Medulloblastoma is a highly malignant primary brain tumor that originates in the part of
the brain that is towards the back and the bottom, on the floor of the skull, in the
cerebellum or posterior fossa.
The brain is divided into two main parts, the larger cerebrum on top and the smaller
cerebellum below towards the back.
They are separated by a membrane called the tentorium.
Tumors that originate in the cerebellum or the surrounding region below the tentorium
are therefore called infratentorial.
Another term for medulloblastoma is infratentorial primitive neuroectodermal tumor.
Medulloblastoma is the most common PNET originating in the brain.
All PNET tumors of the brain are invasive and rapidly growing tumors that, unlike most
brain tumors, spread through the cerebrospinal fluid and frequently metastasize to different
locations in the brain and spine.
The cumulative relative survival rate for all age groups and histology follow-up was
60%, 52%, and 47% at 5 years, 10 years, and 20 years, respectively, with children doing
better than adults.
Incidence When looking at an estimated 68,530 primary
brain and central nervous system tumors for 2012 in the USA, between 2005 and 2009 embryonal
tumors represented about 3,707 cases and of which 2,617 were in children between 0 and
19 years of age during the stated period.
Medulloblastomas affect just under 2 people per million per year, and affect children
10 times more than adults.
Medulloblastoma is the second most frequent brain tumor in children after Pilocytic astrocytoma
and the most common malignant brain tumor in children, comprising 14.5% of newly diagnosed
cases.
In adults, medulloblastoma is rare, comprising fewer than 2% of CNS malignancies.
The incidence of childhood medulloblastoma is higher in males than females, a feature
which is not seen in adults.
Medulloblastoma and other PNET`s are more prevalent in younger children than older children.
40% of medulloblastoma patients are diagnosed before the age of 5, 31% are between the ages
of 5 and 9, 18.3% are between the ages of 10 and 14, and 12.7% are between the ages
of 15 and 19.
Pathogenesis Medulloblastomas usually form in the vicinity
of the fourth ventricle, between the brainstem and the cerebellum.
Tumors with similar appearance and characteristics originate in other parts of the brain, but
they are not identical to medulloblastoma.
Although it is thought that medulloblastomas originate from immature or embryonal cells
at their earliest stage of development, the exact cell of origin, or "medulloblast" has
yet to be identified.
It is currently thought that medulloblastoma arises from cerebellar stem cells that have
been prevented from dividing and differentiating into their normal cell types.
This accounts for the varying histologic variants seen on biopsy.
Both perivascular pseudorosette and Homer-Wright rosette pseudorosettes formation are highly
characteristic of medulloblastoma and is seen in up to half of the cases.
Homer-Wright rosettes are pseudorosettes consisting of tumor cells surrounding a fibrillar area.
Also, the classic rosette with tumor cells around a central lumen can be seen.
Recent integrated genomic studies have revealed that medulloblastoma is composed of four distinct
molecular and clinical variants termed WNT, SHH, Group 3 and Group 4.
Of these subgroups WNT patients have an excellent prognosis and Group 3 have a dismal prognosis.
There also exists subgroup specific alternative splicing which further confirms the existence
of distinct subgroups and highlights the transcriptional heterogeneity between subgroups.
Medulloblastomas are also seen in Gorlin syndrome as well as Turcot syndrome.
Recurrent mutations in the genes CTNNB1, PTCH1, MLL2, SMARCA4, DDX3X, CTDNEP1, KDM6A and TBR1
were identified in individuals with medulloblastoma.
Clinical manifestation Symptoms are mainly due to secondary increased
intracranial pressure due to blockage of the fourth ventricle and are usually present for
1 to 5 months before diagnosis is made.
The child typically becomes listless, with repeated episodes of vomiting, and a morning
headache, which may lead to a misdiagnosis of gastrointestinal disease or migraine.
Soon after, the child will develop a stumbling gait, frequent falls, diplopia, papilledema,
and sixth cranial nerve palsy.
Positional dizziness and nystagmus are also frequent and facial sensory loss or motor
weakness may be present.
Decerebrate attacks appear late in the disease.
Extraneural metastasis to the rest of the body is rare, and generally occurs only after
craniotomy.
Diagnosis The tumor is distinctive on T1 and T2-weighted
MRI with heterogeneous enhancement and typical location adjacent to and extension into the
fourth ventricle.
Histologically, the tumor is solid, pink-gray in color, and is well circumscribed.
