Medulloblastoma

Medulloblastoma

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First used by Bailey and Cushing in 1925, [1] the term medulloblastoma described a series of tumors found in the cerebellum of children. Originally classified as a glioma, medulloblastoma is referred to now as a primitive neuroectodermal tumor (PNET). This tumor accounts for approximately 7-8% of all intracranial tumors and 30% of pediatric brain tumors. Medulloblastoma is the most common malignant pediatric tumor in the central nervous system (CNS), accounting for nearly 20% of all childhood brain cancers and ~40% of all childhood tumors in the posterior fossa. This set of tumors is considered the most common brain malignancy among pediatric population. [2] Medulloblastoma is a type of embryonal tumor. Embryonal tumors were described over the years as a collection of histologic entities that includes medulloblastoma and also included medulloepithelioma, CNS neuroblastoma, CNS ganglioneuroblastoma and atypical teratoid/rhabdoid tumor (ATRT) as well as primitive neuroectodermal tumors (PNET). All of that changed after the 2016 World Health Organization (WHO) reclassification. [3]

In the brain, medulloblastoma most often arises in the posterior fossa as shown in the image below. The tumor has the propensity of spreading throughout the CNS. Systemic metastases of this tumor, especially to bone, also have been recognized.

Epidemiology data is changing ever since we have a better understanding of molecular and genetic behaviors of these tumors and especially after the new World Health Organization (WHO) classification from 2016. [3]

Age and Sex

Incidence of medulloblastoma is 1.5-2 cases per 100,000 population, with 350 new cases in the United States each year.

Medulloblastoma accounts for 64.3% of all embryonal tumors in pediatric patients (0-19 years old), according to the Central Brain Tumor Registry of the United States (CBTRUS). Males displayed higher incidence rate relative to females (males: 0.16 vs. females: 0.12), except in patients < 1 year-old. [2] Overall ratio tend to be 1.5:1 for males. Males also tend to have poorer prognosis. Among all age group, the reports from CBTRUS citing the embryonal tumor group together, with total incidence rate of 0.25 per 100,000 per year with slight male predominance (0.29 vs. 0.2). Incidence of medulloblastoma decreases with age. Incidence was 0.55 per 100,000 population, 0.57 per 100,000 population, 0.32 per 100,000 population, and 0.16 per 100,000 population in children aged 0–4, 5–9, and 10–14 years, and adolescents aged 15–19 years, respectively. Incidence was highest in patients aged 1–4 years at diagnosis, but patients aged 10–14 years showed increased incidence from 2000 to 2013, and when looking at all age groups the total incidence peaks at ages 9 years and below. When looking at CBTRUS and SEER databases covering roughly the same period of time (2000/2001 to 2013) adult patients (20 years of age and older) are about 28% from all medulloblastoma patients. Interestingly enough, for the adult group there was a significant rise in incidence rate between 2001 and 2009 with subsequent significant decline in the rate between 2009 and 2013. [2, 4]

Race

In the United States, when looking at race for pediatric population (0-19 years), there is Caucasian and Asian/Pacific Islander predominance. In the collection of data from CBTRUS and SEER, white race was reported in the majority of cases (more than 80%). [2] Yet, when comparing black population to white population for the years 2001 to 2013, blacks displayed a non-significant increase in incidence and in mortality risk.

Mortality/Morbidity

The 5-year and 10-year survival rates among all patients are 73% and 64.7%, respectively. Patients aged 1–4 years have lower survival rates for each year post diagnosis relative to patients aged 5–9, 10–14, and 20+ years up to 5 years post diagnosis. Survival rates for males and females are similar up to 10 years post diagnosis. Black patients displayed slightly lower survival rates for each year post diagnosis compared to white patients. [2] Yet the reader needs to take into consideration that these survival numbers are from before the adjustment by molecular subtypes. When looking at the new classification (even before changing from 4 subtypes to 5), certain unsettled issues in epidemiology can become clearer. The group of infants < 1 year of age has a much poorer prognosis. In previous works it was described that the age group of children less than 4 years old are divided mainly to SHH (more than 50%) and group 3 (~40%). Whereas SHH pathway-driven tumors usually lead to a fair survival rate of 75% in 5 years for children below 3 years of age, group 3 for the same age group is having significantly worse survival rates. This accounts for the discrepancy between the old survival rates in CBTRUS of about 48% for children < 1 year old and 62% for children between 1 and 4 years of age, and the more positive picture that sometime can be seen in daily life. [5, 6]

In terms of morbidity, there are a lot of potential causes and complications for the patient diagnosed with medulloblastoma:

Incidence of medulloblastoma worldwide seems to approximate that in the United States.

