Medulloblastoma
Encyclopedia
Medulloblastoma is a highly malignant
primary brain tumor
that originates in the cerebellum
or posterior fossa
.
Previously, medulloblastomas were thought to represent a subset of primitive neuroectodermal tumor (PNET) of the posterior fossa. However, gene expression profiling has shown that medulloblastomas have a distinct molecular profile and are distinct from other PNET tumors.
Tumors that originate in the cerebellum are referred to as infratentorial because they occur below the tentorium
, a thick membrane that separates the cerebral hemispheres of the brain from the cerebellum. Another term for medulloblastoma is infratentorial PNET. 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
(CSF) and frequently metastasize to different locations in the brain and spine.
s are the second most common malignancy among people under 20 years of age. Medulloblastoma is the most common malignant brain tumor, 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 (62%) than females (38%). Medulloblastoma and other PNET tumors 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.
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 from 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.
Molecular genetics reveal a loss of genetic information on the distal part of chromosome 17, distal to the p53
gene, possibly accounting for the neoplastic transformation of the undifferentiated cerebellar cells. Medulloblastomas are also seen in Gorlin syndrome as well as Turcot syndrome
. Other research has strongly implicated the JC virus
, the virus that causes multifocal leukoencephalopathy
.
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, 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 metastases to the rest of the body is rare, but usually only after craniotomy
.
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 (ATRT)
of the tumor. The addition of radiation to the entire neuraxis and chemotherapy
may increase the disease-free survival. 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
.
, cisplatin
, carboplatin
, vincristine
or cyclophosphamide
. In younger patients (less than 3–4 years of age), 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
(GDC-0449) 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.
of 260 medulloblastomas by Pfister S, et al. resulted in the following clinical subgroups based on cytogenetic profiles:
The most recent population-based (SEER) 5-year relative survival rates
are 69% overall, but 72% in children (1-9 years) and 67% in adults (20+ years). 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 (after controlling for increased background mortality). Before the 4th year, survival probabilities are nearly identical. Longterm sequalae 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.
Malignant
Malignancy is the tendency of a medical condition, especially tumors, to become progressively worse and to potentially result in death. Malignancy in cancers is characterized by anaplasia, invasiveness, and metastasis...
primary brain tumor
Brain tumor
A brain tumor is an intracranial solid neoplasm, a tumor within the brain or the central spinal canal.Brain tumors include all tumors inside the cranium or in the central spinal canal...
that originates in the cerebellum
Cerebellum
The cerebellum is a region of the brain that plays an important role in motor control. It may also be involved in some cognitive functions such as attention and language, and in regulating fear and pleasure responses, but its movement-related functions are the most solidly established...
or posterior fossa
Posterior cranial fossa
The posterior cranial fossa is part of the intracranial cavity, located between the foramen magnum and tentorium cerebelli. It contains the brainstem and cerebellum.This is the most inferior of the fossae. It houses the cerebellum, medulla and pons....
.
Previously, medulloblastomas were thought to represent a subset of primitive neuroectodermal tumor (PNET) of the posterior fossa. However, gene expression profiling has shown that medulloblastomas have a distinct molecular profile and are distinct from other PNET tumors.
Tumors that originate in the cerebellum are referred to as infratentorial because they occur below the tentorium
Tentorium cerebelli
The tentorium cerebelli or cerebellar tentorium is an extension of the dura mater that separates the cerebellum from the inferior portion of the occipital lobes.-Anatomy:...
, a thick membrane that separates the cerebral hemispheres of the brain from the cerebellum. Another term for medulloblastoma is infratentorial PNET. 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
Cerebrospinal fluid
Cerebrospinal fluid , Liquor cerebrospinalis, is a clear, colorless, bodily fluid, that occupies the subarachnoid space and the ventricular system around and inside the brain and spinal cord...
(CSF) and frequently metastasize to different locations in the brain and spine.
Incidence
Brain tumorBrain tumor
A brain tumor is an intracranial solid neoplasm, a tumor within the brain or the central spinal canal.Brain tumors include all tumors inside the cranium or in the central spinal canal...
s are the second most common malignancy among people under 20 years of age. Medulloblastoma is the most common malignant brain tumor, 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 (62%) than females (38%). Medulloblastoma and other PNET tumors 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 from 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.
Molecular genetics reveal a loss of genetic information on the distal part of chromosome 17, distal to the p53
P53
p53 , is a tumor suppressor protein that in humans is encoded by the TP53 gene. p53 is crucial in multicellular organisms, where it regulates the cell cycle and, thus, functions as a tumor suppressor that is involved in preventing cancer...
gene, possibly accounting for the neoplastic transformation of the undifferentiated cerebellar cells. Medulloblastomas are also seen in Gorlin syndrome as well as Turcot syndrome
Turcot syndrome
Mismatch repair cancer syndrome is a condition associated with biallelic DNA mismatch repair mutations. It is also known as Turcot syndrome after Jacques Turcot who described the condition in 1959.-Genetics:...
. Other research has strongly implicated the JC virus
JC virus
The JC virus or John Cunningham virus is a type of human polyomavirus and is genetically similar to BK virus and SV40. It was discovered in 1971 and named using the two initials of a patient with progressive multifocal leukoencephalopathy...
, the virus that causes multifocal leukoencephalopathy
Progressive multifocal leukoencephalopathy
Progressive multifocal leukoencephalopathy , also known as progressive multifocal leukoencephalitis, is a rare and usually fatal viral disease that is characterized by progressive damage or inflammation of the white matter of the brain at multiple locations .It occurs almost exclusively in...
