Embryonal and Pineal Region Tumors
Murali M. Chintagumpala
Arnold Paulino
Ashok Panigrahy
Cynthia Hawkins
Andrew Jae
Williams D. Parsons
EMBRYONAL TUMORS
Embryonal tumors constitute approximately 25% of all primary central nervous system (CNS) tumors occurring in patients 18 years or younger,1,2,3 and nearly 40% of all malignant CNS neoplasms. Although embryonal tumors occur throughout the pediatric age spectrum, they often arise early in life, with one-fifth or more diagnosed in the first 3 years, making diagnosis and management even more challenging.1,2,3,4 In the World Health Organization (WHO) classification of CNS tumors, embryonal tumors constitute a collection of biologically heterogeneous lesions that are malignant and share the tendency to disseminate in the nervous system via the cerebrospinal fluid (CSF) pathways early in the course of illness.1 The most common embryonal tumor is medulloblastoma (Table 26B.1), with others including CNS primitive neuroectodermal tumors (PNETs) and atypical teratoid/rhabdoid tumors.1,5,6
Tumors of the pineal region are considered a distinct subset of neoplasms in the WHO classification, although they are composed of a number of biologically and clinically different tumor types, including pineoblastoma, which histologically most closely resembles embryonal tumors, such as medulloblastoma1,7 (Table 26B.2). Although primary CNS germ cell tumors may occur anywhere within the neuroaxis, they most commonly arise in the pineal region; and for this reason, the subgroup of germ cell tumors will also be discussed in this chapter.1,8 General considerations and the approach to a child with a brain tumor is covered separately in Chapter 26A.
Medulloblastoma
Introduction
Medulloblastoma, the most common malignant brain tumor of childhood, occurs in the posterior fossa and, like other embryonal tumors, may metastasize either early or late in the disease course.1,3,4,9 Multiple subtypes of medulloblastoma have previously been recognized based on histopathologic features, as noted in Table 26B.1. The classical medulloblastoma makes up the majority of cases, and the diagnosis of other subtypes, such as the anaplastic or desmoplastic form, is often subjective, as tumors may share overlapping histologic features or only focally display a specific histologic feature.10,11,12 Recent advances in our understanding of medulloblastoma biology have divided medulloblastoma into four distinct molecular subtypes, which are each associated with characteristic genetic and clinical features that offer the potential for tailored therapies in the future.13,14,15,16 This is of great significance because although institutional and consortium studies have demonstrated an improved survival rate for medulloblastoma,3,4,16,17 specific subsets of tumors remain resistant to therapy and disease- and treatment-related morbidities remains a major issue, especially in young children.18,19
TABLE 26B.1 WHO Classification of Medulloblastoma and Other Embryonal Tumors1 | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| ||||||||||||
TABLE 26B.2 WHO Classification of Pineal and Germ Cell Tumors1 | ||||
|---|---|---|---|---|
| ||||
Demographics
Medulloblastomas constitute approximately 20% of all primary CNS tumors in children between the ages of 0 and 14 years.1,2 They are less common in patients between 15 and 19 years of age, constituting 6% of brain tumors in this age group. Medulloblastomas do also arise in adulthood; however, they comprise less than 2% of all adult brain tumors.20,21,22 Medulloblastomas have a bimodal age distribution, peaking at 3 to 4 years, and then again between 8 and 10 years of age. Fifteen percent or more of tumors are diagnosed in infancy. As will be further discussed later in the chapter, specific molecular subtypes of medulloblastoma have been associated with characteristic demographic features, such as the finding that sonic hedgehog (SHH) pathway tumors are typically found in either infants and young children (<3 years of age) or older adolescents and adults.
Medulloblastomas are more likely to occur in Caucasians, as compared with other ethnic groups, at a ratio of 1.75:1. In most epidemiologic studies in the United States, nearly 80% of all medulloblastomas have been diagnosed in non-Hispanic White children.1,23,24,25 This ethnic pattern is even more marked in cooperative group trials, raising issues concerning disparity of access or utilization of health care.23,24,25 However, the relative ratio of medulloblastoma to other childhood brain tumors is similar in other ethnic groups.26,27,28,29
Etiology
The etiology of medulloblastoma is unknown for the majority of patients. Several familial syndromes have been associated with an
increased risk of developing medulloblastoma, including Turcot syndrome, Gorlin syndrome, and Li-Fraumeni syndrome.30,31,32,33,34,35,36,37 The associations with Gorlin syndrome and Turcot syndrome have stimulated research into the molecular pathways active in medulloblastoma.
increased risk of developing medulloblastoma, including Turcot syndrome, Gorlin syndrome, and Li-Fraumeni syndrome.30,31,32,33,34,35,36,37 The associations with Gorlin syndrome and Turcot syndrome have stimulated research into the molecular pathways active in medulloblastoma.
Gorlin syndrome, also known as the nevoid basal cell carcinoma syndrome, is diagnosed by characteristic dermatologic and skeletal features, including multiple basal cell carcinomas and odontogenic keratocysts of the jaw.30,31 However, some stigmata may be present only later in life. This association accounts for less than 2% of all patients with medulloblastoma but has led to a better understanding of the molecular underpinnings of a subset of these tumors. Gorlin syndrome is caused by an inherited germ line mutation of the PATCHED1 (PTCH1) gene on chromosome 9, which encodes the SHH receptor PATCHED1 that normally suppresses SHH signaling.30,31,37 In addition to these germ line mutations in Gorlin syndrome patients, somatic (tumor-specific) mutations of PTCH1 have found to be characteristic of the SHH subtype of medulloblastoma.38 An important consideration in the association of medulloblastoma with Gorlin syndrome is that these children are predisposed to development of basal cell carcinoma years after treatment, especially in the fields of radiation utilized to treat medulloblastoma.30,31 This makes the use of craniospinal radiotherapy problematic in children with the syndrome. Diagnosis of Gorlin syndrome early in life is quite difficult, although the presence of skeletal abnormalities, including bifid or fused ribs, macrocephaly, or early calcification of the falx cerebri, should raise concerns. Overall, 3% to 5% of patients with Gorlin syndrome will develop medulloblastoma.
