain tumors has risen during the past 10 years, and most recent evaluations suggest that between 250 and 350 children will be diagnosed with medulloblastoma in the United States each year. The age at diagnosis ranges between 5 and 77 years, and 80% are found in children younger than 15 years.2 Medulloblastomas, although more commonly seen in childhood, can occur in adults, in which case they are usually located in the cerebellar hemispheres and are histologically characterized as desmoplastic.3,4
Most studies indicate that there is a slight male predominance; it is 1.4 to 4.8 times more common in males than in females.5,6 The incidence is 42% higher among whites than blacks.7 A protective effect of maternal folate, iron, and multivitamin supplementation has been suggested to correlate with a decreased incidence of medulloblastomas seen in some studies.8,9 The effect of environmental factors on tumor formation has been debated for several years. N-nitroso compounds are found in beer. Mothers who report drinking one or more beers per week have been associated with a slightly increased incidence of medulloblastoma. Children born of mothers living on a farm during pregnancy also have a mildly increased disease incidence. This association was not significant in mothers who handled animals but was statistically significant with children who resided on a farm for more than 1 year. There were no significant associations with maternal or early childhood medication exposures.10
Several syndromes are associated with a familial increased incidence of medulloblastoma. Although the incidence of medulloblastoma has not been shown to be increased in patients with phakomatosis, such as neurofibromatosis or tuberous sclerosis, it has been shown to be increased in patients with Gorlin’s syndrome (nevoid basal cell carcinoma), Li-Fraumeni syndrome, and Turcot’s syndrome. Gorlin’s syndrome is characterized by the occurrence of multiple nevoid basal cell carcinomas, multiple skeletal anomalies (including jaw cysts), cutaneous anomalies (including pits on the hands and soles of the feet), calcifications of the dura, hydrocephalus, and developmental delay. In Gorlin’s syndrome, about 5% of children develop medulloblastoma when they are younger than 5 years.11,12 The medulloblastoma subtype in Gorlin’s syndrome is often desmoplastic and is thought to be due to inactivation of the tumor suppressor gene on chromosome 9q.13 Gorlin’s syndrome is an autosomal dominant disorder in which the gene mutated is the human homologue of the Drosophila melanogaster patched gene (PATCHED). PATCHED codes for a transmembrane receptor for the secreted ligand sonic hedgehog homologue (SHH). The SHH signaling pathway is vital during the development and formation of the central nervous system (CNS). PATCHED has been localized to chromosome 9q, and medulloblastomas have been shown to have a loss of heterozygosity on chromosome 9q.14
In Turcot’s syndrome, or multiple familial polyposis, the inheritance of medulloblastoma is variable and is believed to be either autosomal recessive or dominant. The frequency with which medulloblastomas develop is uncertain.6,15 In Turcot’s syndrome, the patient has a primary brain tumor but also develops multiple colorectal adenomas, colorectal adenocarcinoma, or both. These patients tend to have mutations in the adenomatous polyposis coli (APC) gene on chromosome 5q21.14
Supratentorial PNETs may also be seen in conjunction with retinoblastoma. Often termed pinealoblastomas because of their location, these tumors can be associated with bilateral retinoblastomas and are caused by germline mutations in the Rb gene. Suprasellar or parasellar PNET tumors may also be seen in these patients.14
Pathology
Historically, the terminology used to describe medulloblastomas or PNETs has been confusing. Initially termed spongioblastoma cerebelli by Bailey and Cushing,1 they had earlier been termed spongioblastoma multiforme. In 1983, Rorke16 named them primitive neuroectodermal tumors, recognizing that histologically these tumors were identical to those seen supratentorially and elsewhere. Histologically similar tumors found in the pineal gland are termed pinealoblastomas (Fig. 124-1), whereas those in the supratentorial space are termed either PNETs or neuroblastomas (Fig. 124-2), and those in the eye are termed retinoblastomas. Medulloblastoma is the term now applied to PNETs arising in the posterior fossa. Subcategories have been described based on differentiation, and thus medulloblastomas have been categorized as having or not having glial, ependymal, or neuronal differentiation.
