8 Pediatric Neuro-Oncology
Introduction
EPIDEMIOLOGY
The incidence of brain tumors among children (ages 0 to 14 years) is highest in the Scandinavian countries (31.4 per 106 per annum) followed by Western Europe, the United States of America, and New Zealand (24 to 27 per 106). The age-specific incidence for brain tumors is highest among children less than 5 years of age (36 per 106 per annum), then declines among those 5 to 9 years (31.9 per 106) and 10 to 14 years (24.6 per 106) to the 15-19 age group (20.2 per 106 annually).1–4
Age correlates with the relative site of origin among cancers of the brain, in a pattern that is quite different than that observed among adults. Brainstem gliomas (BSG) are more common in children between 5 and 9 years of age (5.9 per 106 per annum) than among preschoolers (4.7 per 106), adolescents of 10 to 14 years (2.8 per 106), or older teenagers (1.7 per 106 per annum). Cerebellar neoplasms are similarly distributed, occurring most frequently between 5 and 9 years of age (9.7 per 106). By comparison, the relative distribution of tumors arising in the cerebrum gradually increases following the first 5 years of life (5.8 per 106 per annum) through adolescence (15 to 19 years of age) (7 per 106).4 In contrast, during adulthood, the vast majority of primary CNS neoplasms are supratentorial in origin.
Reliable epidemiologic data confirm an increase in the incidence of children with gliomas between 1973 and 1992. This increase has been restricted to the AST (World Health Organization Grades I and II), with an average yearly rise of 3%. The trend has been more notable among females, in whom there has been an average annual increase of 3.9%. During this period, there was no change in the relative incidence of the other “classic” childhood CNS tumors, such as MBL and EPD.5
Among children and adolescents, tumors of astrocytic lineage constitute about 52% of reported cases. Other types of gliomas, such as gangliogliomas or mixed AST-OLG, contribute an additional 15.5%.4 There are two clearly defined peaks in relative incidence, observed at five years (20.7 per 106 per annum) and thirteen (19.7 per 106) years of age.3 After puberty, the incidence of AST and malignant astrocytomas (MA) falls to 12.3 per 106 annually.1
The PNETs comprise neoplasms considered “embryonal” in their pathogenetic derivation, and include the MBL, medulloepithelioma, pineoblastoma and the “cerebral neuroblastoma.” Overall, this family of cancers comprises only 3.6% of all brain tumors.6 As a group, the PNET constitute about 22% of primary CNS neoplasms occurring during childhood and adolescence.4 Their relative incidence declines throughout childhood, from the peak seen among children less than 5 years of age (9.6 per 106 per annum), through those of 5 to 9 years of age (7.4 per 106), 10 to 14 years (4 per 106), and older adolescents (2.5 per 106 annually).4 According to the National Cancer Institute’s SEER data, the incidence of MBL-PNET rose 23% between 1973-1976 and 1993-1998, that is from 4 to 4.9 per 106 person-years (PY).10
Ependymomas constitute about 9% of tumors arising within the CNS during childhood and adolescence, but represent only 3% of brain tumors overall.4,9 The relative incidence varies among age cohorts, being highest among infants, toddlers, and preschoolers (5.6 per 106 per annum), then falling to 1.1-1.6 per 106 annually among children older than 5 years of age.1 The peak age at diagnosis is during the second year of life (8.6 per 106).4
Germ cell tumors present in three principal age periods. Congenital GCTs are typically benign teratomas, and during infancy (1 month to 3 years), endodermal sinus tumors and/or malignant teratomas predominate. Adolescence and young adulthood are usually associated with endodermal sinus tumors and embryonal carcinomas, often with teratomatous elements. In contrast to the prevalence of these nongerminomatous GCTs (NG-GCT) among the young, the majority of adult GCTs are pure germinomas.8 In Japan, Taiwan, and South Korea, GCTs comprise 2.1% to 9.4% of primary intracranial neoplasms.9 This is consistently higher than the 0.4% to 3.4% reported in western series.10 In North America, origin within the brain accounts for 14% of all GCTs occurring among persons less than 20 years of age. Their relative incidence has steadily risen from 0.5 per 106 per annum in the 1970s to 1.5 per 106 in the late 1990s, which, within the industrialized countries, has suggested an environmental influence for their pathogenesis.