Type II Turcot syndrome is an autosomal dominant disorder caused by mutations of the adenomatous polyposis coli gene (type 2) of the Wnt signaling pathway. The syndrome is associated with extensive colorectal adenomas and extra-colonic manifestations such as osteomas, desmoid tumors, jaw cysts, and supernumerary teeth, as well as an increased risk of developing medulloblastoma.33 Somatic alterations of CTNNB1 and other genes in the Wnt molecular pathway have been identified in approximately 10% of medulloblastoma patients and define the Wnt subset of these tumors, which carries a relatively good prognosis.38,39
Clinical Presentation
Medulloblastoma, by definition, arises in the posterior fossa, predominantly in the region of the roof of the fourth ventricle, and causes signs and symptoms by obstruction of the CSF pathways or by direct damage to the cerebellum or other brainstem structures.3,4 The most common presentation of medulloblastoma is vomiting and headache, occurring in nearly 80% of patients by the time of diagnosis, usually associated with obstruction of cerebrospinal CSF flow at the outlet of the third or fourth ventricle and secondary hydrocephalus. Symptom duration is usually 1 to 3 months before diagnosis, and the majority of children are diagnosed within 45 and 60 days after the onset of symptoms. There is significant overlap between the symptoms caused by medulloblastoma and other posterior fossa tumors, such as ependymomas, cerebellar astrocytomas, and atypical teratoid/rhabdoid tumors (Table 26B.3).
TABLE 26B.3 Clinical Presentation of Posterior Fossa Tumors | ||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| ||||||||||||||||||||||||||||
The headache pattern in children with medulloblastoma is often nonspecific early in the course of illness. Later in the course of disease, especially when hydrocephalus is present, the headaches are more likely to be those classically associated with increased intracranial pressure, occurring upon wakening, with accompanying morning nausea and vomiting. Unsteadiness is noted in 50% to 80% of children by the time of diagnosis. Because of the tumor’s primary midline location, unsteadiness is more frequently truncal than lateralized. Sixth nerve palsies, manifest by turning in of one or both eyes, occur in 90% of children with medulloblastoma. Other ophthalmologic findings such as nystagmus are less well characterized in reports but are also frequent. Papilledema is present in approximately three-fourths of patients at the time of diagnosis. Nonspecific findings such as head tilt, stiff neck, and weight loss may also occur.4
Medulloblastomas may present acutely, especially when there is hemorrhage within the tumor.40 This characteristically results in acute alternations of consciousness, including coma, probably secondary to both acute hydrocephalus and direct brainstem compression.
Diagnosis in infants and very young children may be more difficult and delayed. Symptoms and signs in infants include macrocephaly, unexplained intermittent lethargy, head tilt, and poorly characterized ophthalmologic findings.4,41 The classical “setting sun” sign, manifest by downward deviation of the eyes due to tectal pressure and loss of upgaze may occur, but is documented in less than 10% of infants at diagnosis.
Presentation in older children and adults does not differ dramatically from that seen in younger patients. In adult series, the time to diagnosis has been slightly longer than in series reporting children alone. The majority of older patients do have headaches, nausea, and ataxia. Cerebellopontine involvement due to laterally placed lesions with the resultant sixth, seventh, and possibly eighth nerve paresis is somewhat more common in older patients, including adults.42,43,44
Neuroimaging
Medulloblastomas are characteristically relatively well-defined mass lesions that arise in the inferior medullary velum/roof of the fourth ventricle, and grow anteriorly into the fourth ventricle; they can invade the middle cerebellar peduncle or the dorsal brain stem (Fig. 26B.1). In older children and adolescents, medulloblastomas have the tendency to present either in the
lateral cerebellar hemisphere or near the cerebellopontine angle cistern (Fig. 26B.2). Ninety percent of tumors demonstrate some hyperattenuation compared with normal cerebellar attenuation on computed tomography (CT), a reliable imaging feature that distinguishes medulloblastomas from pilocytic astrocytomas.45 Calcifications are present in 10% to 20% of cases.
lateral cerebellar hemisphere or near the cerebellopontine angle cistern (Fig. 26B.2). Ninety percent of tumors demonstrate some hyperattenuation compared with normal cerebellar attenuation on computed tomography (CT), a reliable imaging feature that distinguishes medulloblastomas from pilocytic astrocytomas.45 Calcifications are present in 10% to 20% of cases.
 Figure 26B.1 Typical medulloblastoma in a 3-year-old child. Axial T2 (A) and postcontrast sagittal T1 (B) images show a midline tumor filling the fourth ventricle, with suspect invasion of the right middle cerebellar peduncle and the dorsal right hemipons (arrow, A). T2 signal is hypointense (A); the mass does not enhance, though small, weakly-enhancing metastatic nodules are evident in the upper cervical canal (arrow, B). The tumor shows reduced apparent diffusion coefficient (ADC) with low signal on the ADC map (C). |
On magnetic resonance imaging (MRI), medulloblastomas are usually homogeneous with iso- to hypointense signal on T1-weighted images, and generally hypointense signal (between gray matter and white matter) on T2-weighted images; signal is often isointense to gray matter on FLAIR images and hyperintense on diffusion-weighted images.46 Although most medulloblastomas show moderate to intense contrast enhancement, approximately 5% to 10% of tumors do not enhance, and another 10% to 15% show only minimal (<25%) contrast enhancement (Fig. 26B.1). In infancy, “medulloblastomas with extensive nodularity” may occur, which display multiple, discrete, contrast-enhancing masses in almost a grape-like cluster.
Both diffusion imaging and MR spectroscopy can be helpful in the differentiation of medulloblastomas from other posterior fossa tumors, namely, juvenile pilocytic astrocytomas and ependymomas. The apparent diffusion coefficient values of medulloblastoma are significantly lower than those of ependymoma and pilocytic astrocytomas, a reflection of the high cellularity and large nuclear areas of medulloblastoma.47,48,49 Using a discriminant analysis, single-voxel magnetic resonance spectroscopy of pediatric cerebellar tumors has been proven capable of separating medulloblastomas from pilocytic astrocytomas and ependymomas and from normal cerebellar tissue based on a plot of creatine-choline (Cr:Cho) ratios against N-acetyl aspartate (NAA):Cho ratios50 (Fig. 26B.3). Medulloblastomas have very high levels of choline and very low, lower, or absent NAA peak (decreased NAA-to-creatine ratio). High choline levels indicate a high degree of membrane metabolism, which usually takes place in rapidly proliferating malignant tumors. Lactate and lipid peaks can also be identified as a result of metabolic acidosis and tissue breakdown. Taurine (Tau) has been consistently observed by several groups in medulloblastoma51,52,53,54 and is an important differentiator of medulloblastoma from other tumors of the posterior fossa (Fig. 26B.4). A possible caveat is that it has been observed that taurine levels are low in some medulloblastomas with desmoplastic nodular histology.
