lunes, 23 de septiembre de 2019

Childhood Medulloblastoma and Other Central Nervous System Embryonal Tumors Treatment (PDQ®) 1/5 –Health Professional Version - National Cancer Institute

Childhood Medulloblastoma and Other Central Nervous System Embryonal Tumors Treatment (PDQ®)–Health Professional Version - National Cancer Institute

National Cancer Institute

Childhood Medulloblastoma and Other Central Nervous System Embryonal Tumors Treatment (PDQ®)–Health Professional Version

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General Information About Medulloblastoma and Other Central Nervous System (CNS) Embryonal Tumors

Primary brain tumors, including medulloblastoma and embryonal tumors, are a diverse group of diseases that together constitute the most common solid tumor of childhood. Brain tumors are classified according to histology, but tumor location and extent of spread are important factors that affect treatment and prognosis. Immunohistochemical analysis, cytogenetic and molecular genetic findings, and measures of mitotic activity are increasingly used in tumor diagnosis and classification.

World Health Organization (WHO) Classification for CNS Embryonal Tumors and Pineoblastoma

Embryonal tumors are a collection of biologically heterogeneous lesions that share the tendency to disseminate throughout the nervous system via cerebrospinal fluid (CSF) pathways. Although there is significant variability, histologically these tumors are grouped together because they are at least partially composed of hyperchromatic cells (blue cell tumors on standard staining) with little cytoplasm, which are densely packed and demonstrate a high degree of mitotic activity. Other histologic and immunohistochemical features, such as the degree of apparent cellular transformation along identifiable cell lineages (ependymal, glial, etc.), can be used to separate these tumors to some degree. However, a convention, which has been accepted by the WHO, also separates these tumors on the basis of presumed location of origin within the central nervous system (CNS). Molecular studies have substantiated the differences between tumors arising in different areas of the brain and give partial credence to this classification approach.[1]
As of 2016, the WHO has proposed an integrated phenotypic and genotypic classification system for CNS tumors in which diagnoses are layered with WHO grade, histologic classification, and molecular classification.[2] The term primitive neuroectodermal tumor (PNET) has been removed from the newest WHO diagnostic lexicon, although some rare entities (e.g., medulloepithelioma) have remained. A molecularly distinct entity, embryonal tumor with multilayered rosettes (ETMR), C19MC-altered, has been added, encompassing embryonal tumor with abundant neuropil and true rosettes (ETANTR), ependymoblastoma, and medulloepithelioma. The WHO classification will be updated as other molecularly distinct entities are defined.
The pathologic diagnosis of embryonal tumors is based primarily on histological and immunohistological microscopic features. However, molecular genetic studies are employed increasingly to subclassify embryonal tumors. These molecular genetic findings are also being utilized for risk stratification and treatment planning.[3-6]
The 2016 WHO categorization of embryonal tumors is as follows:[2]
  • Medulloblastoma, genetically defined.
    • Medulloblastoma, WNT-activated.
    • Medulloblastoma, sonic hedgehog (SHH)–activated and TP53-mutant.
    • Medulloblastoma, SHH-activated and TP53–wild-type.
    • Medulloblastoma, non-WNT/non-SHH.
      • Medulloblastoma, group 3.
      • Medulloblastoma, group 4.
  • Medulloblastoma, histologically defined.
    • Medulloblastoma, classic.
    • Medulloblastoma, desmoplastic/nodular.
    • Medulloblastoma with extensive nodularity (MBEN).
    • Medulloblastoma, large cell/anaplastic.
  • Medulloblastoma, not otherwise specified (NOS).
  • ETMR, C19MC-altered.
  • ETMR, NOS.
  • Medulloepithelioma.
  • CNS neuroblastoma.
  • CNS ganglioneuroblastoma.
  • CNS embryonal tumor, NOS.
  • CNS atypical teratoid/rhabdoid tumor. (Refer to the PDQ summary on Childhood Central Nervous System Atypical Teratoid/Rhabdoid Tumor Treatment for more information about CNS atypical teratoid/rhabdoid tumors.)
  • CNS embryonal tumor with rhabdoid features.
Pineoblastoma, which in the past was conventionally grouped with embryonal tumors, is categorized by the WHO as a pineal parenchymal tumor. Given that therapies for pineoblastomas are quite similar to those utilized for embryonal tumors, pineoblastomas are discussed in this summary. A somewhat closely aligned tumor, pineal parenchymal tumor of intermediate differentiation, has been identified but is not considered an embryonal tumor and primarily arises in adults.[2]
The PDQ childhood brain tumor treatment summaries are organized primarily according to the World Health Organization (WHO) classification of nervous system tumors.[2] For a full description of the classification of nervous system tumors and a link to the corresponding treatment summary for each type of brain tumor, refer to the PDQ summary on Childhood Brain and Spinal Cord Tumors Treatment Overview.