The observed survival rates for malignant CNS tumors diagnosed between 1973 and 1999 were grim: 50.0% at 1 year, 35.0% at 2 years, 25.6% at 5 years, and only 19.5% at 10 years from diagnosis. This translates to a mortality rate of 5.3/100,000 PY for males and 3.6/100,000 PY among females.2
PROPOSED ETIOLOGIC FACTORS
There is an approximately three- to nine-fold increased risk of developing a brain tumor should a family member be so affected; however, the nature of this association is not understood.11 Allegations have been raised regarding electromagnetic waves, nitrosourea derivatives in processed meats, pesticides, and unique occupational hazards. However, no chemical agent not already known to be carcinogenic for other human tissues has been found to be uniquely associated with cancer of the brain. Neuroectodermal tissue is vulnerable to the carcinogenic effects of external-beam radiation therapy (EBRT). A strong dose-response relationship exists, as exposures higher than 2.5 Gray (Gy) are associated with a 20-fold increased carcinogenic potential.12 The latency period for postradiation neuro-oncogenesis stretches from 12 years to 15 years (range 4 to 30 years).13
CLINICAL PRESENTATION
Low-Grade and Malignant Glioma
The child afflicted with a cerebral neoplasm complains of symptoms referable to its location. Cognitive impairment (15% to 20%) and seizures, either at presentation (about one third) or during the course of the illness (50% to 70%), are common problems that bring the patient to medical attention.14 Superficial cerebral tumors may produce partial, complex partial, or secondarily generalized seizures. Symptoms of dysphasia, mental confusion, or motor deficit are predictive of significantly impaired physical, cognitive, emotional, and social function.15 Motor or sensory compromise will reflect proximity to eloquent cortex. Deeply seated neoplasms, or those situated so as to obstruct the drainage of cerebrospinal fluid (CSF), produce headache, altered mental status, and, possibly, visual obscuration with or without localizing corticospinal tract findings. The pattern of headache, such as those which awaken the patient from sleep (10% to 32%), early morning occurrence followed by vomiting, as well as the influence of position, posture, or exercise (20% to 32%), contribute to the recognition of increased intracranial pressure. Recent onset, evolution of the headache’s intensity, papilledema and/or focal deficits on exam also expedite a diagnostic investigation.16 Brainstem gliomas are recognized by the combination of multiple cranioneuropathies, corticospinal tract findings, ataxia, and/or obstructive hydrocephalus.
Medulloblastoma
Park et al.17 reviewed 144 patients treated at a major Canadian referral center between 1950 through 1980. The prediagnosis symptomatic interval was less than 6 weeks in 51%, and less than 12 weeks in 76%. The age at the time of diagnosis ranged from 7 weeks to 15 years. Eighty-one percent of patients were between 1 and 10 years of age. The clinical presentation was that of a posterior fossa mass, i.e., intracranial hypertension from hydrocephalus (Figure 8-1). Seventy-six percent had papilledema and 65% complained of headache. Recurrent vomiting occurred in 47%. Axial ataxia (62%), nystagmus (44%), and appendicular dysmetria (35%) were common neurologic signs. Hemorrhage into the primary tumor occurred in four, who presented with abrupt neurological deterioration.17
Figure 8-1 Axial (A) and sagittal (B) T1 contrast-enhanced MRI showing medulloblastoma in the posterior wall of the 4th ventricle. C, Axial T2 MRI.
(Slides courtesy Susan Chi, M.D., Dana-Farber Cancer Institute and Boston Children’s Hospital.)
Staging evaluation is an important aspect in establishing the clinical diagnosis. Harisiadis and Chang18 stratified patients based on tumor size (“T”) and extent of metastatic spread (“M”). Spinal subarachnoid dissemination has been identified in 36% to 43% of prospectively studied patients.19 Dissemination to the bone marrow has been reported to be as high as 18% at the time of diagnosis.19 The frequency of this complication at recurrence rises to approximately 35%.20
The “atypical teratoid/rhabdoid tumor” has previously been confused with the MBL. This early childhood neoplasm of the CNS arises either supra- or infra-tentorially and is composed of rhabdoid cells and undifferentiated small cells, with epithelial, mesenchymal, and neural elements. Overall survival (OS) periods of only 11 to 13 months have been reported following surgery and EBRT.21,22
Ependymoma
Supratentorial origin is more likely to be associated with corticospinal tract deficits and increased intracranial pressure at the time of presentation. Intratentorial location is frequently identified because of cranioneuropathies, ataxia, hydrocephalus, and a briefer prodrome because of the higher grade of malignancy encountered (Figure 8-2). Spinal EPDs present with back and/or radicular pain as well as lower motor neuron signs. The overall incidence of subarachnoid dissemination with intracranial EPD is reported to be approximately 10% to 22%, but this is influenced by site of origin and tumor grade. Anaplastic infratentorial tumors have a rate approaching 30%, while the incidence of spinal dissemination among the supratentorial EPD is negligible.23
Figure 8-2 Axial (A) coronal (B) and sagittal (C) T1 contrast-enhanced MRI showing large ependymoma, effacing the 4th ventricle and invading into the brain stem There is associated hydrocephalus.
(Slides courtesy Susan Chi, M.D., Dana-Farber Cancer Institute and Boston Children’s Hospital.)
