Medulloblastoma

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(medicine) A malignant neoplasm of the brain with a tendency to metastasize in the meninges.

Key Terms: Ataxia, Cerebellum, Chemotherapy.

Definition

Medulloblastoma is a solid, cancerous tumor originating in the cerebellum of the brain. It is also known as a primitive neuroendocrine tumor.

Description

Medulloblastoma is the most common cancerous brain tumor of childhood. It accounts for 20% to 25% of all childhood tumors. Medulloblastomas can occur soon after birth and into puberty, but most tumors occur either before age ten or sometime in the late teens or early twenties. If these tumors are left untreated, they can spread to other areas of the brain and to the spine.

Medulloblastomas occur in the area of the brain known as the cerebellum. The cerebellum, located in the back of the brain above the neck, is the area of the brain responsible for controlling and integrating movement. A person could move his or her muscles without the aid of the cerebellum, but those movements would be clumsy and disorganized. Medulloblastoma tumors in the cerebellum can cause loss of functioning of the cerebellum, leading to this uncoordinated movement, called cerebellar ataxia.

If medulloblastomas are not detected early, they may spread cancer throughout the brain or spinal cord. If the cancer spreads to the spinal cord, a child may begin experiencing severe back pain, difficulty walking, and the inability to control bladder and bowel functions.

Demographics

As stated earlier, medulloblastoma is a childhood cancer, occurring mainly in the first ten years of life. About half of all medulloblastomas occur in children aged five or younger. Boys tend to develop the tumors more than girls at a rate of approximately two to one. There are no current studies comparing the incidence of medulloblastoma between different racial and ethnic groups.

Causes and Symptoms

Besides being male, there are no other known risk factors for medulloblastoma. This type of tumor can occur in association with two rare types of genetically linked family cancer syndromes. Gorlin's syndrome and Turcot's syndrome. Gorlin's syndrome is caused by a defect in a gene known as PTC located on chromosome 9. This defect can cause medulloblastoma as well as cancers of the skin and ovary. Turcot's syndrome is caused by a defective gene known as APC, and can present with cancer of the intestinal tract as well as medulloblastoma. It should again be stated that both of these syndromes are quite rare and only account for a fraction of medulloblastoma cases seen and reported.

Medulloblastoma can present in many ways. In infants, symptoms of the tumor can include an unusual increase in head size, vomiting, irritability, and lethargy. Since all infants generally have these symptoms at one time or another, it can be difficult for a parent or even a health care worker to recognize the initial presentation of medulloblastoma in babies and toddlers.

In older children and teenagers, medulloblastoma can present the same as in infants or much differently. Non-specific symptoms such as nausea and vomiting, headache, and vague visual disturbances can be the first sign of a tumor in the cerebellum. Other, more striking signs can be double vision, sudden difficulty writing, and problems walking and moving that worsen over time.

Diagnosis

The diagnosis of medulloblastoma is made with both clinical observation and imaging studies. If a parent has noticed some of the signs and symptoms listed above, then a visit to a pediatrician is certainly warranted. During the office visit, various specialized neurological tests will be done to see if there is any sign of a problem in the cerebellum or surrounding brain structures.

If there are indications of a tumor, then imaging studies can be done to see if a tumor can be detected. The two types of imaging studies done to detect medulloblastoma are magnetic resonance imaging (MRI) and computed tomography (CT) scan. The MRI uses a high-strength magnetic field to visualize the brain, and is very useful for detecting medulloblastomas. The CT scan uses x-ray images reconstructed by computer. Like the MRI, a CT scan is also useful for detecting brain tumors as well as tumors that may have spread to the spine.

Treatment Team

The treatment of medulloblastoma is optimally carried out in a medical center that has experience in treating this often difficult-to-treat cancer. Treatment and treatment planning is usually carried out by a multidisciplinary team of cancer specialists, including a pediatric oncologist (a doctor specializing in the treatment of childhood cancers), a pediatric neurosurgeon (a doctor specializing in childhood brain surgery), as well as a pediatric neurologist and radiation oncologist (a doctor specializing in the use of radiation to treat cancer).

Clinical Staging, Treatment, and Prognosis

The staging of childhood brain tumors has become important to the selection of treatment plans, as well as giving information to make a more accurate prognosis. For medulloblastoma, there are four stages defined, as follows:

• T1: the tumor is less than 3 cm in diameter.
• T2: the tumor is greater than 3 cm in diameter and has invaded one other brain structure in addition to the cerebellum.
• T3: the tumor has invaded two other brain structures besides the cerebellum.
• T4: the tumor has spread down into the midbrain or upper spinal cord.

The treatment options for medulloblastoma have changed significantly over the past few decades. The first treatment option for medulloblastoma was surgery, and this is still the most common treatment. Surgeons try to remove the entire tumor, although this is sometimes not possible. After the surgery is completed, further treatment will depend upon whether or not the child has been placed in an "average risk" or "high risk" group. An average-risk child is defined as three years or older, with the tumor initially confined to the cerebellum with little to no tumor left after surgery. A high-risk child is defined as a child under three years of age, with the tumor initially spread into other areas of the brain besides the cerebellum, and with some of the tumor remaining in the brain after surgery.