About 50% of medulloblastomas demonstrate neuronal or glial differentiation.17 Homer Wright pseudorosettes, in which nuclei surround a central clear area made up of cell processes rather than a vessel, are present in more than 40% of medulloblastomas (Fig. 124-3). Astrocytic differentiation is seen in more than 50% of tumors and is identified by cell processes that stain positive for glial fibrillary acidic protein (GFAP).18,19
Grossly, medulloblastomas appear as soft, unencapsulated but relatively well-circumscribed, friable, purplish tumors, usually located in proximity to the fourth ventricle in the region of the vermis. They may invade the cerebellum, brainstem, or cerebellar peduncle. Unlike ependymomas, lateral extension into the cerebellopontine angle is a rare occurrence.20 The four histologic subtypes of medulloblastomas, according to the World Health Organization (WHO) classification of CNS tumors, include desmoplastic (or nodular) medulloblastomas, medulloblastomas with extensive nodularity, anaplastic medulloblastomas, and large cell medulloblastomas.21 The desmoplastic subtype, which represents 29% of all medulloblastomas, tends to be located within the cerebellar hemisphere and is usually firmer and often more well demarcated. After hematoxylin and eosin staining, they appear as small, round, blue-cell tumors with hyperchromatic nuclei and minimal cytoplasm.22 This variant is characterized by nodular reticulin-free zones surrounded by densely packed proliferative cells with hyperchromatic and pleomorphic nuclei. The nodules represent regions of neuronal maturation with a reduced nuclear-to-cytoplasmic ratio. Medulloblastoma with extensive nodularity occurs in infants. These tumors differ from the desmoplastic subtype in that the reticulin-free zones become enlarged and rich in a neuropil-like tissue. Anaplastic medulloblastomas display widespread cellular atypia, including marked nuclear pleomorphism, high mitotic activity, atypical cell shape, and cell-to-cell wrapping. Apoptosis is a prominent feature in this subtype. Large cell medulloblastoma represents 2% to 4% of all medulloblastomas. Characteristics of this subtype include large round cells with prominent nucleoli and varying amounts of cytoplasm. Apoptotic features and regions of anaplasia are common.21
The cell of origin in medulloblastomas remains controversial. The fetal external granule cell layer has been hypothesized as the area of origin. Scattered foci of this fetal external granule cell layer persist in the medullary velum, often considered a point of origin for medulloblastomas.23,24 Other candidate cells have included undifferentiated subependymal cells and neurons within the internal granular layer. It has been suggested that exposure to toxins or viruses during the perinatal period may induce some of these pluripotential cells to become medulloblastomas. Posterior fossa tumors similar in histopathology to medulloblastomas have been induced in hamsters by intracerebral injection of JC virus and in rats through the large T-antigen of SV40 during the perinatal period.24
A variety of chromosomal abnormalities have been reported in medulloblastomas, but no specific genetic abnormality has been consistently associated with its pathogenesis. The most consistent chromosomal abnormality reported involves chromosome 17. Abnormalities may include loss or gain of parts of chromosome 17.25,27 The most frequent aberration involves the coincidental loss of part of 17p and gain of 17q through formation of an isochromosome of the long arm of 17q.27 This can be seen in up to 66% of medulloblastomas, but it is thought to be related to tumor progression rather than tumor origin.25–27 The breakpoint is usually the proximal p-arm at the 17p18318880-19046234 region.29,30 It is now generally accepted that isochromosome 17q represents an unbalanced translocation between the two copies of chromosome 17.31 The breakpoint occurs within the EPN2 gene. This gene is expressed in the cerebellum and interacts with proteins related to protein transport. The tumor suppressor gene p53 is located in the 17p region and is included within the region of loss; however, it is only mutated in 5% to 10% of medulloblastomas.32 The p53 gene has therefore been postulated to contribute to the pathogenesis of medulloblastomas but is unlikely to be the cause.33,34 Other frequent losses are seen on chromosomes 8p, 10q, 16q, and 20p. Frequent gains are seen on chromosomes 2p, 4p, 7, and 19.27
Medulloblastoma tumor cells have been shown to overexpress various factors. Among these, platelet-derived growth factor-α receptor expression has been associated with neuronal differentiation.35 Various growth factors have been associated with medulloblastomas, but none has been found that is specific to medulloblastomas. The overamplification of MYC, occurring in 16% of medulloblastomas on chromosome 8, has been associated with unfavorable patient outcomes. Favorable outcomes for medulloblastoma have been associated with high levels of TrkC transcripts and low levels of MYC, MYCN, and erbB-2 transcription.27,36,37 Cytogenetic analysis has shown that some cells may be diploid, some tetraploid, and others aneuploid.38,39
A separate subtype of medulloblastoma was recognized by Rorke and associates40 in 1995. Termed atypical teratoid-rhabdoid tumors of the cerebellum, these tumors are often mistaken for medulloblastomas. They show loss of heterozygosity on chromosome 22q. The tumor suppressor gene altered in these tumors is on chromosome 22 and was identified as hSNF5/INI1. The hSNF5 gene has been identified as altered in sporadic medulloblastomas and PNETs.14,28,41,42
Clinical Evaluation
Signs and Symptoms
Children with medulloblastoma generally present with symptoms of increased intracranial pressure (ICP). Symptoms are generally present for several weeks to months, are typical for all posterior fossa tumors, and are not specific for medulloblastomas. Among the common symptoms are headaches, nausea, and vomiting. These symptoms are also related to hydrocephalus, which often occurs simultaneously with these tumors. Morning headaches and vomiting are often seen, and many children have undergone extensive gastrointestinal evaluation before a diagnosis of a brain tumor is made. Other symptoms include an unsteady gait, ataxia, and diminished coordination. Rarely, children may present with head tilt or torticollis. This can be related to cranial nerve palsy, particularly sixth nerve palsy or secondary to pain because of dural traction.43,44 In very young children, the diagnosis can be difficult, and such children may present only with macrocephaly, loss of milestones, irritability, and vomiting.