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Subtype

Age group

Molecular characteristics

Genetic mutations

Incidence

Prognosis (10-year overall survival)

WNT activation

Found in children and adults (not infants)

WNT pathway activation

CTNNB1


DDX3X Chromatin-remodeling genes


TP53

Least common

Favorable

72%

SHH activation

5–18 years old

SHH pathway activation

TP53

About 25% of the cases

Worse

All age groups

SHH pathway activation

Non TP53 (wild type):

PTCH1


SMO
(mainly adults)

SUFU
(mainly infants)

TERT promoter Chromatin-remodeling genes

If no MYCN amplification and no metastatic disease – favorable

Group 3

Infants and children (more common in boys than in girls)

Elevated expression of MYC

GABRA5

over-expression

SMARCA4 Chromatin-remodeling genes


Genes of TGF-β pathway

About 25% of the cases

If MYC amplification present – very poor prognosis

Metastatic disease – very poor prognosis

Group 4

More common in children (not infants) than in adults


Lmx1A expression

Chromatin-remodeling genes

Most common

If no metastatic disease and chromosome 11 loss – favorable

George I Jallo, MD Professor of Neurosurgery, Pediatrics, and Oncology, Director, Clinical Pediatric Neurosurgery, Department of Neurosurgery, Johns Hopkins University School of Medicine

George I Jallo, MD is a member of the following medical societies: American Association of Neurological Surgeons, American Medical Association, American Society of Pediatric Neurosurgeons

Disclosure: Nothing to disclose.

Brooks R Osburn, MD Resident Physician, Department of Neurosurgery, University of South Florida Morsani College of Medicine

Brooks R Osburn, MD is a member of the following medical societies: American Association of Neurological Surgeons, Congress of Neurological Surgeons

Disclosure: Nothing to disclose.

Nir Shimony, MD Neurosurgeon, Pediatric, Epilepsy, NeuroOncology, Neuroscience Researcher, Geisinger Health System, Johns Hopkins University School of Medicine

Nir Shimony, MD is a member of the following medical societies: American Association of Neurological Surgeons, American Epilepsy Society, Congress of Neurological Surgeons, Society for Neuro-Oncology

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Amy Kao, MD Attending Neurologist, Children’s National Medical Center

Amy Kao, MD is a member of the following medical societies: American Academy of Neurology, American Epilepsy Society, Child Neurology Society

Disclosure: Have stock (managed by a financial services company) in healthcare companies including AbbVie, Allergan, Celgene, Cellectar Biosciences, Danaher Corp, Mckesson.

Raj D Sheth, MD Chief, Division of Pediatric Neurology, Nemours Children’s Clinic; Professor of Neurology, Mayo College of Medicine; Professor of Pediatrics, University of Florida College of Medicine

Raj D Sheth, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Pediatrics, American Epilepsy Society, American Neurological Association, Child Neurology Society

Disclosure: Nothing to disclose.

David A Chesler, MD, PhD Clinical Assistant Professor of Neurological Surgery and Pediatrics, Stony Brook University Hospital; Co-Director of Pediatric Neurosurgery, New York Spine and Brain Surgery, UFPC

David A Chesler, MD, PhD is a member of the following medical societies: American Association of Neurological Surgeons, American Medical Association, Congress of Neurological Surgeons, International Society of Pediatric Neurosurgery, Medical Society of the State of New York, Suffolk Pediatric Society

Disclosure: Nothing to disclose.

Faisal A Almayman, MBBS Post Doctorate Research Fellow, Department of Neurosurgery, Johns Hopkins University School of Medicine

Faisal A Almayman, MBBS is a member of the following medical societies: American Association of Neurological Surgeons, Saudi Stroke Association

Disclosure: Nothing to disclose.

Alvin Marcovici, MD Consulting Staff, Southcoast Neurosurgery

Alvin Marcovici, MD is a member of the following medical societies: American Association of Neurological Surgeons, Congress of Neurological Surgeons, and Phi Beta Kappa

Disclosure: Nothing to disclose.

Medulloblastoma

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