 Figure 26B.2 Teenage boy with a medulloblastoma in the left cerebellopontine angle. Axial T2 (A) and postcontrast axial T1 (B) images reveal a predominately T2 isointense mass in the CP angle cistern, with a mild amount of surrounding cerebellar edema, and fairly homogeneous, intense enhancement following gadolinium (B). Enhancement in the right foramen of Luschka represents normal choroid, not metastatic disease (arrow, B). |
Atypical teratoid/rhabdoid tumors (AT/RTs) can also mimic medulloblastomas but have a greater propensity to present with hemorrhagic components. In the posterior fossa, AT/RTs are often located in the cerebello-pontine angle, in contrast to medulloblastomas, which favor the midline (vermis, fourth ventricle) in the first decade. Leptomeningeal invasion, surrounding edema, and enhancement from breakdown of the blood-brain barrier are also common. Ependymomas may be distinguished by their different anatomic location and pattern of spread through the foramina of Luschka and Magendie, and their characteristic appearance of speckled calcification on CT. MRs can give additional support to the diagnosis, especially in those cases in which the size and extent of the mass render difficult the identification of its point of origin. Solitary cerebellar hemangioblastoma usually will demonstrate serpiginous flow voids, reflecting the vascularity of the lesion, in addition to intense enhancement after intravenous contrast.55
 Figure 26B.3 N–acetyl aspartate-choline (NAA:Cho) versus creatine-choline (Cr:Cho) scattergram for astrocytoma, ependymoma, medulloblastoma, and normal cerebellar tissue. The straight lines are boundaries between the three tumor types found by discriminant analysis. PNET, primitive neuroectodermal tumor. |
Pathologic Classification of Medulloblastoma
PNETs arising in the cerebellum are termed medulloblastoma and are classified into five histologic groups in the current WHO classification of CNS tumors1: classic, desmoplastic nodular, medulloblastoma with extensive nodularity (MBEN), anaplastic, and large cell.1,56 Of note, there is significant morphologic overlap
between PNETs arising in different regions of the CNS as well as in extra-CNS locations. The nomenclature used by the WHO classification relies on both the location of the tumor and the histologic appearance to render a diagnosis.
between PNETs arising in different regions of the CNS as well as in extra-CNS locations. The nomenclature used by the WHO classification relies on both the location of the tumor and the histologic appearance to render a diagnosis.
 Figure 26B.4 Unfiltered individual spectra (thin lines) and the averaged spectrum (thin lines), respectively, of embryonal tumors. All spectra were acquired with single-voxel PRESS, TE = 35 ms. Spectra are scaled to measured concentration to allow direct comparison. Taurine is readily detected in classic medulloblastoma (A) and in CNS primitive neuroectodermal tumors (PNET) (C). There is no evidence of taurine in the mean spectra of the desmoplastic subtype of medulloblastoma (B) or in atypical teratoid/rhabdoid (AT/RT) (D). Choline levels in AT/RT are more moderate; however, there is considerable variation in individual spectra. |
 Figure 26B.5 Typical histologic features of medulloblastoma (primitive neuroectodermal tumor). Tumor formed by apparently undifferentiated, basophilic, round-to-oval nuclei with minimal perceptible cytoplasm (hematoxylin and eosin, ×3,400). |
Classic medulloblastomas are highly cellular, soft, friable tumors composed of cells with deeply basophilic nuclei of variable size and shape, little discernible cytoplasm, and, often, abundant mitoses (Fig. 26B.5) although they may exhibit surprising histologic heterogeneity. Homer Wright rosettes and pseudorosettes are variably present. Various degrees of glial or neuronal differentiation are noted, suggesting that the primitive cell of origin possesses the capacity for bipotential differentiation. A histologic variant with an abundant stromal component, desmoplastic nodular medulloblastoma (Fig. 26B.6), occurs dominantly in the lateral cerebellar areas of adolescents and adults and in the setting of Gorlin syndrome in infants and young children.35,36 These may have a nodular appearance. A variant of desmoplatic nodular medulloblastoma, called medulloblastoma with extensive nodularity (MBEN), occurs predominantly in very young children.
Aggressive variants of medulloblastoma, termed large-cell and anaplastic (frequently grouped together as large-cell anaplastic), have also been described. As the names imply, the histologic features that distinguish this subset of medulloblastoma are large round nuclei with prominent nucleoli, frequent mitoses, abundant apoptosis, and, in the anaplastic subset, nuclear pleomorphism. These tumors typically express synaptophysin and chromogranin. Monosomy 22 has not been seen in the cases described, but they tend to be associated with MYC or MCYN amplification.57 The large-cell anaplastic variant represented 4% of the nearly 500 cases of medulloblastoma reviewed by Brown et al.58,59
 Figure 26B.6 Desmoplastic medulloblastoma showing linear arrangement of cells along delicate background fibers (hematoxylin and eosin, ×3,400). |
Biologic Classification and Prognosis
Correlations have been noted between histologic subtypes and clinical outcomes, prominently including an improved prognosis for nodular desmoplastic medulloblastoma and a poor prognosis for large-cell anaplastic tumors. More recently, genomic methods have enabled the identification of biologically distinct subsets of medulloblastoma and provided a biologic basis for those clinical observations. These studies have led to a current consensus that medulloblastoma consists of four molecular subtypes with characteristic genetic, demographic, and clinical features: Wnt, SHH, Group 3 and Group 4 (Table 26B.4).60,61,62 Groups 3 and 4 medulloblastomas are frequently categorized together as “non-Wnt, non-SHH” tumors. Retrospective analyses have revealed this classification to have important prognostic significance in patients with medulloblastoma. Patients with tumors demonstrating Wnt pathway activation have an overall survival rate greater than 90%, while SHH subtype and Group 4 tumors have an intermediate survival of approximately 75% and Group 3 tumors have the poorest outcome with overall survival ranging from 40% to 60%.62 Classification of medulloblastomas into Wnt, SHH and non-Wnt, non-SHH subtypes (which can be performed using immunohistochemical methods on Formalin-Fixed Paraffin-Embedded [FFPE] specimens) has facilitated the subtyping of medulloblastomas for the conduct of future prospective clinical trials.63
Wnt Subtype
Medulloblastomas with activation of the Wnt signaling pathway constitute approximately 10% of medulloblastomas overall and have the best prognosis (>90% survival) (Fig. 26B.4). This subtype is most common in older children and adolescents (median age of 10 years) and is generally associated with tumors with classic histology. Greater than 90% of Wnt medulloblastomas have mutations in the β-catenin gene (CTNNB1) that result in a mutant protein that is resistant to degradation and accumulates in the nucleus of tumor cells. These tumors consistently show deletion of one copy of chromosome 6, allowing monosomy 6 and nuclear β-catenin accumulation to serve as specific and sensitive markers for Wnt pathway medulloblastoma. Mutations of the DDX3X gene are also frequent, occurring in approximately 50% of Wnt tumors.64,65,66,67,68 Of note, mutations in TP53, although associated with a poor prognosis in SHH pathway tumors, do not have a significant effect on the prognosis for this group of patients.69
SHH Subtype
Approximately 30% of medulloblastomas are defined by upregulation of the SHH signaling cascade through a variety of genetic mechanisms: most frequently, mutation of the PTCH1 tumor suppressor gene (a negative regulator of SHH signaling) and less often, alterations of other pathway members such as SMO, SUFU, and GLI2 (Fig. 26B.4). Bimodal peaks of SHH medulloblastoma incidence are seen: the first in children less than 3 years of age, and the second in older adolescents and young adults. Mutations in the SUFU gene are more common in tumors occurring in children less than 3 years of age, and SMO mutations are more frequent in adult tumors, which have potential implications for the use of molecularly-targeted therapies targeting SHH tumors in those populations. Although the prognosis for the group of patients with SHH tumors is intermediate (˜75%), TP53 gene mutation in an SHH pathway tumor carries a particularly poor prognosis and
may frequently be a germ line rather than somatic (e.g., in a child with Li-Fraumeni syndrome).70 Although SHH tumors do occur in the midline location, a cerebellar hemispheric location almost always indicates a tumor of SHH subtype.