Anatomy

ENLARGEDrawing of the inside of the brain showing the supratentorial area (the upper part of the brain) and the posterior fossa/infratentorial area (the lower back part of the brain). The supratentorial area contains the cerebrum, lateral ventricle, third ventricle, choroid plexus, hypothalamus, pineal gland, pituitary gland, and optic nerve. The posterior fossa/infratentorial area contains the cerebellum, tectum, fourth ventricle, and brain stem (pons and medulla). The tentorium and spinal cord are also shown.
Figure 1. Anatomy of the inside of the brain, showing the pineal and pituitary glands, optic nerve, ventricles (with cerebrospinal fluid shown in blue), and other parts of the brain. The posterior fossa is the region below the tentorium, which separates the cortex from the cerebellum and essentially denotes the region containing the brain stem, cerebellum, and fourth ventricle.

Incidence

Embryonal tumors comprise 20% to 25% of primary CNS tumors (malignant brain tumors and pilocytic astrocytomas) arising in children. These tumors occur along the pediatric age spectrum but tend to cluster early in life. The incidence of embryonal tumors in children aged 1 to 9 years is fivefold to tenfold higher than is the incidence of embryonal tumors in adults (refer to Table 1).[7,8]
Table 1. Annual Incidence Rates for Childhood Central Nervous System Embryonal Tumors According to Agea
Age Group (y)Annual Incidence Rate (Cases per 1 Million)
aSource: Childhood cancer by the International Classification of Childhood Cancer [7] and Smoll et al.[8]
<511
5–97
10–193–4
Medulloblastomas comprise the vast majority of pediatric embryonal tumors and by definition arise in the posterior fossa (refer to Figure 1), where they constitute approximately 40% of all posterior fossa tumors. Other forms of embryonal tumors each make up 2% or less of all childhood brain tumors.

Diagnostic and Staging Evaluation

Imaging studies and CSF analysis are included in the diagnostic and staging evaluation.

Imaging studies

Diagnosis is usually readily made by either magnetic resonance imaging (MRI) or computed tomography (CT) scan. MRI is preferable because the anatomic relationship between the tumor and surrounding brain and tumor dissemination is better visualized with this method.[9]
After diagnosis, evaluation of embryonal tumors is quite similar, essentially independent of the histologic subtype and the location of the tumor. Given the tendency of these tumors to disseminate throughout the CNS early in the course of illness, imaging evaluation of the neuraxis by means of MRI of the entire brain and spine is indicated. Preferably, this is done before surgery to avoid postoperative artifacts, especially blood. Such imaging can be difficult to interpret and must be performed in at least two planes, with and without the use of contrast enhancement (gadolinium).[10] A study of the significance of equivocal findings on spinal MRIs in children with medulloblastoma identified equivocal findings in 48 of 100 patients (48%). The study reported the following results:
  • Of the 48 patients with equivocal findings, 45 had preoperative MRI scans.
  • Analysis by subgroup identified a higher proportion of equivocal findings in the SHH subgroup (P = .007).
  • Five-year overall survival (OS) in children with equivocal findings (80%) was not different from 5-year OS in patients who had normal MRI findings (84.8%), while OS in patients with M3 metastases was worse (54.7%) (P = .02).[11]
However, in a paper describing the experience in patients without metastatic disease at diagnosis treated with 23.4 Gy of craniospinal radiation therapy, equivocal findings were associated with poorer event-free survival (EFS) and OS.[10] Consensus guidelines for timing and neuroimaging techniques have been suggested, including preoperative assessment of the entire neuroaxis and postoperative assessment of amount of residual disease.[12]
After surgery, imaging of the primary tumor site is indicated to determine the extent of residual disease.

CSF analysis

After surgery, lumbar CSF analysis is performed, if deemed safe. Neuroimaging and CSF evaluation are considered complementary because as many as 10% of patients will have evidence of free-floating tumor cells in the CSF without clear evidence of leptomeningeal disease on MRI scan.[13]
CSF analysis is conventionally done 14 to 21 days after surgery. If CSF is obtained within 14 days of the operation, detection of tumor cells within the spinal fluid is possibly related to the surgical procedure. In most staging systems, if fluid is obtained in the first few days after surgery and found to be positive for tumor cells, the positivity must be confirmed by a subsequent spinal tap to be considered diagnostically significant. When obtainment of fluid by lumbar spinal tap is deemed unsafe, ventricular fluid can be obtained; however, this method may not be as sensitive as lumbar fluid assessment.[13]
Because embryonal tumors are very rarely metastatic to the bone, bone marrow, or other body sites at the time of diagnosis, studies such as bone marrow aspirates, chest x-rays, or bone scans are not indicated, unless there are symptoms or signs suggesting organ involvement.

