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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 primitive neuroectodermal tumor (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.
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 (of which medulloblastomas are the majority) 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 (62%) than females (38%), 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.
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.
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.
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.
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.
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 Genomics
- 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 (Wnt, Shh, Group 3, and Group 4).
- Very good prognosis: WNT group, CTNNB1 mutation
- Infants good prognosis, others intermediate: SHH group, PTCH1/SMO/SUFU 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
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 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.
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.
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