may frequently be a germ line rather than somatic (e.g., in a child with Li-Fraumeni syndrome).70 Although SHH tumors do occur in the midline location, a cerebellar hemispheric location almost always indicates a tumor of SHH subtype.
Group 3 Subtype
This subtype of medulloblastoma accounts for approximately 25% of tumors and has both the highest rate of metastases and the worst survival rate (˜50%). Unlike Wnt and SHH medulloblastomas, no defining pathway alterations have been identified, although recurrent amplifications of the MYC and OTX2 genes and mutations of SMARCA4 are seen. Group 3 medulloblastomas occur more commonly in males (male:female ratio of 2:1) and primarily affect infants and young children rather than teenagers.
Group 4 Subtype
This subtype of medulloblastoma accounts for approximately 35% of tumors and has an intermediate survival rate (˜75%) although metastatic disease is relatively frequent (˜35%). As for Group 3 tumors, the biologic basis of Group 4 tumors is poorly understood, with amplification of MYCN found in a minority of tumors and no recurrent mutations occurring in more than 10% to 15% of tumors. Isochromosome 17q is seen more commonly in Group 4 than in Group 3 tumors and is rarely seen in Wnt or SHH subtypes. Group 4 tumors are seen in children of all ages but relatively rarely in infants. Like Group 3 medulloblastoma, Group 4 tumors occur more frequently in males (male:female ratio of 3:1).
Additional genetic and biologic studies are required to further clarify the basis of medulloblastoma, and in particular Group 3 and Group 4 tumors. Future prospective studies will incorporate this subtype information for risk stratification, treatment assignment, and selection of agents to target specific subtypes of medulloblastoma with the ultimate goal of improving outcomes and decreasing treatment-related morbidities.
Staging and Risk Stratification
Although the future holds great promise with the possible incorporation of the biologic findings described earlier, clinical studies so far have relied on clinical staging and risk stratification.4 Staging remains predominantly based on determination of the extent of tumor at the time of diagnosis and the degree of surgical resection. Complete staging requires pre- or postoperative MRI of the entire brain and spine, postoperative MRI of the tumor site, and CSF analysis.14
As with other CNS tumors of presumed primitive neuroepithelial origin, widespread seeding of the subarachnoid space may occur. The reported frequency of CNS spread outside the area of the primary tumor at diagnosis is 11% to 43%, and such spread eventually occurs in as many as 93% of patients who come to necropsy.71,72
TABLE 26B.4 Demographic, Clinical, and Genetic Characteristics of Medulloblastoma Subtypes. | |||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
|
Extraneural spread has been observed in 20% to 35% of patients in smaller institutional studies, but more recent larger series suggest that the rate of such events is less than 4%. Bone and bone marrow are the most common extraneural sites, accounting for more than 80% of extraneural metastases; lymph nodes, liver, and lung are the other reported sites.73,74,75,76
Historically, the Chang staging system, utilizing preoperative imaging studies, the surgeon’s intraoperative impression, and CSF cytology, was used to assign the stages of primary (T stage) and metastatic (M stage) disease14 (Table 26B.5). This system has been significantly modified and the assessment of the preoperative size of the tumor (T stage) has been supplanted by a postoperative evaluation of the extent of resection or, more specifically, the amount of postoperative residual disease, at times, modified by the impression of the surgeon at the time of diagnosis (Table 26B.6).
The M stage of the disease remains the single, most prognostic clinical parameter.77,78 The prognostic significance of M1 disease, indicating positive CSF cytology, without radiographic evidence of disseminated disease, has been debated and has been found to be predictive in some, but not all, studies. Part of this difference may be due to the means to assess the presence of free-floating tumor cells. Lumbar CSF cytology has been shown to be the most sensitive, but in some studies, either ventricular and/or spinal fluid have been used for assessment. Gajjar et al.79 found lumbar CSF to be more sensitive in the detection of disseminated disease than ventricular fluid and found cytologic assessment to be complementary to neuroaxis neuroimaging. In the German HIT 1991 study, 13% of patients had M1 disease and their overall survival (OS) rate of 65% did not differ from those with M0 disease.77 A similar finding was noted for a small number of patients with M1 disease in the French M7 study.78 In contradistinction, the Children’s Cancer Group (CCG)-921 study found that 18% of patients had M1 disease, utilizing almost exclusively lumbar CSF, and found a 5-year and progression-free survival of 57% for those patients with positive cytology, a rate lower than that for those with M0 disease, and higher than that for patients with M2 or M3 disease, although differences were of borderline significance.80
CSF for staging is most predictive if obtained 2 weeks or more following tumor resection.4,79 Preoperative lumbar puncture may be contraindicated if there is mass effect of the tumor and the potential for cerebellar herniation. Cisternal fluid, obtained at the time of diagnosis, has been variably related to outcome. Arachnoid biopsy, at the time of surgery, is presently being evaluated as a possible independent prognostic factor.
Neuroradiographically confirmed metastatic disease (M2 or M3) has been prognostic in all series.77,78,79,80,81 Extraneural spread at diagnosis (M4 disease) is rare outside of infancy, and assessment for extraneural disease by bone scans and bone marrow analysis is now not recommended, in most prospective studies, as part of initial staging. The sensitivity of MRI for the detection of metastatic disease is much greater than that of CT or myelography. Because of this, it is likely that patients who in the past would have been
diagnosed as nonmetastatic, or with M1 disease, are now being classified as having M2 disease.
diagnosed as nonmetastatic, or with M1 disease, are now being classified as having M2 disease.
