Medulloblastoma

Medulloblastoma is a primary brain tumor that originates from the cerebellum or posterior fossa. Classified as a primitive neuroectodermal tumors, PNETs, due to medulloblastoma’s microscopic appearance of primitive appearing cells, which are small, round and blue, consisting of mainly nucleus and little to no cytoplasm.

Medulloblastoma is an aggressive brain tumor that invades adjacent structures and frequently metastasize to different parts of the body.

Medulloblastoma is the second most common tumor in children.

Medulloblastoma Information

Medulloblastoma.

Dhall G. Children’s Center for Cancer and Blood Diseases, Division of Pediatric Hematology-Oncology, Childrens Hospital Los Angeles, Los Angeles, CA 90027, USA. gdhall@chla.usc.edu

 J Child Neurol. 2009 Nov;24(11):1418-30.
Medulloblastoma is the most common malignant brain tumor in children. Patients with medulloblastoma are stratified into ”standard” and ”high” risk categories based on age at diagnosis, degree of surgical resection, and disease spread. In children older than 3 years of age, the long-term survival can be achieved in approximately 85% of standard risk patients and 70% of high risk patients with a combination of chemotherapy and irradiation. Younger children, particularly infants, are at a significantly higher risk of side-effects of treatment. Despite tremendous progress in the field of molecular biology of medulloblastoma, much remains to be achieved in understanding the pathogenesis, critical pathways responsible for medulloblastoma, and molecular risk stratification, and in devising treatment strategies with even better survival and less long-term sequelae.

Medulloblastoma Biology

Childhood medulloblastoma: current status of biology and treatment.

Klesse LJ, Bowers DC.  CNS Drugs. 2010 Apr;24(4):285-301.

Division of Pediatric Hematology-Oncology, Department of Pediatrics, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USA.

Medulloblastoma, a primitive neuro-ectodermal tumour that arises in the posterior fossa, is the most common malignant brain tumour occurring in childhood. Over the past half century, the long-term survival for children with medulloblastoma has improved remarkably from a certain fatal diagnosis to a cancer that is often curable. Although overall survival for children with non-disseminated and non-anaplastic medulloblastoma can approach 80%, the current multidisciplinary therapeutic approach is not without long-term sequelae. Chemotherapy has improved the long-term survival and allowed for reductions in the amount of radiation given, thereby reducing some of the long-term toxicities. In this review, we describe the current understanding of the basic biology of medulloblastoma and report on the current active chemotherapeutic agents utilized in medulloblastoma therapy. Ultimately, our understanding of the basic biology of medulloblastoma may lead to further advances in therapy by providing targets that are more specific and potentially less toxic.

Medulloblastoma Genetics

Genomics of medulloblastoma: from Giemsa-banding to next-generation sequencing in 20 years.

Northcott PA, Rutka JT, Taylor MD. Neurosurg Focus. 2010 Jan;28(1):E6.

Division of Neurosurgery, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, University of Toronto, Ontario, Canada.

Advances in the field of genomics have recently enabled the unprecedented characterization of the cancer genome, providing novel insight into the molecular mechanisms underlying malignancies in humans. The application of high-resolution microarray platforms to the study of medulloblastoma has revealed new oncogenes and tumor suppressors and has implicated changes in DNA copy number, gene expression, and methylation state in its etiology. Additionally, the integration of medulloblastoma genomics with patient clinical data has confirmed molecular markers of prognostic significance and highlighted the potential utility of molecular disease stratification. The advent of next-generation sequencing technologies promises to greatly transform our understanding of medulloblastoma pathogenesis in the next few years, permitting comprehensive analyses of all aspects of the genome and increasing the likelihood that genomic medicine will become part of the routine diagnosis and treatment of medulloblastoma.

Semin Radiat Oncol. 2010 Jan;20(1):58-66.

Brain tumors across the age spectrum: biology, therapy, and late effects.

