Biological Behaviour of Craniopharyngiomas

Jakob Erdheim (1874-1937) first described craniopharyn-giomas (CPs) as "hypophyseal duct tumours" and postulated the existence of two tumour types based on their histological features: (1) an aggressive type showing similarities to adamantinomas (tumours of the jaw) and (2) a more benign form characterised by the presence of papillary structures. More than a century later, these initial observations have been confirmed; based on their distinct genetic, epigenetic, and histological features, the WHO classifies CPs into two types: adamantinomatous CPs (ACPs) and papillary CPs (PCPs). Considerable knowledge has been generated on the biology of CPs in the last 20 years. Mutations in CTNNB1 (encoding β-catenin) are prevalent in ACP, whilst PCPs frequently harbour mutations in BRAF (p.BRAF-V600E). The consequence of these mutations is the activation of either the WNT/β-catenin (ACP) or the MAPK/ERK (PCP) pathway. Murine models support a critical role for these mutations in tumour formation and have provided important insights into tumour pathogenesis, mostly in ACP. A critical role for cellular senescence has been uncovered in murine models of ACP with relevance to human tumours. Several gene profiling studies of human and murine ACP tumours have identified potential targetable pathways, and novel therapeutic agents are being used in clinical and pre-clinical research, in some cases with excellent results. In this review, we will present the accumulated knowledge on the biological features of these tumours and summarise how these advances are being translated into potential novel treatments.