TABLE 26B.5 Chang Staging System for Posterior-Fossa Medulloblastoma | ||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
|
Despite the accepted use of MRI for staging, performance and interpretation of neuroimaging studies for the evaluation of disease dissemination at the time of diagnosis remains imperfect. In a recent Children’s Oncology Group (COG) study and French prospective studies, upon central review, inadequate imaging studies, due to patient movement or incomplete staging, were noted in up to 10% of patients.17 Another 5% to 10% of patients, upon central neuroimaging review, were found to have significant residual postoperative disease or evidence of dissemination not appreciated by the treating institutions. Patients with evidence of dissemination, upon central review, had a particularly poor prognosis if treated on reduced-radiotherapy protocols. Patients with inadequate imaging had intermediary outcomes between those with evidence of disease dissemination and those with no evidence of disseminated disease upon central review. Determination of the extent of disease on neuroimaging studies is particularly challenging in those with nonenhancing tumors, as spinal metastasis can be quite difficult to appreciate. Similarly, spread to the third ventricle and cisterns around the brain stem was problematic to appreciate.
Extent of Resection
A near-total (arbitrarily defined as more than a 90% resection) or a total resection is now achieved in approximately 80% of children with medulloblastoma, utilizing contemporary microsurgical techniques, entered in cooperative group studies.82 Evidence suggesting that the extent of resection correlates with outcome has been provided by several single institutions and by multi-institutional studies.83,84 For example, in the series reported by Jenkin, a 93% 5-year progression-free survival rate was noted in children undergoing gross-total resection as comparedwith only 45% in those undergoing a partial resection.85 In one CCG study, a clear relationship was found between the presence of greaterthan-1.5-cm2 residual disease on postoperative imaging and a significantly lower progression-free survival rate in patients with nonmetastatic disease.80,83 Arbitrarily, most cooperative group studies have continued to utilize some measure of the extent of residual disease after surgery as a staging criteria, as children with less than 1.5 cm2 of postoperative residual disease have been included in the average-risk category, while those with a greater amount of disease are classified as high-risk. It is widely accepted that patients who undergo only a minimal degree of resection fare poorly.
TABLE 26B.6 Stratification of Medulloblastoma | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
|
Brain stem involvement at the time of diagnosis was found in older studies, in which patients were predominantly treated with radiation therapy alone, to be predictive of poor outcome.9,80 However, in most studies that have coupled chemotherapy with radiation therapy, the presence of brain stem involvement has not been found to be a significant prognostic variable.20,77,86
Age at Diagnosis
Younger children, predominantly those 3 years of age or less at the time of diagnosis, have been shown to have poorer outcome than older patients with medulloblastoma.85,86,87 Determining the influence of age as an independent prognostic factor is difficult for a variety of reasons, including younger age at diagnosis, which has been associated with a higher rate of disease dissemination at diagnosis and an overall lower rate of complete tumor resection.88,89 In past reports, younger children with medulloblastoma, in general, have received lower doses of both craniospinal and local radiotherapy or were more likely to receive chemotherapy prior to the initiation of radiation therapy. The inclusion of the atypical teratoid/rhabdoid tumor, which tends to arise in children younger than 3 years, within the medulloblastoma subgroup may have also skewed the outcome, as this tumor type has a very poor prognosis. Despite all these caveats, there is now strong evidence that there are biologic differences between medulloblastomas arising in
different ages and these differences at least partially underlie the poorer prognosis of infants.90 The exception is M0 desmoplastic medulloblastoma in children less than 3 years of age which carries an excellent prognosis.91,92
different ages and these differences at least partially underlie the poorer prognosis of infants.90 The exception is M0 desmoplastic medulloblastoma in children less than 3 years of age which carries an excellent prognosis.91,92
Histology
The significance of different histologic patterns on survival has been variable. In infants, the desmoplastic variant of medulloblastoma has been related to improved survival.11,12 More recently, the anaplastic or large-cell variant had been linked with more extensive and/or disseminated tumors and poorer prognosis, even in cases without dissemination.12,22,44 This latter finding has been demonstrated predominantly by retrospective reviews and in at least one prospective study.93 In the most recent COG prospective national studies, patients with nonmetastatic disease but with extensive or “diffuse” anaplasia have been included on high-risk protocols. Most of the children with large-cell anaplastic medulloblastoma fall into the Group 3 and 4 subtypes and tend to have a poorer prognosis. The significance of anaplasia as an outcome measure has been confounded by its subjectivity and relationship to biologic markers (such as higher MYC expression) that have been related to poorer prognosis.22
Treatment
General Aspects
Therapy for medulloblastoma in older children (generally older than 3 years) consists of maximal surgical resection, craniospinal radiation therapy, and chemotherapy.4 With the identification of subgroups based on biologic features and their prognostic significance, current treatment challenges include the determination of the optimal dose of radiation therapy, combination of chemotherapy agents, and the development of therapeutic agents that can target specific mutations in pathways, thereby contributing to prevention of recurrences while decreasing toxicities.
Surgery
A fundamental decision in evaluating a child with a posterior fossa tumor is determining whether the tumor is a mass lesion arising from the cerebellar hemisphere, vermis, or fourth ventricular floor or is an intrinsic tumor of the brain stem. Children with the former lesion types (e.g., medulloblastomas, ependymomas, cerebellar astrocytomas) undergo surgical intervention to allow for diagnosis, open CSF pathways, address mass effect on the brain stem, and achieve cytoreduction.
In children with a resectable lesion, such as a medulloblastoma, the timing of surgery is determined by the clinical status of the child. If they are alert, high-dose corticosteroids are administered and a spinal MRI scan is obtained to determine the presence of evidence of leptomeningeal dissemination; the craniotomy is then performed on the following day.94 This approach is also reasonable if such children are lethargic but become alert after administration of corticosteroids. However, in the rare situations in which such children are extremely somnolent, urgent surgical intervention is preferred. If there is evidence of hydrocephalus, it is imperative that the child, who needs sedation for the MRI, be intubated and placed under general anesthesia such that the end-tidal pCO2 can be well-controlled to maintain hypo- to normocarbia. Conscious sedation alone leads to hypoventilation, hypercarbia, cerebral vasodilation, increased intracranial pressure (ICP), and possible herniation during MRI.
