Medulloblastoma - Pathogenesis

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.

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.