Children in the average-risk group will often have radiation therapy applied to the area in their brain where the medulloblastoma tumor was, especially if the surgeon was not able to remove all of the tumor. Using radiation on children younger than three years may result in the child having growth retardation along with learning disabilities.

Because of the possible side effect of radiation, especially in children younger than three years of age, the use of certain medications called chemotherapy is being used more frequently for medulloblastoma. Researchers have found that medulloblastoma tumors are highly sensitive to chemotherapy, giving hope that chemotherapy can be used instead of radiation, especially for children at average risk. For children at high risk, the current recommendation is to use both radiation and chemotherapy, since this combination has been shown to improve overall survival rates for high-risk children.

In 1930, the anticipated survival rate for a child with medulloblastoma after surgery was less than 2%. Today, with the use of better surgical techniques, radiation, and chemotherapy, the prognosis for children in the average risk group has increased to a 60% survival rate over a five-year period. Children in the high-risk group do not fare as well, having a 30% to 35% survival rate over a five-year period.

Alternative and Complementary Therapies

Alternative and complementary therapies are those that fall outside the scope of traditional, first-line therapies such as surgery, chemotherapy and radiation. Complementary therapies are meant to supplement those traditional therapies with the objective of relieving symptoms. Alternative therapies are nontraditional, unproven attempts to cure the disease.

Common complementary therapies used in many types of cancer include aromatherapy, massage, meditation, music therapy, prayer, and certain forms of exercise. These therapies have the objective of reducing anxiety and increasing a patient's feeling of well-being.

Numerous alternative therapies exist in cancer treatment. Plant extracts, vitamins, protein therapies, and natural substances such as mistletoe and shark cartilage have all been touted as cancer-fighting remedies. However, some alternative therapies, such as Laetrile, can produce dangerous side effects and have shown no anticancer activity in clinical trials. Patients interested in alternative therapies should consult their doctors to ensure that the products are safe, especially for children, and do not interfere with regular cancer treatment.

Coping With Cancer Treatment

During treatment, a child's health will be followed by the team of physicians involved. Those physicians will be able to monitor the child for any side effects from the treatments, especially if the child is receiving chemotherapy. The most frequent side effects of chemotherapy can include nausea and vomiting, diarrhea, fatigue, and hair loss (alopecia). With medications, physicians can often treat some of the side effects, especially nausea, vomiting, and diarrhea.

Cancer treatment can be especially frightening for a young child. Family support is critical, and parents should consult their physicians about any organizations in the area that can help their child cope with the effects of medulloblastoma and its treatment.

Clinical Trials

There are many clinical trials being done to help better the treatment options for medulloblastoma. Some of the most promising ones are studies in which peripheral stem cell transplantation is used. This is a technique in which certain cells in the body known as stem cells are used to replace other, depleted cells, such as the immune cells and blood cells that are destroyed when chemotherapy is used. It is hoped that with stem cell use, physicians will be able to use higher doses of chemotherapy in order to destroy the medulloblastoma cancer.

Prevention

There are currently no known ways to prevent medulloblastoma. Those who have the very rare genetic disorders which predisposes them to medulloblastoma, Gorlin's and Turcot's syndrome, should be especially aware of any signs or symptoms of medulloblastomas. Children of parents with these genetic disorders should have routine screening done by a pediatrician for any signs of a brain tumor.

Resources

Books

Abeloff, Martin, James O. Armitage, Allen S. Lichter, and John E. Niederhuber. Clinical Oncology. New York: Churchill Livingstone, 2000.

Organizations

American Brain Tumor Association. Suite 146, 2720 River Rd., Des Plaines, IL 60018. (800) 886-2282. .

National Cancer Institute, National Institutes of Health. Building 31, Room 10A31, 31 Center Dr., MSC 2580, Bethesda, MD 20892-2580. (800) 4-CANCER. .

St. Jude Children's Research Hospital. 332 N. Lauderdale St., Memphis, TN 38105. (901) 495-3300. .

Other

National Cancer Institute CancerTrials. [cited July 23, 2005]. .

—Edward R. Rosick, D.O., M.P.H.

A brain tumor composed of medulloblasts.

Medulloblastoma
Classification and external resources
CT scan, showing a tumorous mass in the posterior fossa, giving rise to obstructive hydrocephalus, in a six year old girl.
ICD-O:	M9470/3
OMIM	155255
DiseasesDB	31105
eMedicine	neuro/624  ped/1396 radio/434
MeSH	D008527

Medulloblastoma is a highly malignant primary brain tumor that originates in the cerebellum or posterior fossa.

Originally considered to be a glioma, medulloblastoma is now known to be of the family of cranial primitive neuroectodermal tumors (PNET).^[1]

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.^[2]

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.