Merchant TE, Pollack IF, Loeffler JS. Division of Radiation Oncology, St. Jude Children’s Research Hospital, Memphis, TN 38105-3678, USA.
The clinical difference between brain tumors in adults and children is striking. Compared with adults, pediatric tumor types (mostly glial and neuronal) are more sensitive to adjuvant irradiation and chemotherapy. Pediatric tumors more often require craniospinal irradiation based on their propensity to disseminate within the neuraxis. The spectrum of side effects is broader in the child based on age and extent of treatment: radiation therapy brings increased risk of severe long-term sequelae affecting neurologic, endocrine, and cognitive function. In this review of glioma, ependymoma, and medulloblastoma, we highlight the differences between adults and children, including the higher incidence of spinal cord ependymoma and supratentorial high-grade glioma in the adult and a higher incidence of medulloblastoma in the child. With the exception of completely resected low-grade glioma, radiation therapy remains a standard of care for most patients. In some settings, the radiation oncologist should suggest further surgery or additional adjuvant therapy in an effort to optimize local tumor control. An effort is underway to better characterize adult and pediatric brain tumors biologically with an emphasis on improving our understanding of tumor genesis, malignant transformation, and some of the similarities and differences between tumor types and their response to conventional therapy.

Brain cancer propagating cells: biology, genetics and targeted therapies.

Hadjipanayis CG, Van Meir EG. aboratory of Molecular Neuro-Oncology, Department of Neurosurgery, Emory University, School of Medicine, Atlanta, GA. 30322, USA. chadjip@emory.edu

Trends Mol Med. 2009 Nov;15(11):519-30. Epub 2009 Nov 2.

Cancer propagating cells (CPCs) within primary central nervous system (CNS) tumors (glioblastoma multiforme (GBM), medulloblastoma (MB) and ependymoma) might be integral to tumor development and perpetuation. These cells, also known as brain cancer propagating cells (BCPCs), have the ability to self-renew and proliferate. BCPCs can initiate new tumors in mice with high efficiency and these exhibit many features that are characteristic of patient’s brain tumors. Accumulating evidence suggests that BCPCs might originate from the transformation of neural stem cells (NSCs) and their progenitors. Furthermore, recent studies have shown that NSC surface markers also define BCPCs. Ultimately, treatments that include specific targeting of BCPCs might potentially be more effective at treating the entire tumor mass, translating to improved patient survival and quality of life.

Medulloblastoma: role of developmental pathways, DNA repair signaling, and other players.

Saran A. Biotechnologies, Agro-Industry and Health Protection Department, Ente per le Nuove tecnologie, l’Energia e l’Ambiente, Centro Ricerche Casaccia, 00123 Rome, Italy. anna.saran@enea.it

 Curr Mol Med. 2009 Dec;9(9):1046-57.

Medulloblastoma is a cerebellar tumor affecting children and young adults, and accounts for approximately one fifth of all pediatric brain tumors. Despite multimodal therapy that includes surgery, radiotherapy and chemotherapy, recurrence is frequent and overall mortality rate remains relatively high. Moreover, radiation therapy results in severe effects on intellect, and younger age of treatment correlates with larger deficits. Improvements in therapy of this childhood tumor will focus increasingly on the clarification of the exact cellular origin and the genetic mechanisms contributing to tumor formation, and on new targeted therapeutic options. Aberrant activation of the Hedgehog (Hh) and Wnt developmental pathways is associated with medulloblastoma, but deregulation of other molecular pathways, including insulin-like growth factor (IGF) signaling, has also been implicated in the pathogenesis of the tumor. Recent observations in mouse models have demonstrated the importance of genome surveillance, as defects in DNA repair pathways in animals can lead to genomic instability in neural progenitor cells, resulting in medulloblastoma. The current review will focus on the most recent findings on the molecular pathology of medulloblastoma and discuss their potential contribution to treatments directed by the molecular alterations.