Oligodendroglioma
A series of 37 patients demonstrated that the common presenting symptoms were seizures (43%), headache (38%), motor deficits (38%), and to a lesser degree, behavioral changes (16%). The most common site of origin was the frontal lobe (43%). Low grade histopathology (WHO grades I and II) was documented in 60%, with the remainder being grade III or IV disease.24
Germ Cell Tumor
Ninety-five percent of primary intracranial GCTs arise along an axis from the suprasellar cistern (37%) to the pineal gland (48%) (Figure 8-3). In one study, germinomas were found to preferentially involve the suprasellar region (57%), while 68% of NG-GCT’s originated in the pineal recess (P < .0001). Germ-cell tumors were found in the suprasellar region in 75% of female patients; pineal involvement was more frequent (67%) among males (P = .0001). The age distribution peaked during early puberty. Nongerminomatous GCTs (24%) were more frequently diagnosed between birth and 9 years than were germinomas (11%) (P < .0001). Among patients with germinomas, 35% were reported to be symptomatic for 6 months or longer, with half of these in excess of 24 months. The prodrome was much shorter among patients with NG-GCT (P = .0007).8
Figure 8-3 Axial (A) and sagittal (B) T1 contrast-enhanced MRI sho- wing enhancing, partially cystic, mixed germ cell tumor.
(Slides courtesy Susan Chi, M.D., Dana-Farber Cancer Institute and Boston Children’s Hospital.)
Patients with germinomas, which were commonly suprasellar, presented with chiasmal visual field defects (33%), diabetes insipidus (41%), and hypothalamic-pituitary dysfunction (33%). These neuroendocrine deficits included delay or regression of sexual development (16%), hypopituitarism (16%), and growth failure (9%). Presenting symptoms and signs among the NG-GCTs, which usually localized the lesion to the pineal recess, included hydrocephalus (47%), Parinaud’s sign (34%), obtundation (26%), pyramidal tract findings (21%), and ataxia (19%). Spinal cord metastases were more prevalent among patients with germinomas (11%) and endodermal sinus tumor (23%). Abdominal and pelvic metastases developed in approximately 10% of the 106 patients who were known to have received ventriculoperitoneal shunting.8
Brain Tumors Arising During Infancy
Primary CNS neoplasms during the first 2 years of life are considered quite uncommon in individual practice. However, they actually constitute 13% of all childhood brain tumors. The ratio between malignant (47%) and low-grade tumors is nearly equal in this age-group. Symptoms and signs are related to the site of origin, which is infratentorial in most (40% to 57%).25 The most common symptom has been vomiting (43%), with early morning occurrence in only a third of infants. Headache may be suspected in 33% because of head banging and irritability. Gait ataxia (38%) and macrocephaly (19%) were other findings. The nonspecific nature of these symptoms contributes to the frequent delay in diagnosis. Tonsillar herniation has been documented in 43% at the time of diagnosis, presenting with head tilt (one third) or opisthotonic arching (one third), the latter has been misinterpreted as tonic seizure activity. As many as 10% of these children have presented as failure to thrive secondary to hypothalamic involvement, termed “the diencephalic syndrome.”25
PROGNOSTIC VARIABLES
Malignant Glioma
It has proven difficult to identify biologic determinants of survival that can be conveniently assayed in a timely manner at the time of diagnosis in order to better guide the intensity of therapy. However, some attempts have been encouraging. For example, identification of the labeling index has shown an encouraging prognostic correlation with the histopathologic grade of MG, which in the future may allow stratification of pediatric subjects in clinical trials by relative risk.26 The literature also suggests that expression of the multiple drug resistance (PgP/MDR) proteins and intratumoral hypoxia may also influence outcome.
Histopathologic Grade and Age among Malignant Astrocytomas
The Children’s Cancer Group (CCG) #943 study showed the median survival among children with anaplastic astrocytomas (AAST) was greater than 6 years; among GBM patients, overall survival averaged less than 15 months (P = .012).27 Age and histopathologic grade jointly influenced outcome. The CCG #921 study found that among children less than 24 months old, the 3-year progression-free survival (3Y-PFS) was 36%. The 3Y-PFS for patients with AAST was 44%, which was dramatically better than that for GBM (0%) (Table 8-1).28
Multidrug Resistance Phenotype
The PgP and MRP proteins are thought to function as ATP-dependent transmembrane transporters, which nonspecifically remove large molecular weight solutes from the brain and/or prevent hematogenously borne chemicals from entering the CNS.29 PgP/MDR-1-associated resistance is hypothesized to function at the interface between the blood-brain and blood-tumor barriers as well as within the neoplastic cells themselves. Despite their association with progressive anaplasia and an adverse prognosis, there is actually little evidence that the PgP/MDR1 is a major mechanism of acquired resistance among MG.29–31 Resistance to therapy appears to be a more complex phenomenon which disrupts the mechanisms of repair of genotoxic injury and/or induction of apoptosis.