Prognostic Factors

Various clinical and biologic parameters have been shown to be associated with the likelihood of disease control of embryonal tumors after treatment.[4] The significance of many of these factors have been shown to be predictive for medulloblastomas, although some are used to assign risk, to some degree, for other embryonal tumors. Parameters that are most frequently utilized to predict outcome include the following:[14,15]
It has become increasingly clear, especially for medulloblastomas, that outcome is also related to the molecular characteristics of the tumor, but this has not been definitively shown for other embryonal tumors.[1,5,6,16-18] OS rates range from 40% to 90%, depending on the molecular subtype of the medulloblastoma and possibly other factors, such as extent of dissemination at time of diagnosis and degree of resection. Children with medulloblastoma who survive for 5 years are considered cured of their tumor. Survival rates for other embryonal tumors are generally poorer, ranging from less than 5% to 50%; specific survival rates are discussed within each subgroup in the summary.[19-22]
In older studies, the presence of brain stem involvement in children with medulloblastoma was found to be a prognostic factor; it has not been found to be of predictive value in subsequent studies utilizing both radiation and chemotherapy.[10,14]
An accurate diagnosis is a critical issue for patients with embryonal tumors. For example, in the ACNS0332 (NCT00392327) trial that enrolled 80 patients with high-risk medulloblastoma, supratentorial CNS-PNET tumors, and pineoblastoma, 60 patients had sufficient tissue for evaluation. Thirty-one tumors were nonpineal in location, 22 (71%) of which represented tumors that were not intended for trial inclusion, including 18 high-grade gliomas, 2 atypical teratoid/rhabdoid tumors, and 2 ependymomas. Outcomes across tumor types were strikingly different. Patients with supratentorial embryonal tumors/pineoblastomas exhibited a 5-year EFS of 62.8% (95% confidence interval [CI], 43.4%–82.2%) and OS of 78.5% (95% CI, 62.2%–94.8%), whereas patients with molecularly classified high-grade gliomas had an EFS of 5.6% (95% CI, 0%–13%) and OS of 2% (95% CI, 0%–24.7%). Survival rates for patients with high-grade gliomas were similar to those of patients who were enrolled in historic studies that avoided craniospinal irradiation and intensive chemotherapy. Thus, for patients with CNS-PNET/pineoblastoma, prognosis is considerably better than previously assumed when molecularly confirmed high-grade gliomas are removed.[23]
Prognosis is poor for patients with medulloepithelioma and ETMR, with 5-year survival rates ranging between 0% and 30%.[24-26] In a retrospective multivariate analysis of 38 patients, total or near-total resection, the use of radiation therapy, and the use of high-dose chemotherapy were associated with an improved prognosis.[27][Level of evidence: 3iA]

Extent of CNS disease at diagnosis

Patients with disseminated CNS disease at diagnosis are at highest risk of disease relapse.[13-15] Ten percent to 40% of patients with medulloblastoma have CNS dissemination at diagnosis, with infants having the highest incidence and adolescents and adults having the lowest incidence.
Nonmedulloblastoma embryonal tumors and pineoblastomas may also be disseminated at the time of diagnosis, although the incidence of dissemination may be somewhat less than that of medulloblastomas, with dissemination at diagnosis being documented in approximately 10% to 20% of patients.[19,20] Patients with nonmedulloblastoma embryonal tumors and pineoblastomas who have disseminated disease at the time of diagnosis have a poor OS, with reported survival rates at 5 years ranging from 10% to 30%.[19-22]

Age at diagnosis

Age younger than 3 years at diagnosis (except for desmoplastic medulloblastoma/MBEN) portends an unfavorable outcome for those with medulloblastoma and, possibly, other embryonal tumors.[28-32]

Amount of residual disease after definitive surgery

As a predictor of outcome, postoperative MRI measurement of the amount of residual disease after definitive surgery has been supplanted by extent of resection after surgery.[10]
In older studies, the extent of resection for medulloblastomas was found to be related to survival.[14,15,33,34] A Hirntumor and International Society of Paediatric Oncology (HIT-SIOP) study of 340 children reported that residual disease (>1.5 cm2) connoted a poorer 5-year EFS.[35] Extent of resection after surgery is still used to separate patients into risk groups, with patients having more than 1.5 cm2 of residual disease stratified into high-risk groups, with intensification of craniospinal irradiation to 36 Gy.
An international, retrospective, collaborative study included 787 patients of all ages with medulloblastoma who were treated in a variety of ways and incorporated molecular subgrouping and clinical factors in the analysis. The multivariate analysis found that subtotal resection (>1.5 cm2 residual), but not near-total resection (<1.5 cm2 residual), was associated with inferior progression-free survival compared with gross-total resection. This study suggested that attempts to completely remove the tumor, especially when the likelihood of neurological morbidity is high, are not warranted because there appears to be little or no benefit to gross-total resection when compared with near-total resection. It gives some credence to the present approach in which patients with more than 1.5 cm2 of disease are considered higher-risk patients.[36] Prospective studies are needed to better define the impact of extent of resection on outcome within molecularly defined subgroups.
In patients with other forms of embryonal tumors, the extent of resection has not been definitively shown to impact survival.[21] However, in a Children's Oncology Group study of 66 children with supratentorial embryonal tumors, extent of resection was found to be prognostic for those with localized disease at the time of diagnosis.[37]

