Investigate the clinicopathological characteristics at the initial diagnosis of the pituitary tumor and at pituitary carcinoma (PC) diagnosis, alongside with the management and outcomes of PCs, and identify potential prognostic factors and therapeutic strategies associated with the clinical outcome.Pubmed was searched in May 2021 for articles in English and French reporting PCs, of which diagnosis was made on the presence of metastases. The cases without histological proof and with either another cancer present or an atypical history for a pituitary tumor, were excluded. 181 articles reporting 207 cases were included, of which 38% corticotroph and 29% lactotroph carcinomas. An initial Ki67 index ≥10% was associated with shorter survival after the initial diagnosis (p=0.01). Cases with early metastases were associated with both higher initial Ki67 index (p=0.01) and shorter survival after PC diagnosis (p=0.001). Interestingly, cases with short survival after PC diagnosis were associated with shorter time between the initial diagnosis and PC diagnosis (p=0.0006), and had both higher initial Ki67 index (p=0.003), and higher Ki67 index of the metastasis (p=0.03). In addition, cases with long survival after PC diagnosis had received more frequently both systemic treatment after PC diagnosis (p=0.0005), and local treatment for metastases (p<0.0001). An initial Ki67 index ≥10% is associated with worse outcome, and appears as a promising early marker of future metastasis. Its presence should lead to an intensified surveillance and to a more timely management. Clinicians should not hesitate to use local treatment, independent of whether systemic treatment is used.
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Perrine Raymond, Gerald Raverot, and Mirela-Diana Ilie
Audrey Ziverec, Marie Chanal, Perrine Raymond, Mirela Diana Ilie, Dario De Alcubierre, Arja Pasternack, Olli Ritvos, Gerald Raverot, and Philippe Bertolino
Pituitary tumours are benign neoplasms that derive from hormone-producing cells of the pituitary gland. While medical treatments have emerged for most subtypes, gonadotroph tumours that express follicle-stimulating hormone (FSH) and/or luteinizing hormone still lack therapeutic options apart from surgery and radiotherapy. Activin ligands are physiological regulators of production and secretion of FSH by gonadotroph cells, but their role in gonadotroph tumourigenesis remains little explored. Using the LβT2 mouse gonadotroph cell line which produces FSH under activin stimulation, we first tested whether subcutaneous xenografts of LβT2 cells resulted in tumour formation in Rag2KO mice. Histological analysis confirmed the presence of LβT2 tumours with endothelial cells and macrophages in their microenvironment. FSH expression was found in a subset of clusters of LβT2 cells in the tumours. We subsequently addressed the consequences of targeting activin signalling via injection of a soluble activin decoy receptor (sActRIIB-Fc). sActRIIB-Fc treatment resulted in significantly decreased LβT2 tumour volume. Reduced Smad2 phosphorylation as well as inhibition of tumour-induced FSH production confirmed the efficient targeting of activin-downstream signalling in treated tumours. More interestingly, treated tumours showed significantly fewer endothelial cells associated with reduced Vegfa expression. In vitro treatment of LβT2 cells with sActRIIB-Fc had no effect on cell proliferation or apoptosis, but Vegfa expression was inhibited, pointing to a likely paracrine effect of LβT2 cells on endothelial cells through activin-mediated Vegfa regulation. Further in vitro and in vivo studies are now needed to pinpoint the exact roles of activin signalling in these processes prior to translating these observations to the clinic.