The tumor is very cellular, many mitoses, little cytoplasm, and has the tendency to
form clusters and rosettes.
Correct diagnosis of medulloblastoma may require ruling out atypical teratoid rhabdoid tumor
Treatment and prognosis Treatment begins with maximal resection of
the tumor.
The addition of radiation to the entire neuraxis and chemotherapy may increase the disease-free
survival.
There is some evidence that Proton beam irradiation provides some benefits in terms of reducing
the impact of radiation on the cochlear and cardiovascular areas and that it reduced the
cognitive late effects of cranial irradiation.
This combination may permit a 5 year survival in more than 80% of cases.
The presence of desmoplastic features such as connective tissue formation offers a better
prognosis.
Prognosis is worse if the child is less than 3 years old, there is an inadequate degree
of resection, or if there is any CSF, spinal, supratentorial or systemic spread.
Dementia post radiotherapy and chemotherapy is a common outcome appearing two to four
years following treatment.
Increased intracranial pressure may be controlled with corticosteroids or a ventriculoperitoneal
shunt.
Chemotherapy Chemotherapy is now an important part of treatment
for all patients with medulloblastoma.
It can significantly reduce risk of recurrence.
There are a couple of different chemotheraputic regimens for medulloblastoma, but most involve
a combination of lomustine, cisplatin, carboplatin, vincristine or cyclophosphamide.
In younger patients, chemotherapy can delay, or in some cases possibly even eliminate,
the need for radiotherapy.
Currently an NCI supported Phase I clinical trial involving the Curis/Genentech compound
vismodegib is being evaluated in pediatric medulloblastoma patients, and has been tested
in some PNET patients as well.
This compound targets a cellular signalling pathway of the cancer cells, which controls
how they divide and grow.
Outcome Prediction Based on Genomics Array-based karyotyping of 260 medulloblastomas
by Pfister S, et al. resulted in the following clinical subgroups based on cytogenetic profiles:
Poor prognosis: gain of 6q or amplification of MYC or MYCN
Intermediate: gain of 17q or an i(17q) without gain of 6q or amplfication of MYC or MYCN
Excellent prognosis: 6q and 17q balanced or 6q deletion
Transcriptional profiling show the existence of four main subgroups.
Very good prognosis: WNT group, CTNNB1 mutation Infants good prognosis, others intermediate:
SHH group, PTCH1SUFU mutation, GLI2 amplification, or MYCN amplification
Poor prognosis: Group 3, MYC amplification, photoreceptor/GABAergic gene expression
Intermediate prognosis: Group 4, gene expression of neuronal/glutamatergic, CDK6 amplification,
MYCN amplification Survival
The cumulative relative survival rate for all age groups and histology follow-up was
60%, 52%, and 47% at 5 years, 10 years, and 20 years, respectively.
Patients diagnosed with a medulloblastoma or PNET are 50 times more likely to die than
a matched member of the general population.
The most recent population-based 5-year relative survival rates are 69% overall, but 72% in
children and 67% in adults.
The 20 year survival rate is 51% in children.
Children and adults have different survival profiles, with adults faring worse than children
only after the 4th year post-diagnosis.
Before the 4th year, survival probabilities are nearly identical.
Longterm sequelae of standard treatment include hypothalamic-pituitary and thyroid dysfunction
and intellectual impairment.
The hormonal and intellectual deficits created by these therapies causes significant impairment
of the survivors.
Model Using gene transfer of SV40 large T-antigen
in neuronal precursor cells of rats, a brain tumor model was established.
The PNETs were histologically indistinguishable from the human counterparts and have been
used to identify new genes involved in human brain tumor carcinogenesis.
The model was used to confirm p53 as one of the genes involved in human medulloblastomas,
but since only about 10% of the human tumors showed mutations in that gene, the model can
be used to identify the other binding partners of SV40 Large T- antigen, other than p53.
See also primitive neuroectodermal tumor
malignant brain tumor References
Additional images
External links Samantha Dickson Brain Tumour Trust: UK brain
tumour research and support charity Brain and Spinal Tumors: Hope Through Research
Hypertext of Radiology article on medulloblastoma.html Collaborative Hypertext of Radiology article
on medulloblastoma at CHORUS Solving Kids Cancer
I'll get better tomorrow a documentary film following for 16 months the treatments of
3 children with medulloblastoma.
Medulloblastoma Images MedPix Medical Image Database
Cancer.Net: Medulloblastoma - Childhood