Tumor histopathology

For medulloblastomas, histopathologic features such as large cell variant, anaplasia, and desmoplasia have been shown in retrospective analyses to correlate with outcome.[29,38,39] In prospective studies, immunohistochemical and histopathologic findings have not predicted outcome in children older than 3 years at diagnosis, with the exception of the large cell/anaplastic variant, which has been associated with poorer prognosis.[10,18,40] Several studies have observed that the histologic finding of desmoplasia, seen in patients aged 3 years and younger with desmoplastic medulloblastoma, especially MBEN, connotes a significantly better prognosis compared with outcomes for infants and young children with classic or large cell/anaplastic medulloblastoma.[18,28-30,41]; [31][Level of evidence: 2A]
For other embryonal tumors, histologic variations have not been associated with differing outcome.

Biological/molecular tumor cell characteristics

Genomic analyses (including RNA gene expression and DNA methylation profiles, as well as DNA sequencing to identify mutations) on both fresh-frozen and formalin-fixed, paraffin-embedded sections have identified molecular subtypes of medulloblastoma.[3-6,16,17,42-49] These subtypes include those characterized by WNT pathway activation and SHH pathway activation, as well as additional subgroups characterized by MYC or MYCN alterations and other genomic alterations.[3-6,16,17,42-48] Children with medulloblastoma whose tumors show WNT pathway activation usually have an excellent prognosis, while patients with SHH pathway–activated tumors have a prognosis that is influenced by the presence or absence of TP53 mutations (favorable vs. unfavorable prognosis, respectively).[50] The outcome for the remaining patients is less favorable than that for patients with WNT pathway activation. Mutations in medulloblastoma are observed in a subtype-specific manner, with CTNNB1 mutations observed in the WNT subtype and with PTCH1, SMO, and SUFU mutations observed in the SHH subtype. The prognostic significance of recurring mutations is closely aligned with that of the molecular subtype with which they are associated.[4,51] At recurrence, the subtype remains unchanged from the original molecular subtype at diagnosis.[52]
Refer to the Molecular subtypes of medulloblastoma section of this summary for more information about the subtypes of medulloblastoma and the prognostic significance of specific molecular alterations.
For nonmedulloblastoma embryonal tumors, integrative genomic analysis has also identified molecular subtypes with different outcomes. (Refer to the Subtypes of nonmedulloblastoma embryonal tumors section of this summary for more detailed information.)

Follow-up After Treatment

Relapse in children with embryonal tumors is most likely to occur within the first 18 months of diagnosis.[35,53] Surveillance imaging of the brain and spine is usually undertaken at routine intervals during and after treatment (refer to Table 2). The frequency of such imaging, designed to detect recurrent disease at an early, asymptomatic state, has been arbitrarily determined and has not been shown to clearly influence survival.[54-57] Growth hormone replacement therapy has not been shown to increase the likelihood of disease relapse.[30]
Table 2. Surveillance Testing During and After Treatment for Medulloblastoma and Other Central Nervous System Embryonal Tumors
Surveillance PeriodFrequency of Visits During Surveillance PeriodTesting
MRI = magnetic resonance imaging.
aFor pineoblastoma, continue spinal evaluations every 6 months until 5 years from diagnosis. Although these suggestions are based on a small sample size, there is evidence for continuing surveillance testing of the spine until 5 years after diagnosis.[58]
First 3 years after diagnosisEvery 3 monthsPhysical exam
Imaging of the brain every 3 months for the first 3 years, then every 6 months for the ensuing 2 years, and then as per preference of the treating physician or per protocol; MRI of the spine every 3 months for the first 2 years, then every 6 months for 1 year, and then as per preference of the treating physician or per protocol.a
Endocrinology evaluation once a year
Neuropsychologic testing every 1–2 years
3–5 years after diagnosisEvery 6 monthsPhysical exam
Imaging of the brain and spine once a year
Endocrinology evaluation once a year
Neuropsychologic testing every 1–2 years
More than 5 years after diagnosisOnce a yearPhysical exam
Imaging of the brain once a year
Endocrinology evaluation once a year
Neuropsychologic testing every 1–2 years (optional)
Childhood and adolescent cancer survivors require close monitoring because cancer therapy side effects may persist or develop months or years after treatment. (Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)
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