The O6-methylguanine-DNA methyltransferase (MGMT) enzyme’s function is to counteract the cytotoxic effects of alkylating agents; its expression correlates inversely with survival among adult MG patients. Archival histopathologic specimens from 109 patients treated on the CCG Study #945 were analyzed, and 11% had overexpression of MGMT. The 5Y-PFS was 8.3% among these patients, in contrast to those whose tumors did not show overexpression of MGMT (5Y-PFS of 42%, P = .017). This adverse correlation was independent of age, histopathologic grade, tumor location, or extent of residual disease.32
Hypoxia and the Abrogation of Apoptosis
Intratumoral hypoxia is known to be the most significant predictor of radiotherapeutic resistance.33 Radiation therapy has only one third the effectiveness against hypoxic tumor cells that it does against well-oxygenated cells. It was previously thought that radiation-induced DNA damage required the presence of oxygen radicals. Instead, normal cells, when deprived of oxygen, will arrest in late G1 and early S phase, in concert with hypophosphorylation of the retinoblastoma gene protein, pRB, and die through induction of apoptosis.33 Arrest of the DNA-damaged cell at the G1/S interface is associated with stabilization of intact wild-type TP53 (TP53wt) expression, inhibition of replicative DNA synthesis, and possibly the initiation of repair. TP53wt appears to achieve G1/S arrest through transcriptional regulation of at least one critical downstream target, the Cdk inhibitor p21WAF1/CIP1. This protein inactivates cyclin D/Cdk4, D/Cdk6, and E/Cdk2 complex activity and directly inhibits PCNA, a regulatory subunit of DNA polymerase (the principal replicative DNA polymerase).34
Ionizing radiation also produces G1 arrest in cells with TP53wt and increases TP53 protein expression.35 In contrast, the hypoxic regions within the tumor actually create a reservoir for malignantly transformed cells, which do not arrest at the G1/S interface, are more likely to have mutations in the TP53 gene (TP53 m), and become resistant to TP53-induced apoptosis (Graeber et al., 1996).36 Stable cytoplasmic TP53wt expression has been shown to a favorable predictor for survival among AAST patients (P = .015). By comparison, such expression was not found among the GBM (P = .8), which by definition contain areas of necrosis.37 Intratumoral hypoxia thus constitutes a key mechanism of clonal selection.
Furthermore, hypoxia has also been correlated with insensitivity to carmustine (BCNU) and cisplatin, independently of the putative drug resistance genes MDR1, MRP, O6MGMT, or ERCC.38 Here too, the acquisition of resistance appears be mediated through TP53 m. For example, 86% of TP53wt positive MG cell lines have been shown to be responsive to currently available chemotherapy drugs. In contrast, there were no effective cytotoxic agents against 75% of the glioma cultures expressing TP53 m (P = .0006). Supporting this specificity, the resistance conferred by TP53 m is restricted to alkylators and platinators, which damage DNA, rather than against the microtubular toxins.39
The Molecular Basis for Multiple Models of Glioma Progression: The Tumor Suppressor Genes
There is a large literature on the nonrandom cytogenetic aberrations observed among MGs, which include gains or losses of chromosomes, as well as rearrangements. Some of these changes, such as 10q, 9p, 11p15.5-pter and 19q may be found only among AASTs and/or GBMs.40,41 Loss of heterozygosity (LOH) analysis has correlated 17p deletions with allelic loss of the tumor suppressor gene (TSG), TP53.42 Hence, it has been hypothesized that such nonrandom patterns of genetic loss can be exploited to predict the location of other as yet unknown TSGs. This in turn has generated the concept of modeling mechanisms for tumor progression.