.
Clinical manifestation
Symptoms are mainly due to secondary increased intracranial pressureIntracranial pressure
Intracranial pressure is the pressure inside the skull and thus in the brain tissue and cerebrospinal fluid . The body has various mechanisms by which it keeps the ICP stable, with CSF pressures varying by about 1 mmHg in normal adults through shifts in production and absorption of CSF...
due to blockage of the fourth ventricle
Fourth ventricle
The fourth ventricle is one of the four connected fluid-filled cavities within the human brain. These cavities, known collectively as the ventricular system, consist of the left and right lateral ventricles, the third ventricle, and 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, the child will develop a stumbling gait, frequent falls, diplopia
Diplopia
Diplopia, commonly known as double vision, is the simultaneous perception of two images of a single object that may be displaced horizontally, vertically, or diagonally in relation to each other...
, papilledema
Papilledema
Papilledema is optic disc swelling that is caused by increased intracranial pressure. The swelling is usually bilateral and can occur over a period of hours to weeks. Unilateral presentation is extremely rare....
, and sixth cranial nerve palsy. Positional dizziness and nystagmus are also frequent and facial sensory loss or motor weakness may be present. Decerebrate
Decerebrate
Decerebration is the elimination of cerebral brain function in an animal by removing the cerebrum, cutting across the brain stem, or severing certain arteries in the brain stem....
attacks appear late in the disease.
Extraneural metastases to the rest of the body is rare, but usually only after craniotomy
Craniotomy
A craniotomy is a surgical operation in which a bone flap is temporarily removed from the skull to access the brain. Craniotomies are often a critical operation performed on patients recording, brain imaging, and for neurological manipulations such as electrical stimulation and chemical...
.
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 (ATRT)
Treatment and prognosis
Treatment begins with maximal resectionResection
Resection may refer to:*Segmental resection , the partial removal of an organ or other body structure*Resection , a means of establishing a location...
of the tumor. The addition of radiation to the entire neuraxis and chemotherapy
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
may increase the disease-free survival. 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
Shunt (medical)
In medicine, a shunt is a hole or a small passage which moves, or allows movement of fluid from one part of the body to another. The term may describe either congenital or acquired shunts; and acquired shunts may be either biological or mechanical.* Cardiac shunts may be described as...
.
Chemotherapy
Chemotherapy is now an important part of treatment for all patients with medulloblastoma. It can significantly reduce risk of recurrence (which is typically fatal). There are a couple of different chemotheraputic regimens for medulloblastoma, but most involve a combination of lomustineLomustine
Lomustine is an alkylating nitrosourea compound used in chemotherapy. It is in the same family as streptozotocin. This is a highly lipid soluble drug, and thus crosses the blood brain barrier. This property makes it ideal for treating brain tumors, and is its primary use...
, cisplatin
Cisplatin
Cisplatin, cisplatinum, or cis-diamminedichloroplatinum is a chemotherapy drug. It is used to treat various types of cancers, including sarcomas, some carcinomas , lymphomas, and germ cell tumors...
, carboplatin
Carboplatin
Carboplatin, or cis-Diammineplatinum is a chemotherapy drug used against some forms of cancer...
, vincristine
Vincristine
Vincristine , formally known as leurocristine, sometimes abbreviated "VCR", is a vinca alkaloid from the Catharanthus roseus , formerly Vinca rosea and hence its name. It is a mitotic inhibitor, and is used in cancer chemotherapy.-Mechanism:Tubulin is a structural protein that polymerizes to...
or cyclophosphamide
Cyclophosphamide
Cyclophosphamide , also known as cytophosphane, is a nitrogen mustard alkylating agent, from the oxazophorines group....
. In younger patients (less than 3–4 years of age), 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
Vismodegib
Vismodegib is an investigational drug for the treatment of various types of cancer. It has completed a Phase II clinical trial for metastasizing basal-cell carcinoma and is in Phase II trials for metastatic colorectal cancer, small-cell lung cancer, advanced stomach cancer, pancreatic cancer,...
(GDC-0449) 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 Cytogenetic Subgroups
Array-based karyotypingVirtual Karyotype
Virtual karyotype detects genomic copy number variations at a higher resolution level than conventional karyotyping or chromosome-based comparative genomic hybridization .-Background:...
of 260 medulloblastomas by Pfister S, et al. resulted in the following clinical subgroups based on cytogenetic profiles:
- Poor prognosis: gain of 6qChromosome 6 (human)Chromosome 6 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 6 spans more than 170 million base pairs and represents between 5.5 and 6% of the total DNA in cells...
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
Survival
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 (SEER) 5-year relative survival rates
Five-year survival rate
The five-year survival rate is a term used in medicine for estimating the prognosis of a particular disease.Analysis performed against the Surveillance, Epidemiology, and End Results database facilitates calculation of Five-year survival rates....
are 69% overall, but 72% in children (1-9 years) and 67% in adults (20+ years). 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 (after controlling for increased background mortality). Before the 4th year, survival probabilities are nearly identical. Longterm sequalae 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.External links
- Samantha Dickson Brain Tumour Trust: brain tumour research and support charity
- Brain and Spinal Tumors: Hope Through Research (National Institute of Neurological Disorders and Stroke)
- Medulloblastoma support resources
- HELP KIDS NOW WITH MEDULLOBLASTOMA
- I'll get better tomorrow (2009) a documentary film following for 16 months the treatments of 3 children with medulloblastoma.
- Medulloblastoma Images MedPix Medical Image Database
- Latest news and research on medulloblastoma