Endocrine Abstracts

Pituitary adenomas are not rare, with a prevalence of around 1/1000 population. However, their pathogenesis has defied decades of careful study. Many groups including our own have shown a plethora of changes within these tumours, with silencing, often epigenetic, of many tumour suppressors, suggesting activation of a pro-proliferative programme. However, apart from the Milan group’s Gsp mutation in somatotrophinomas no single mutational oncogenic event has been demonstrated. Many of the transcriptional and cell cycle-related changes appear to be secondary to overdrive of cell signalling pathways, but analysis of growth patterns does not indicate a step-wise series of oncogenic changes, but rather a growth process leading to a new steady state modulated by cell surface contact. In an analogous situation of a benign tumour with growth interrupted by long periods of quiescence, adamantinomatous craniopharyngiomas have been shown to contain clusters of cells which have stem cell characteristics. Many of these tumours, probably the great majority, show activating mutations of the proto-oncogene β-catenin, but the mutation is widespread and the translocation of β-catenin to the nucleus only occurs in the stem cells. In papillary craniopharyngiomas the dominant mutation is of BRAF. In animal models these mutant stem cells give rise to secondary tumours, and one may speculate that a similar process may occur in non-functioning pituitary tumours (NFPAs). Whole-exome sequencing of NFPAs reveal a different oncogenic mutation in each tumour, which does not generalise to other tumours. It is therefore hypothesised that NFPAs arise from stem cell mutations which lead to localised proliferation with no common oncogenic denominator: the stem cell originators may be sparsely present or even absent at the time of tumour presentation. Indeed, the origin of pituitary adenomas my lie far back in past development, the ‘potter’s hand’ having shaken in early embryogenesis or soon after.