TP53
One pathway in the evolution of the MG involves TP53 m, which occurs in 14% to 46% of adult patients and is preferentially associated with development of the glioma (often an AAST) between 18 and 45 years of age.42,43 Clonal expansion of TP53 m cells have been observed from a small subpopulation within a primary AST to become the dominant cell type within a recurrent, or “secondary” MG.44
Alternate means of TP53 wt inactivation exist as TP53 wt may be complexed by the MDM2 oncogene product. In 8% to 10% of GBM, the MDM2 gene is amplified and overexpressed, supporting the importance of TP53 wt in glial cell cycle dysregulation. A more recent study has identified that about 35% of gliomas demonstrate either TP53 m or methylation of p14(ARF), suggesting that TP53 wt is controlled by down-regulation of p14(ARF).45 Inactivation of the astrocyte’s apoptotic response may therefore be effected either by deletion of 17p, mutation of TP53, MDM2 overpression, or hypermethylation of p14(ARF), thus unmasking multiple points of vulnerability along a common pathway that permit further progression towards the endpoint of malignant transformation.45
PTEN
Another fraction of about 30% (23% to 62%) of adult GBM patients has been characterized by the association of LOH of chromosome 10 with epidermal growth factor receptor (EGFR) amplification. In contrast to the previous group, these patients (typically older individuals) appear to present de novo with a “primary” GBM. The LOH at 10q23 has been demonstrated in approximately 70% of GBMs, and therefore predicted to be the site of another glial TSG.42,43 The “Mutated in Multiple Advanced Cancers” and “Phosphatase and Tensin” gene (MMAC/PTEN) has been localized to chromosome 10q25 and shown to function as a phosphatidylinositol 3,4,5-triphosphate phosphatase, which modulates cell growth as well as apoptosis.46,47
Patients with GBM have demonstrated a significantly higher incidence of LOH at the MMAC/PTEN locus (72%) than did patients with AAST (29%)(P < .0001). The clinical relevance is that patients with LOH at the MMAC/PTEN locus have a more adverse prognosis (P < .0001), even when controlled for age at surgery and histologic grade.48 Conversely, Kaplan-Meier analysis has demonstrated significantly better survival for patients whose MG exhibited high MMAC/PTEN expression.49 These results have been interpreted to implicate alteration or loss of the MMAC/PTEN locus as a late marker of disease progression with ominous significance.
RB
About 15% to 44% of MG patients are reported to have loss of chromosome 13 as well as LOH or partial deletions of the 13q14 allele, which suggests the possibility that the RB gene is also a glioma TSG. Loss of heterozygosity at the RB 1.20 region has not been detected among low-grade gliomas, but occurred in 20% of AAST and 32% of GBM. The presence of LOH at the RB 1.20 region has also been associated with an adverse prognosis, implying that loss/inactivation of pRB contributes to disease progression.50
Investigation suggests that aberrant function of cyclin D, Cdk4, p16INK4A/MTS1, and/or pRB is critical for both the process of transformation and that of progression towards increasing anaplasia among glial neoplasms. Cyclin D1 was originally cloned from a human GBM cDNA library, where its transcript and 34 kD product were in abundant expression. Deletion of p16INK4A/MTS1 and/or amplification of its target Cdk4 occur in 50% of AAST and 85% of GBM.51,52 The coordinate deletion of both p15INK4B/MTS2 and p16INK4A/MTS1 among GBMs suggests that selection favors homozygous deletions of chromosome 9p21 as more efficient for the simultaneous inactivation of both Cdk inhibitors than independent intragenic mutations would be.51 This remarkable specificity suggests that knocking out p16INK4A/MTS1’s inhibition of cyclin D1/Cdk4-induced hyperphosphorylation of pRB marks a critical event in the progression to the most advanced grade of glioma, the GBM.52
Evidence is accumulating that cyclin D1 overexpression, absence of pRB expression, failure of pRB dephosphorylation, and/or pRB cleavage may also contribute to chemotherapeutic drug resistance as well, although the mechanism or mechanisms are not understood. Altered CDKN2/p16 function has been correlated with increased sensitivity to antimetabolite agents as opposed to the alkylators, topoisomerase inhibitors, and microtubular toxins.53
To conclude, the genetic mechanism of glial transformation in children is not understood. In one series of 20 pediatric GBMs, 25% were associated with TP53m, the majority of which presented with a brief prodromal period and were considered “primary.” Loss of p16CDKN2/INK4A/MTS1 was detected in 61% of these GBMs. Overexpression of EGFR was infrequent (11%) and was coincidental with TP53 m in one case. Of the four GBMs, which progressed from lower-grade tumors, only one contained TP53 m.54 In another series of 29 childhood MGs, 95% of cases were found to harbor an alteration in at least one member of the TP53/MDM2/p14ARF tumor suppressor pathway. Overexpression of MDM2, which downregulates TP53 transcriptional activity, was present in 65%, and loss of p14AFT, which inactivates the pathway through MDM2, was found in 10%.55
Among pediatric MGs, the presence of MMAC/PTEN mutations has also been confirmed as a marker of an adverse outcome that is independent of patient age or histopathologic grade (III vs. IV).56 In tumor specimens of 62 evaluable patients treated on the Children’s Cancer Group (CCG) #945 protocol for children with MG (vide infra), alteration of PTEN sequence was detected in just one, in conjunction with loss of chromosome 10. Deletions of PTEN without mutations were found in seven additional specimens. The PTEN alterations were more common among GBM than other histopathologic grades (P = .0056). Although 37% (14/38) of evaluable tumors had increased EGFR expression, only one exhibited amplification of the EGFR gene. This may be interpreted to indicate that pediatric MGs differ in the mechanisms of tumorigenesis from those of adulthood.57
Brainstem Glioma
Favorable prognostic features include (a) protracted symptoms, (b) origin within the optic tectum, the mesencephalon, or at the cervicomedullary junction, (c) lesions which are cystic, focal, and/or dorsally exophytic, (d) onset in adulthood, and (e) neurofibromatosis type I (NF1). By comparison, the adverse markers for disease progression are diffuse pontine infiltration, a high mitotic index, a brief symptomatic prodrome, and multiple cranioneuropathies at presentation.58
Low-Grade Astrocytoma
Low-grade glial neoplasms (LGGN), which include AST, mixed astrocytoma-oligodendroglioma (AST-OLG), and pure OLG, constitute a heterogenous group of tumors without a predictable natural history. The 5Y-OS and 10Y-OS rates for LGGN following resection and EBRT are reported to range between 40% to 70% and 11% to 50%, respectively.59 In a review of 461 AST patients, the 5Y-OS rate was 36%; that is a third of the predicted actuarial survival for a comparable population of unaffected individuals.59 Only 16% of LGGN patients of any age were alive at 15 years following diagnosis.60 Otherwise stated, the long-term survival rate among patients with LGGN is less than that of their peers suffering from acute lymphocytic leukemia.
