Aggressive pituitary tumours and pituitary carcinomas

Abstract

Although usually benign, anterior pituitary tumours occasionally exhibit aggressive behaviour, with invasion of surrounding tissues, rapid growth, resistance to conventional treatments and multiple recurrences. In very rare cases, they metastasize and are termed pituitary carcinomas. The time between a ‘classical’ pituitary tumour and a pituitary carcinoma can be years, which means that monitoring should be performed regularly in patients with clinical (invasion and/or tumour growth) or pathological (Ki67 index, mitotic count and/or p53 detection) markers suggesting aggressiveness. However, although both invasion and proliferation have prognostic value, such parameters cannot predict outcome or malignancy without metastasis. Future research should focus on the biology of both tumour cells and their microenvironment, hopefully with improved therapeutic outcomes. Currently, the initial therapeutic approach for aggressive pituitary tumours is generally to repeat surgery or radiotherapy in expert centres. Standard medical treatments usually have no effect on tumour progression but they can be maintained on a long-term basis to, at least partly, control hypersecretion. In cases where standard treatments prove ineffective, temozolomide, the sole formally recommended treatment, is effective in only one-third of patients. Personalized use of emerging therapies, including peptide receptor radionuclide therapy, angiogenesis-targeted therapy and immunotherapy, will hopefully improve the outcomes of patients with this severe condition. Anterior pituitary tumours (APTs) are usually benign but sometimes exhibit aggressive behaviour. In very rare cases, they metastasize and are termed pituitary carcinomas. Here, the authors provide an overview of APTs and pituitary carcinomas, including their epidemiology, diagnosis, predictive markers, and current and emerging therapeutic approaches. Aggressive pituitary tumours are defined by current guidelines as being invasive tumours not responding to standard therapies and presenting with multiple local recurrences; if metastases occur, the tumours are defined as pituitary carcinomas. A pituitary carcinoma is suspected in individuals with neurological complaints, neck and/or back pain, discordance between biochemical and radiological findings, or when an initially silent tumour evolves into a functioning tumour. Future aggressive behaviour remains difficult to predict: no unique prognostic marker is available; however, a combined clinicopathological classification has shown value in predicting potential aggressive clinical behaviour. Temozolomide, the recommended first-line chemotherapy, increases overall and progression-free 5-year survival rates in responders but leads to complete or partial radiological response in only one-third of patients. Peptide receptor radionuclide therapy, molecularly targeted therapies (bevacizumab, tyrosine kinase inhibitors and everolimus) and immunotherapy have been used in a small number of patients but have shown limited effectiveness. An improved understanding of pituitary tumour biology, including genetic and epigenetic mechanisms, and the tumour microenvironment, will hopefully lead to personalized and timely therapeutic decisions in the future. Aggressive pituitary tumours are defined by current guidelines as being invasive tumours not responding to standard therapies and presenting with multiple local recurrences; if metastases occur, the tumours are defined as pituitary carcinomas. A pituitary carcinoma is suspected in individuals with neurological complaints, neck and/or back pain, discordance between biochemical and radiological findings, or when an initially silent tumour evolves into a functioning tumour. Future aggressive behaviour remains difficult to predict: no unique prognostic marker is available; however, a combined clinicopathological classification has shown value in predicting potential aggressive clinical behaviour. Temozolomide, the recommended first-line chemotherapy, increases overall and progression-free 5-year survival rates in responders but leads to complete or partial radiological response in only one-third of patients. Peptide receptor radionuclide therapy, molecularly targeted therapies (bevacizumab, tyrosine kinase inhibitors and everolimus) and immunotherapy have been used in a small number of patients but have shown limited effectiveness. An improved understanding of pituitary tumour biology, including genetic and epigenetic mechanisms, and the tumour microenvironment, will hopefully lead to personalized and timely therapeutic decisions in the future.