A ventriculostomy is placed in most cases for temporary CSF diversion in the case of associated hydrocephalus, and this is “weaned” by gradual elevation of the drip chamber during the postoperative period. If affected children need prolonged CSF drainage after tumor removal, permanent CSF diversion usually is performed. Some centers are now advocating endoscopic third ventriculostomy (ETV) at the time of presentation as a tool to avoid CSF shunting.95,96 Whether an ETV can prevent posttumor removal shunting and its inherent risks is yet to be properly defined. A useful tool to predict the possibility of needing CSF diversion after tumor resection takes into account the patient’s age (score of 3), moderate-to-severe preoperative hydrocephalus (score of 2), the presence of papilledema (score of 1), the presence of leptomeningeal metastasis (score of 3), and the tumor histology (score of 1); patients with scores ≥ 5 are deemed high-risk (42% to 73% chance of requirement for CSF diversion).97
The tumor usually is approached through a suboccipital craniotomy or craniectomy, with the patient in a prone or modified prone (Concorde) position. The dura is opened in a Y-shaped fashion. Cerebellar hemispheric lesions, which are encountered most commonly in older children, are exposed fully by a transverse or vertical incision in the cerebellar hemisphere. The more common vermian and fourth ventricular lesions may be visible within the foramen of Magendie but, if not, are exposed by dividing the caudal 1 to 2 cm of the inferior vermis. Because approximately 20% of patients develop a postoperative syndrome of pseudobulbar symptoms and mutism (the “posterior fossa syndrome”) after vermian tumor resections,98,99,100,101,102 which may be related in part to the extent of the vermis incision, an attempt is made to incise only as much vermis as is needed to provide adequate exposure of the tumor. Some authors have advocated the “telo-velar” approach in which the Foramen of Luschka is opened up to allow retraction of the cerebellum superiorly, and thereby decrease the amount of resection of the inferior cerebellar vermis. The central portion of the lesion is then debulked using the ultrasonic aspirator. The plane between the tumor and the vermis is followed rostrally until the roof of the fourth ventricle is reached. There is usually a very discrete plane between the purplish medulloblastoma and the grayish cerebellum.
Once the tumor has been partially debulked, a cottonoid patty is inserted under the caudal aspect of the tumor along the floor of the fourth ventricle to minimize the risk of injury to the brain stem as additional tumor is removed from within the fourth ventricle. Some surgeons monitor electromyograms of the lateral rectus and facial muscles during the resection to reduce the risk of abducens and facial nerve palsies, as well as brain stem auditory evoked responses to survey longitudinal white matter tracts through the brain stem. Next, tumor extending laterally within the foramina of Luschka or the cerebellar peduncles is removed. Finally, tumor adherent to the floor of the fourth ventricle is carefully removed. The aggressiveness of the resection in this region is guided by the frozen-section diagnosis. For medulloblastomas, the tumor can be shaved down to just above the floor of the fourth ventricle, but removal of tumor below the floor is unnecessary, as it does not appear to improve outcome and clearly increases the potential for morbidity.
Once the tumor has been removed, the dura is closed, generally with a graft. Because a CSF examination is an important component of the postoperative staging of children with medulloblastomas and because blood and debris can settle in the lumbar thecal sac within several hours of surgery, complicating interpretation of the cytology for several weeks, many groups delay the puncture until the third postoperative week. A postoperative MRI is performed, preferably within 24 to 72 hours after surgery, to confirm the extent of resection.
Postoperative Considerations
The postoperative recovery of patients who undergo a complete or partial resection of a posterior fossa tumor, particularly a tumor in or around the cerebellar vermis, may be complicated by the posterior fossa syndrome. Posterior fossa syndrome, also known as “cerebellar mutism,” may range from a mild to severe disorder that is characterized by mutism, ataxia, hemiparesis, cognitive impairment, behavioral changes, cranial nerve palsies, bulbar palsy, and tremor.98,99,100,101,102 The onset is typically within the first week after surgery103,105 and appears to occur more commonly with medulloblastoma than with other posterior fossa tumors.
The etiology of the posterior fossa syndrome is unknown but has been suggested to be secondary to damage to the cerebellar vermis, the floor of the fourth ventricle, the deep cerebellar nuclei, the middle cerebellar peduncle, the superior cerebellar peduncle, or the dentate-thalamo-cortical white matter tracts.103 None of the suggested etiologies accounts very well for the delayed onset of symptoms. Previously reported as a rare complication of posterior fossa surgery, for unclear reasons this syndrome is now observed in greater than 25% of children following tumor resection in the posterior fossa.100 Although recovery may be complete, particularly for the mutism, there are patients in whom it is incomplete with long-term neurologic sequelae.99,100,103 Posterior fossa syndrome independently predicted below-average estimated mean intellectual ability at 5 years postdiagnosis.104,105
Radiation Therapy
Medulloblastoma is a radiosensitive CNS tumor; for decades, the standard therapy for medulloblastoma has been postoperative irradiation to the entire subarachnoid space (the “neuraxis,”), termed craniospinal irradiation (CSI), along with a “boost” to the posterior fossa primary site. Attempts at excluding parts of the neuraxis or omitting radiation therapy altogether have resulted in compromised survival.106 Conversely, CSI is associated with dose-related effects on cognition, growth, and endocrine function; long-term functional changes are most marked in younger patients.107 The emphasis of recent trials has been to identify cohorts of children in whom one can reduce CSI dose levels without compromising disease control. A prospective Pediatric Oncology Group (POG)-CCG study in the late 1980s compared standard-dose CSI (36 Gy) with reduced-dose CSI (23.4 Gy) in children with non-metastatic disease. The study showed an excess of subarachnoid failures in the reduced-dose arm, with a marginal benefit following the standard-dose CSI.108 The companion POG neuropsychologic study showed superior cognitive function following the lower CSI dose, significant for those younger than 8 years.109 Treatment regimens using postoperative irradiation alone require standard (36 Gy) CSI dose even with M0 disease.108 Further experience in North America has built upon an encouraging single-arm pilot CCG study in the 1990s documenting disease control in excess of 80% following the same reduced-dose CSI (23.4 Gy/13 fractions) followed by local posterior fossa boost (54 Gy) but in conjunction with postirradiation chemotherapy, cisplatin, vincristine, and CCNU.110 The subsequent COG protocol for standard-risk medulloblastoma used 23.4 Gy CSI with one of two different chemotherapeutic regimens that showed an event-free survival of greater than 80% for both treatment arms, confirming the outcome noted in the earlier CCG pilot study.20 Similar results were seen in a multicenter study utilizing high-dose postradiotherapy chemotherapy supported by peripheral stem cell rescue. In this study, the exposure to cisplatin was 50% less, although the cumulative cyclophosphamide dose was similar.93 The feasibility of further reduction in the CSI dose (18 Gy) is being evaluated for children 3 to 8 years old in the current COG trial. Whether the 18 Gy CSI dose is adequate in preventing recurrences and maintaining the accepted survival rates will be answered in this recently completed COG phase III trial, with power to detect a significant reduction in disease control or a change in the pattern of failure.111,112
For children and adolescents with leptomeningeal metastasis at diagnosis, the accepted CSI dose is 36 Gy.113 One of the most positive results in treating advanced-stage disease was recently reported from St. Jude, where 70% long-term event-free survival (EFS) was achieved with a regimen using CSI at 36 Gy (for positive CSF cytology without imaging evidence of metastasis, M1) and 39.6 Gy (for imaging-positive metastatic disease, M2-3).93 In this study, the radiation therapy was followed by four courses of high-dose chemotherapy and stem cell rescue. The results of POG 9031, a randomized study of chemotherapy before or after radiation therapy for high-risk medulloblastoma, showed similar disease control in both arms with CSI doses of 36 to 40 Gy.114
The time-dose relationship for radiation therapy correlates significantly with outcome. Prolonged interruptions in radiation therapy have consistently been associated with reduced likelihood of disease control.115,116,117 Several series, including a recent randomized trial of hyperfractionated versus conventional radiotherapy (HIT SIOP PNET 4) for standard-risk disease, have assessed hyperfractionated radiation schedules (using 100 to 150 cGy twice daily to cumulative levels of 32 to 40 Gy depending on M status); no obvious benefit in disease control or later toxicities has been demonstrated.118,119 The technique of CSI is well known. However, ensuring at least a 5-mm margin of coverage of the cribriform plate is important, as inadequate irradiation of that area can lead to an increase in recurrence at this location.120 Spinal MRI is key to determining the inferior border of the thecal sac.