The literature suggests that age at presentation, seizures as the sole presenting symptom, site of origin, favorable Karnofsky status, absence of contrast enhancement on imaging, histopathologic grade (i.e., pilocytic vs. diffuse) (Figure 8-4), initial tumor dimensions, extent of resection (i.e., unresectable tumor), presence of hydrocephalus, or coexistence of NF1 are the important variables that influence quality of life as well as survival.61 The prognostic value of the labeling index has been previously reviewed.26
Figure 8-4 Axial (A) and sagittal (B) T1 contrast-enhanced MRI showing typical cystic left cerebellar pilocytic astrocytoma with a posterior mural nodule. C, Axial T2 MRI.
(Slides courtesy Susan Chi, M.D., Dana-Farber Cancer Institute and Boston Children’s Hospital.)
Site of Origin
It is accepted that the biology of LGGN arising within the hypothalamus, optic tectum, and cervico-medullary junction clearly differs from those arising within the pons and cerebrum. Consensus exists that gross total resection of an AST or mixed LGGN during childhood is adequate therapy and does not require immediate postoperative irradiation (Nishio et al., 1989).62 Univariate analysis has demonstrated that optic chiasmal origin and only partial resection are associated with a worsened prognosis.63 This has influenced the controversy regarding EBRT (vide infra).
Neurofibromatosis
The 5Y-OS and 10Y-OS for patients with optic nerve gliomas and NF1 has been reported to be 93% and 81%, respectively. This compares favorably to survival rates of 83% and 76% at 5 and 10 years, respectively, for those children without evidence of NF1. The mean time to disease progression (TDP) was significantly different between the two groups (P < .01) in favor of those with NF1, although this did not impact OS.64 However, this relative advantage does not appear to apply to patients with von Recklinghausen disease who suffer from gliomas of the cerebrum.65
Histopathologic Grade and Malignant Progression among Low-Grade Astrocytomas
The process of malignant transformation was studied among 11 of 65 children with LGGN. The median latency was 5.1 years, and the 15-year cumulative incidence estimate was 6.7 %. Overexpression of TP53 was more common after progression to higher histopathologic grade. Deletions of RB1 and/or CDKN2A were observed in 71% of the LGGN and 90% of their malignant successors. There were PTEN pathway abnormalities found in 76% of patients.66
Medulloblastoma and Primitive Neuroectodermal Tumor
Staging evaluation stratifies patients by tumor size (“T”) and extent of metastatic spread (“M”).18 Table 8-2 summarizes its prognostic significance as derived from the European Societie Internationale Oncologie Pediatrie (SIOP) and the North American CCG study #942.67,68 Stepwise analysis of survival among randomized patients demonstrated earlier age of onset to be the dominant adverse variable (P = .034). There were significant interactions between treatment and M stage, which support postoperative irradiation and chemotherapy among patients with advanced disease, i.e., high T and M stages (P = .004) (Table 8-2).68
The subsequent CCG #921 study of children with MBL (203 patients) demonstrated the significance of residual disease prior to EBRT, whether determined by extent of surgical resection (P = .023) or by evidence of metastatic tumor (M1–3) (P < .003) (Table 8-2).69,70
Pathologic Studies
A series of 330 cases studied by the Pediatric Oncology Group (POG) found significant anaplasia among 24%, which was strongly associated with an unfortunate outcome. Diffuse or extensive anaplasia was worse than focal involvement. In contrast, extensive nodularity conferred a more favorable course.71 Reevaluation of 347 MBL biopsies treated under the SIOP II trial confirmed that severe anaplasia conferred an adverse prognostic effect on 5-year progression-free survival (49.5%) relative to mild-moderate change (65.4%) (P = .001). This effect was magnified when the presence or absence of extensive apoptosis (P = .00216) was factored in.72
Drug Resistance Genes
There is evidence that the expression of the MDR1, MRP1, LRP and BCRP genes does not correlate with overall outcome among patients with MBL/PNET.73
Biologic Determinants of Survival
Established chromosome abnormalities include amplication of isochromosome 17q, novel amplicons, and losses as well as gains of chromosomes; these are known to occur in greater than 20% of MBL. Copy number abnormalities have been identified in specific regions of chromosomes 1, 8p, 10q, 11p, and 16q, which occur frequently among MBLs and may identify distinct subsets.74 Furthermore, differences in DNA copy number at chromosome regions 1p12-22.1, 9p21, 19p, and chromosome 17 have been used to segregate between MBL and supratentorial PNET. The 9p21 deletions correlated with loss of CDKN2A protein expression more frequently among the PNET (P < .001). Gains of 19p were also more evident among the PNET (P = .02), whereas gains of 17q were more common among the MBL (P = .02).75
