Medulloblastoma

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.

Incidence
Brain tumors 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 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)

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. 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 (which is typically fatal). 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 (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.

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 :
 * 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

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 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 virtually identical.

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.