Abstract
The revised WHO classification of tumors of the CNS 2016 has introduced the concept of the integrated diagnosis. The definition of medulloblastoma entities now requires a combination of the traditional histological information with additional molecular/genetic features. For definition of the histopathological component of the medulloblastoma diagnosis, the tumors should be assigned to one of the four entities classic, desmoplastic/nodular (DNMB), extensive nodular (MBEN), or large cell/anaplastic (LC/A) medulloblastoma. The genetically defined component comprises the four entities WNT-activated, SHH-activated and TP53 wildtype, SHH-activated and TP53 mutant, or non-WNT/non-SHH medulloblastoma. Robust and validated methods are available to allow a precise diagnosis of these medulloblastoma entities according to the updated WHO classification, and for differential diagnostic purposes. A combination of immunohistochemical markers including β-catenin, Yap1, p75-NGFR, Otx2, and p53, in combination with targeted sequencing and copy number assessment such as FISH analysis for MYC genes allows a precise assignment of patients for risk-adapted stratification. It also allows comparison to results of study cohorts in the past and provides a robust basis for further treatment refinement.
Highlights
Since the last version of the WHO classification of tumors of the CNS was published in 2007, knowledge on genetic alterations and biological features of medulloblastoma has rapidly increased bygenome- and transcriptome-wide studies
The definition of medulloblastoma entities requires a combination of the traditional histological information with additional molecular/genetic features
RNA expression studies and DNA methylation profiling have led to the identification of “biological” variants of medulloblastoma defined by predominant signalling pathways and DNA methylation patterns associated to their cellular origin [24]
Summary
Since the last version of the WHO classification of tumors of the CNS was published in 2007, knowledge on genetic alterations and biological features of medulloblastoma has rapidly increased by (epi)genome- and transcriptome-wide studies. RNA expression studies and DNA methylation profiling have led to the identification of “biological” variants of medulloblastoma defined by predominant signalling pathways and DNA methylation patterns associated to their cellular origin [24] These molecular subgroups overlap with histological features in some cases but are discordant in others. Most CNS tumor entities are still classified on only histopathological features, but in medulloblastoma, the definition of disease entities requires an integration of additional molecular information This approach improves the definition of the medulloblastoma entities, reduces the interobserver variability in diagnostics, and allows a better selection of patients for treatment stratification as well as improved prediction of treatment response and prognosis. The fourth genetically defined entity represents the majority of medulloblastomas lacking either WNT or SHH pathway activation (non-WNT/non-SHH medulloblastomas) These tumors seem to lack recurrent mutations but show frequent chromosomal copy number alterations such as isochromosome 17q. It allows comparison to results of study cohorts in the past and provides a robust basis for further treatment refinement
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