(i) Tumor suppressor genes
Haploinsufficiency of the 17p13.3 region is the most commonly found disrupted genetic site (35-50%) among MBLs, which may indicate the site of yet another TSG(s). This chromosomal site contains the “Hypermethylated in Cancer” gene (HIC1), a transcriptional repressor, which is a frequent target of epigenetic gene silencing in MBL. HIC1 is a direct transcriptional repressor of “Atonal Homolog 1” gene (ATOH1), a proneural transcription factor essential for cerebellar development. ATOH1 is a putative target of “(Sonic) Hedgehog” (HH) signaling and its expression has been shown to be required for human MBL cell growth in vitro. The PTCH gene, an inhibitor of SHH signaling, is among the characterized TSG in MBL; however, fewer than 20% of MBLs have mutations in this gene. Recent work suggests that the HIC1 and PTCH1 TSG cooperate to silence ATOH1 expression during a critical phase of granule cell precursor differentiation in the cerebellum to contribute to the malignant progression to MBL.76
Specimens of MBL collected from 65 children treated in the SIOP/United Kingdom Children’s Cancer Group PNET3 trial were segregated into the histopathologic groups such as the large cell/anaplastic phenotype and nodular/desmoplastic variant, among others. Loss of 17p13.3 was found among 38% of samples of all variants, whereas MYCC/MYCN amplification (6%/8% respectively of MBLs) was significantly associated with the large cell/anaplastic phenotype. Loss of 9q22 coincided with the nodular/desmoplastic type. Together with metastatic disease at diagnosis, the large cell/anaplastic phenotype, 17p13.3 loss, or high frequency MYC amplification defined a high-risk group of children whose outcome was significantly worse than those without such tumor characteristics (P = .0002).77 However, the relationships between chromosome 17 lesions with anaplastic/large cell MBL and the abnormalities in the Sonic Hedgehog/PATCH (SHH/PTCH) pathway with the desmoplastic variant remain controversial.78
The SHH antagonist, cyclopamine, blocked expression of the SHH pathway targets PTCH1 and GLI1, lowered Bcl2 levels, and increased apoptosis in MBL cells in vitro. Blockade of the SHH pathway sensitized MBL cells to lovastatin, a proapoptotic agent used for lowering cholesterol levels. The combination of cyclopamine and lovastatin target pathways appear crucial for MBL cell survival.79 Agents targeting the SHH pathway are in clinical trials for the therapy of medulloblastomas.
Activation of the canonical WNT/Wingless (WNT/WG) signaling pathway occurs in up to 25% of cases of primary MBL and is associated with a favorable prognosis. Activation of WNT/WG was determined by evidence of CTNNB1 mutations and/or beta-catenin nuclear stabilization. Loss of chromosome 6 has been correlated with WNT/WG active tumors (P < .001), but few other cytogenetic aberrations including chromosome 17. In contrast, WNT/WG-negative MBLs were found to have losses of chromosomes 17p, 8, 10, and 16, with gains of chromosomes 7 and 17q. This supports the hypothesis of independent pathways of tumorigenesis among MBL, which are of potential clinical relevance.80
TP73 is a member of the TP53 TSG family that is overexpressed in a variety of tumors and mediates apoptotic responses to genotoxic stress. Biopsy samples of MBL and MBL cell lines have been reported to contain elevated levels of TP73 RNA and increased expression of the TAp73 and DeltaNp73 protein products. Overexpression of these induced apoptosis among cultured MBL cells in vitro and sensitized them, resulting in cell death upon exposure to chemotherapeutic agents. TAp73 RNA overexpression within biopsy samples was determined to correlate with a favorable PFS by Kaplan-Meier analysis.81
The 10q23.3 chromosomal region is subject to frequent allelic losses in MBL, which is the locus of the PTEN gene. Activation of the phosphoinosityl 3-kinase/ AKT (P13 k/AKT) signaling pathway appears to be associated with alterations of the PTEN gene. Proliferation of MBL cell lines has been shown to be dependent upon P13 k/AKT signaling and inhibited by a P13K antagonist as well as by AKT overexpression. Reduction of PTEN mRNA and protein expression has been found to be correlated with PTEN promoter hypermethylation in 50% of 22 MBL tissue samples. This suggests that PTEN loss or dysregulation by the P13 k/AKT signaling pathway may be an important mechanism of tumorigenesis for a subset of MBL.82 In contrast, PTEN deletion has not been found among supratentorial PNET biopsies or cell lines.83
(ii) The Putative Oncogenes.
