Identification of novel pathways involved in the pathogenesis of human adamantinomatous craniopharyngioma

Activating mutations in the gene encoding β-catenin have been identified in the paediatric form of human craniopharyngioma (adamantinomatous craniopharyngioma, ACP), a histologically benign but aggressive pituitary tumour accounting for up to 10% of paediatric intracranial tumours. Recently, we generated an ACP mouse model and revealed that, as in human ACP, nucleocytoplasmic accumulation of β-catenin (β-catnc) and over-activation of the Wnt/β-catenin pathway occurs only in a very small proportion of cells, which form clusters. Here, combining mouse genetics, fluorescence labelling and flow-sorting techniques, we have isolated these cells from tumorigenic mouse pituitaries and shown that the β-catnc cells are enriched for colony-forming cells when cultured in stem cell-promoting media, and have longer telomeres, indicating shared properties with normal pituitary progenitors/stem cells (PSCs). Global gene profiling analysis has revealed that these β-catnc cells express high levels of secreted mitogenic signals, such as members of the SHH, BMP and FGF family, in addition to several chemokines and their receptors, suggesting an important autocrine/paracrine role of these cells in the pathogenesis of ACP and a reciprocal communication with their environment. Finally, we highlight the clinical relevance of these findings by showing that these pathways are also up-regulated in the β-catnc cell clusters identified in human ACP. As well as providing further support to the concept that pituitary stem cells may play an important role in the oncogenesis of human ACP, our data reveal novel disease biomarkers and potential pharmacological targets for the treatment of these devastating childhood tumours.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-012-0957-9) contains supplementary material, which is available to authorized users

Bifocal extra- and intradural melanocytoma of the spine: case report and literature review

BACKGROUND: Spinal melanocytoma is one of the most infrequent space-occupying lesions of the central nervous system. To the best of our knowledge, this is the first report of primary bifocal intradural melanocytoma of heterogenous pathological grade to date. CASE DESCRIPTION: We report the case of a 43-year old patient with primary bifocal melanocytoma, clinically and radiologically resembling benign schwannoma. The patient presented with myeloradiculopathy of the left C3 dermatome. Magnetic resonance imaging of the upper spine revealed two space-occupying lesions with paraspinal extension, initially diagnosed as neurofibroma. Definitive histopathological classification of both lesions was melanocytoma. Both tumours were only partially removed due to adherence to surrounding structures. The patient underwent stereotactic external beam irradiation (EBR). Follow-up at 1 year after surgery revealed no recurrence and the patient remained free of symptoms. The clinical, radiological and pathological features of this rare tumour entity are presented and the available literature is reviewed. CONCLUSIONS: Intradural melanocytoma, although exceedingly rare, requires a thorough work-up to exclude malignant melanoma. With only two previous reports of multifocal melanocytoma published in the literature, standard therapy has not yet been established and complete surgical removal remains the modality of choice. Patients should be closely monitored to detect local recurrence or malignant degeneration. EBR may be considered in cases where total excision is not achievable and reduces risk of local recurrences