The radiation dose to the posterior fossa or tumor bed is based on earlier observations defining a “threshold” dose of more than 50 Gy, in practice indicating near-tolerance levels of 54.0 to 55.8 Gy. The potential benefit of “boost” irradiation (>55.8 Gy) in cases with overt primary disease residual, either by reducedvolume fractionated radiation therapy (often to 59.4 Gy) or by radiosurgery, has not been demonstrated. Several studies over the past 15 years indicate that one can effectively control medulloblastoma with smaller boost volumes, targeting the tumor bed and any imaging-visible residual with a 2-cm margin rather than the entire posterior fossa.93,121,122 Ongoing trials include a prospective comparison of posterior fossa versus local tumor bed irradiation and, independently, further reduction in the volumetric margin defining the clinical target from a 2-cm expansion to 1 or 1.5 cm beyond the tumor bed itself. The use of three-dimensional (3-D) image-based conformal techniques (including 3-D conformal radiation therapy [3DCRT], intensity-modulated radiation therapy [IMRT], or proton beam radiation therapy [PBRT]) provide greater restriction of the high-dose region to the targeted tumor volume, while selectively reducing the radiation dose to the cochlea and the hypothalamic-pituitary axis.121,123,124,125,126,127 Recent studies have demonstrated that the use of IMRT can reduce the frequency of severe ototoxicity in the setting of cisplatin chemotherapy126 Current planning parameters also seek to relatively reduce radiation dose levels to the temporal lobe(s) and, in sophisticated settings, to the hippocampus region (in attempts to reduce cognitive deficits). The potential advantage of PBRT has been summarized, based on modeling of dosimetry and clinically derived dose:volume:anatomic correlations.128,129
Chemotherapy
Chemotherapy is presently an integral component of treatment for all infants and children with medulloblastoma.4,20,26 It is also used extensively in adults with the disease, although proof of its efficacy for adults is less compelling. Objective response rates, ranging between 40% and 60%, have been documented with cisplatin, etoposide, and a variety of different alkylators, with the best responses being seen with multi-drug regimens.4,20,127,128,129,130,131
Medulloblastoma was one of the first pediatric brain tumors to have chemotherapy extensively evaluated in newly diagnosed patients. Prospective randomized studies performed as early as the late 1970s by the CCG and the International Society of Pediatric Oncology, which compared progression-free and OS in children treated with radiotherapy alone to those receiving radiotherapy plus chemotherapy given during and after radiation, demonstrated a statistically significant 15% to 20% survival advantage for patients with poorer risk disease, defined as those with disseminated disease, larger, more infiltrative tumors, and/or significant amounts of residual tumor after surgery, as determined by the operating neurosurgeon.86,88 Neither group demonstrated a statistically significant survival advantage for children with nondisseminated disease (Table 26B.6). However, because of the encouraging survival rates seen in children with poor-risk disease, chemotherapy was added to radiation therapy in children with nondisseminated (average-risk disease) in attempts to both improve survival and allow a reduction
in the dose of craniospinal radiation.4,9,20 Chemotherapy was also widely utilized for infants and young children with medulloblastoma to delay, if not obviate, the need for radiation therapy.
in the dose of craniospinal radiation.4,9,20 Chemotherapy was also widely utilized for infants and young children with medulloblastoma to delay, if not obviate, the need for radiation therapy.
For children with average-risk disease, 5-year survival rates of 80% to 85% have been seen after radiotherapy and a variety of chemotherapeutic agents used during and after radiotherapy (see Table 26B.7). A recent trial within the COG for average-risk patients is comparing the outcomes of patients randomized to receive 1,800 cGy or 2,340 cGy and either receive posterior fossa boost or a boost confined to tumor bed with a margin. The chemotherapy regimen is the same postradiation.
Recent evidence as discussed in the biology section clearly shows that medulloblastoma is not one disease but can be divided into at least four subgroups. Children with medulloblastoma showing evidence of Wnt pathway activation representing about 10% of all patients with medulloblastoma have an excellent prognosis and clinical trials are underway to decrease the intensity of therapy for these patients. Patients with medulloblastoma with SHH pathway activation who represent approximately 30% of patients could have improved outcomes with the addition of agents targeting the SHH pathway to standard chemotherapy regimens.132,133 Patients who have Group 3 tumors have a relatively poor prognosis and are in need of more effective therapeutic strategies.
In a prospective, single-arm study by Packer et al.,9 the use of radiotherapy with concomitant vincristine and postradiation therapy consisting of CCNU, vincristine, and cisplatin resulted in approximately a 65% progression-free survival rate in patients with metastatic disease (Table 26B.8). A 70% 5-year progression-free survival rate was reported in the St. Jude prospective study utilizing postradiotherapy high-dose chemotherapy and stem cell rescue in a similar group of high-risk patients.93 This is similar to the survival rate noted in a POG trial that used higher doses of craniospinal radiation with pre- or postradiation chemotherapy consisting of cisplatin and cyclophosphamide.114,116 In a pilot study, carboplatin used during radiotherapy and as part of a multi-agent chemotherapy regimen after radiation therapy resulted in a 3-year survival rate of more than 80%.134 In an ongoing randomized study within the COG, the feasibility of using carboplatin during radiation therapy, as both an antineoplastic agent and a radiosensitizer is under evaluation. This study also includes a second randomization to determine the additive benefit of a maturation agent, retinoic acid. All patients in this study are to receive somewhat intensified postradiation chemotherapy. Other studies within the COG and PBTC are attempting to determine whether higher-dose chemotherapy supplemented with peripheral stem cell rescue or the addition of methotrexate to multi-agent chemotherapeutic regimens will improve survival for younger patients with “high-risk” disease.