Radiographic Evaluation
Children with PNETs or medulloblastomas are usually diagnosed by means of computed tomography (CT) or magnetic resonance imaging (MRI). On CT scans, medulloblastomas are typically hyperdense, showing homogeneous contrast enhancement, and may be partially cystic.45 They usually have smaller areas of calcification and small cysts; rarely, they may be extensively calcified.46,47 On MRI scans, the tumors are usually isointense or hypointense on T1-weighted images, hyperintense on T2-weighted images, and intensely enhancing after gadolinium injection (Fig. 124-4).48,49 About 10% to 15% of medulloblastomas are not contrast enhancing on an MRI scan, which makes postoperative assessment of residual disease more difficult. Unfortunately, there are no clear-cut radiologic features that absolutely differentiate a medulloblastoma from other posterior fossa masses; pathologic analysis is the only way to be certain.
Because medulloblastomas can spread throughout the CNS, many physicians obtain an MRI scan of the spine as soon as the diagnosis of medulloblastoma is entertained (Fig. 124-5). Postsurgical blood and protein may confound spinal imaging for weeks after surgery, and thus preoperative spinal MRI may give the best assessment of spinal metastasis. Because most children have concomitant hydrocephalus, performing a lumbar puncture is dangerous and should be avoided until most of the mass has been removed.
Treatment
Management of Hydrocephalus
Hydrocephalus is a common presenting feature, particularly of posterior fossa PNETs or medulloblastomas. Treatment of hydrocephalus usually involves placement of an external ventricular drainage device (EVD) or ventriculostomy at the time of surgical excision of the lesion. Preoperatively, hydrocephalus may also be treated with dexamethasone to help reduce swelling associated with the tumor. The use of EVDs permits easy access to the CSF and allows intermittent fluid drainage at a desired height or pressure. Attention must be paid to the height or pressure at which the ventriculostomy or EVD drainage is maintained when the tumor is still in place. In less than 40% of cases, an EVD will be necessary over the long term after removal of the tumor, and preoperative shunting before removal of the tumor is discouraged to avoid upward herniation.50,51 Upward herniation occurs when there is an imbalance in pressure across the tentorium such that there is increased pressure in the posterior fossa relative to the supratentorial space. Upward herniation is a rare event, occurring in less than 3% of cases.52
The risk for propagation of medulloblastoma cells through a shunt appears to be minimal. Berger and associates51 found that extraneural metastases occurred in only 8 of 415 children with brain tumors, all of whom had medulloblastomas. However, 5 of the 8 children did not even have a shunt. Jamjoom and colleagues,53 in a review of 160 cases of medulloblastomas with systemic metastasis, reported that only 19% of patients had shunts and that propagation through the shunt could be ascribed to only 7% of those cases. The use of millipore filters in shunts to decrease such dissemination through the shunt has largely been abandoned because of the high rate of occlusion of such filters and because of the lack of any evidence suggesting efficacy in preventing metastasis.
In the postoperative period, EVD pressure is gradually increased to allow normal CSF pathways to resume absorption of CSF. Drainage is generally stopped for a time, and pressures are measured before the ventriculostomy catheter is removed. Symptoms of increased ICP, CSF leakage from the wound, and development of a pseudomeningocele can be indicators of failure to wean the patient from the EVD and the need for a shunt. The need for postoperative shunts has been correlated with younger patients, large ventricles at the outset, long-standing ventriculomegaly, and large tumors.54
Tumor Removal
Standard pediatric neurosurgical and anesthetic techniques are used in the removal of PNETs. Because these can be bloody tumors, adequate venous access as well as arterial pressure monitoring is important, and transfusion may be necessary. Such operations may be lengthy, particularly in the case of large tumors with brainstem involvement, and monitoring of urine output through a Foley catheter is useful. Doppler monitoring is rarely necessary because the head is positioned only slightly higher than the heart. Air embolism in this position is rare but must be considered if there is a sudden decrease of end-tidal PCO2 or a drop in O2 saturation. Electromyographic monitoring of the lateral rectus and facial muscles may provide assistance to the surgeon when working near the abducens and facial nuclei along the brainstem,55 but improvement in outcomes with use of such monitoring has not been generally established.
A craniotomy is appropriate for tumors in the supratentorial space, although most will be located in the posterior fossa. For those in the posterior fossa, the patient is usually in the prone position with the head slightly flexed.56,57 This position is also described as the angulated Concorde position. The sitting position has largely been abandoned because of the risk for air embolism, difficulty in positioning, and surgeon fatigue. Many surgeons will perform a suboccipital craniectomy, but with the development of improved high-speed drills, more neurosurgeons now opt for a suboccipital craniotomy and replacement of the bone flap.