Contents 1 Incidence 2 Pathogenesis 3 Clinical manifestation 4 Diagnosis 5 Treatment and prognosis 5.1 Outcome Prediction Based on Cytogenetic Subgroups 6 Model 7 References 8 Additional images 9 External links

Incidence

Brain tumors are the second most common malignancy among children less than 20 years of age. Medulloblastoma is the most common malignant brain tumor, comprising 14.5% of newly diagnosed cases.^[3] In adults, medulloblastoma is rare, comprising less than 2% of CNS malignancies.^[4]

The incidence of childhood medulloblastoma is higher in males (62%) than females (38%). ^[5] 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. ^[6]

Pathogenesis

Medulloblastomas usually form in 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. ^[7]

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.^{[citation needed]}

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 formation are highly characteristic of medulloblastoma and is seen in up to half of the cases.

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.

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, 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.

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)^[8] and primitive neuroectodermal tumor (PNET).

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. 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.

Increased intracranial pressure may be controlled with corticosteroids or a ventriculoperitoneal shunt.

Main article: intracranial pressure

Outcome Prediction Based on Cytogenetic Subgroups

Array-based karyotyping of 260 medulloblastomas by Pfister S, et al. resulted in the following clinical subgroups based on cytogenetic profiles^[9]:

• 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

See also: Virtual Karyotype

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. ^[10]. 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. ^[11]

References

1. ^ George Jallo, MD, Medulloblastoma, eMedicine 2007.
2. ^ Chris Hinz, Deneen Hesser, Focusing On Brain Tumors: Medulloblastoma, American Brain Tumor Association 2006, ISBN 0-944093-67-1.
3. ^ James G. Gurney, Malcolm A. Smith, Greta R. Bunin, CNS and Miscellaneous Intracranial and Intraspinal Neoplasms, SEER Pediatric Monograph, National Cancer Institute
4. ^ Selected Primary Brain and Central Nervous System Tumor Age-Specific Incidence Rates, Central Brain Tumor Registry of the United States, 1998-2002.
5. ^ Selected Childhood Primary Brain and Central Nervous System Tumor Incidence Rates by Major Histology Groupings, Histology and Gender Central Brain Tumor Registry of the United States, 1998-2002.
6. ^ Selected Childhood Primary Brain and Central Nervous System Tumor Age-Specific Incidence Rates, Central Brain Tumor Registry of the United States, 1998-2002.
7. ^ Roger Packer M.D, Medulloblastoma Clinical Trials and Noteworthy Treatments for Brain Tumors 2002.
8. ^ Burger PC; Yu I, Tihan T, et al. (1998). "Atypical teratoid rhabdoid tumors of the central nervous system: a highly malignant tumor of infancy and childhood frequently mistaken for medulloblastoma: a Pediatric Oncology Group Study." (in English). Am J Surg Pathol 1998 22 (22:): 1083–92. doi:10.1097/00000478-199809000-00007. 
9. ^ Pfister S, et al. Outcome Prediction in Pediatric Medulloblastoma based on DNA Copy Number Aberrations of Chromosomes 6q and 17q and the MYC and MYCN Loci. J Clin Oncol 2009 Apr(27)10;1627-1636.
10. ^ Eibl RH, Kleihues P, Jat PS, Wiestler OD (1994) A model for primitive neuroectodermal tumors in transgenic neural transplants harboring the SV40 large T antigen. Am J Pathol. 1994 Mar;144(3):556-64.
11. ^ Ohgaki H, Eibl RH, Wiestler OD, Yasargil MG, Newcomb EW, Kleihues P: p53 mutations in nonastrocytic human brain tumors. Cancer Res (1991) 51:6202-5

Additional images

Cerebellar medulloblastoma (1) in adult

Cerebellar medulloblastoma (2) in adult

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
• 00905 at CHORUS
• 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

v • d • e Nervous tissue tumors/nervous system neoplasm/Neuroectodermal tumor (ICD-O 9350-9589) / brain tumors (C69-C72/D31-D33, 190-192/224-225) Endocrine (9350-9379) Craniopharyngioma · Pinealoma Glioma (9380-9489) Astrocyte Astrocytoma (Pilocytic astrocytoma, Glioblastoma multiforme) Oligodendrocyte Oligodendroglioma Ependyma/choroid plexus Ependymoma · Choroid plexus papilloma · Choroid plexus tumor Multiple/unknown Oligoastrocytoma · Gliomatosis cerebri · Gliosarcoma Neuroepitheliomatous (9490-9529) Mature neuron Ganglioneuroma: Ganglioglioma · Retinoblastoma · Neurocytoma · Dysembryoplastic neuroepithelial tumour PNET Neuroblastoma (Esthesioneuroblastoma, Ganglioneuroblastoma) · Medulloblastoma · Atypical teratoid rhabdoid tumor Meningiomas (meninges) (9530-9539) Meningioma Nerve sheath tumor (9540-9579) Neurofibroma (Neurofibrosarcoma, Neurofibromatosis) · Schwannoma · Neurinoma · Acoustic neuroma · Neuroma · Malignant peripheral nerve sheath tumor Blood/vascular Primary central nervous system lymphoma · Hemangioblastoma Other Eye note: not all brain tumors are of nervous tissue, and not all nervous tissue tumors are in the brain see also non-congenital, congenital

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