TABLE 26B.7 Medulloblastoma: Selected Cooperative Group Studies for Nondisseminated Disease | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
The benefits of chemotherapy have also been widely explored in infants with medulloblastoma (Table 26B.8). As early as the 1970s, small, single-institution studies suggested that some children with medulloblastoma were responsive to chemotherapy and might be cured with chemotherapy alone utilizing drug regimens such as mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) (Table 26B.9).135
Multi-agent chemotherapy regimens were utilized by POG and CCG in attempts to delay the need for radiotherapy in young children with a variety of different tumors, including medulloblastoma, for 1 year or until the child reached 3 years of age.136,137 Thirty-two percent ±5% of patients with medulloblastoma in the latter study had long-term disease control without the use of postchemotherapy radiation therapy. The use of intravenous and intrathecal methotrexate coupled with multi-agent chemotherapy was explored by the German Oncology Group, with 58% ± 9% of patients experiencing long-term control with chemotherapy alone. This study demonstrated that a subgroup of patients, primarily those with desmoplastic tumors and/or tumors that were localized at the time of diagnosis, could be treated with chemotherapy alone, with a disease-free survival rate of more than 80% for those with desmoplastic tumors.91 The incorporation of methotrexate improved survival for a subset of patients, but resulted in a high incidence of leukoencephalopathy (19 of 23 patients in the German study), the significance of which regarding long-term neurologic and neurocognitive outcome is unclear. Similarly, high-dose chemotherapy regimens utilizing stem cell rescue or autologous bone marrow rescue, including the “head-start” studies, those done by the French Society of Pediatric Oncology, and a
recently completed COG study, have demonstrated a possible improvement in survival over treatment with multi-agent chemotherapy regimens delivered at conventional doses.138,139,140,141 A recent COG study showed that focal radiation therapy to the tumor bed in addition to chemotherapy may be effective in a subset of patients, once again demonstrating an improved outcome in young children with nodular desmoplastic medulloblastoma.92 There is a COG trial underway which eliminates radiation therapy completely for children less than 4 years of age who have nodular desmoplastic or MBEN histopathology, utilizing a chemotherapy regimen that includes carboplatin, methotrexate, and cyclophosphamide.
recently completed COG study, have demonstrated a possible improvement in survival over treatment with multi-agent chemotherapy regimens delivered at conventional doses.138,139,140,141 A recent COG study showed that focal radiation therapy to the tumor bed in addition to chemotherapy may be effective in a subset of patients, once again demonstrating an improved outcome in young children with nodular desmoplastic medulloblastoma.92 There is a COG trial underway which eliminates radiation therapy completely for children less than 4 years of age who have nodular desmoplastic or MBEN histopathology, utilizing a chemotherapy regimen that includes carboplatin, methotrexate, and cyclophosphamide.
TABLE 26B.8 Medulloblastoma: Selected Cooperative Group Studies for “High-Risk” Disease | |||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| |||||||||||||||||||||||||||||||||||||||
Relapsed Medulloblastoma
The prognosis for newly diagnosed children with medulloblastoma has improved significantly. However, the outcome of children who develop recurrent disease is dismal. It is the rare patient with recurrent medulloblastoma who is a long-term survivor. There is no standard approach for patients with recurrences. A variety of chemotherapy regimens and single agents were utilized with very little effect. Objective responses have been noted after treatment with a variety of different agents, such as cisplatin, carboplatin, cyclophosphamide, and etoposide.4,142,143,144,145,146 Temozolomide has been used with mixed results, with some studies suggesting only minimal activity and one trial reporting an objective response in the majority of those with leptomeningeal disease.147,148 Ongoing COG clinical trials include temozolomide in combination with irinotecan with or without avastin for recurrent medulloblastoma. In general, after treatment with standard doses of chemotherapy, the vast majority of relapsed patients will relapse again within a few months of initiation of salvage therapy. For this reason, there has been an interest in utilizing further therapies to consolidate response, including high-dose chemotherapy supported by either autologous bone marrow transplant or stem cell rescue, and radiation therapy. Mephalan, cyclophosphamide, busulphan, and thiotepa, with or without carboplatin and/or etoposide, have been most widely used in high-dose consolidation chemotherapy regimens, possibly with the best disease control rates being reported for thiotepa-based approaches.138,139,140
TABLE 26B.9 Consortium Trials for Infants and Young Children with Medulloblastoma | ||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| ||||||||||||||||||||||||||||||||||||
Long-term survival and possibly cure have been noted predominantly in patients with localized relapse, who with further
surgery and/or induction chemotherapy can be shown to have no measurable residual disease at the time of consolidation. Even in these situations, long-term disease control has been seen predominantly in children who have not received radiotherapy previously and are treated with primary site irradiation or in those who are re-irradiated. In a French study in children initially treated on chemotherapy alone, survival rates of greater than 50% have been documented after retreatment with surgery, high-dose thiotepa-based chemotherapy with peripheral stem cell rescue, and localized radiotherapy to the primary tumor site.149 Those children with relapsed disseminated disease are rarely cured even if craniospinal radiotherapy is used at recurrence.
surgery and/or induction chemotherapy can be shown to have no measurable residual disease at the time of consolidation. Even in these situations, long-term disease control has been seen predominantly in children who have not received radiotherapy previously and are treated with primary site irradiation or in those who are re-irradiated. In a French study in children initially treated on chemotherapy alone, survival rates of greater than 50% have been documented after retreatment with surgery, high-dose thiotepa-based chemotherapy with peripheral stem cell rescue, and localized radiotherapy to the primary tumor site.149 Those children with relapsed disseminated disease are rarely cured even if craniospinal radiotherapy is used at recurrence.
With the advent of recent biologic discoveries and identification of different pathogenic molecular pathways and recurrent gene mutations, there has been excitement that these tumors at the time of recurrence may show group migration or a different set of mutations. However, recent evidence suggests that medulloblastoma at recurrence maintains the same molecular profile as the original subgroup at initial diagnosis.150
Related posts:
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