The Duke group studied 31 MBL specimens for MYCC, MYCN and TRKC expression and correlated this with clinical outcome and histopathologic grading. The presence of MYCC mRNA was associated with shorter survival (P = .04) as well as with anaplasia. Regulation of MYCC is influenced by WNT signaling and MXI1 mutations. Nuclear translocation of beta-catenin, a marker of WNT pathway activation, was more common among the MBLs with high MYCC. No MXI1 mutations were detected in the 22 cases examined.84
Archival formalin-fixed, paraffin-embedded MBL samples from 78 patients treated on the prospective European multicenter HIT’91 protocol were studied for DNA amplification of C-MYC and N-MYC and mRNA expression of C-MYC and TRKC. TRKC and C-MYC mRNA expression were identified as independent prognostic factors on multivariate analysis. A favorable-risk group (eight patients), with a 7Y-PFS of 100%, possessed elevated TRKC and reduced C-MYC expression. The poor-risk group (15 patients) had metastatic disease, with high C-MYC and low TRKC mRNA expression. Their 7Y-PFS was only 33%. An intermediate-risk group of the remaining subjects showed a 7Y-PFS of 65%.85 Not all investigators have made similar correlations.86
Ependymoma
Pathologic Grading
The prognostic utility of pathologic grading of ependymomas has engendered a long-standing controversy, as there has been no clear distinction in 5Y-OS rates between “benign” and “malignant” EPD. However, one recent blinded review demonstrated that the PFS at 2 years following postoperative irradiation was 84% for differentiated EPD, and 32% for specimens considered anaplastic.87
Site of Origin
There is a correlation between site of origin and histopathologic grade of malignancy. Approximately two thirds of supratentorial EPDs are high-grade at diagnosis, whereas those arising in the IVth ventricle tend to have a better prognosis.88 A series of 49 patients found that 78% originated infratentorially and exhibited low grade histology.89 Those arising in the spine and cauda equina are usually low-grade and/or myopapillary.
Extent of Surgical Resection
The CCG #921 study accessioned 20 EPD and 12 anaplastic EPD patients, of whom only three had metastatic disease at diagnosis. The prognostic variables of significance included the extent of resection (gross total vs. other, P = .0001) and postoperative residual disease of < 1.5 cm2 (P < .0001), in contrast to age, staging, or treatment, emphasizing the importance of local disease control.90
The French Society of Pediatric Oncology has studied the efficacy of postoperative chemotherapy, with the intent of avoiding EBRT, among 73 children less than 5 years of age with intracranial EPD. The favorable prognostic variables included supratentorial origin (P = .0004) and complete resection (P = .0009). Patients with gross total resection demonstrated a 4Y-OS of 74% in contrast to those with residual disease (35%).91
Univariate and Multivariate Analysis
Three prognostic factors have been identified to have a significant correlation with the 5Y-PFS. These included the extent of surgical resection (P < .0001), age at diagnosis (P = .003), and the prediagnosis symptomatic interval (P = .02).23 Another multicenter retrospective study of 83 children with EPD confirmed that age of less than 3 years, identifiable postoperative residual disease, and Grade III histology were significant adverse factors for PFS in both univariate and multivariate analysis.92
Biologic Determinants of Survival
Overexpression of specific genes (YAP and LOC374491) and downregulation of others such as SULT4A1, NF-[kappa]B2, and PLEK have been implicated in determining the age of onset, relapse potential, and tumor location of pediatric EPD.93,94 The catalytic subunit of telomerase, the human telomere reverse transcriptase (hTERT), which aids in uncontrolled cell proliferation, has been shown to correlate with prognosis among 65 children with EPD. Study of 87 tumors from these patients found the presence of hTERT to be adversely correlated with 5Y-OS (41% vs. 84% in its absence).95
Oligodendroglioma
The accepted favorable prognostic variables for OLG include youth (less than 21 years), low histopathologic grade, and extent of resection.96 Multivariate analysis in a series of 51 patients aged 5 to 75 years found younger age and presentation with seizures alone to be statistically significant for a favorable outcome. Approximately one third of patients of all ages appear to be cured by aggressive treatment including surgical resection, EBRT, and chemotherapy.96
