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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.

Key points

  • 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.

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Fig. 1: Tumour growth and treatment response assessment of anterior pituitary tumours.
Fig. 2: The natural course of a prolactin pituitary carcinoma with a long delay between initial diagnosis and detection of metastasis (Box 1, patient 1).
Fig. 3: An unusual course of a prolactin pituitary carcinoma with a short duration between initial diagnosis and detection of metastasis (Box 1, patient 2).
Fig. 4: Histopathological characteristics of a grade 2b lactotroph tumour.
Fig. 5: TME components associated with and/or influencing aggressiveness-related characteristics (invasion, proliferation, progression) of anterior pituitary tumours (derived from published data13,14,70,71,72,73,74,75,76,77,78).
Fig. 6: Radiological response of pituitary carcinomas and aggressive pituitary tumours treated with PRRT, bevacizumab, TKIs, everolimus and ICIs (derived from published data15,104,107,115,116,118,119,120,123,124,140,141).
Fig. 7: Suggested approach for the management of aggressive pituitary tumours and pituitary carcinomas.

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All authors researched data for the article and were involved in writing the article. T.B., G.R., M.D.I. and F.C. provided a substantial contribution to the discussion of content. T.B., G.R., M.D.I. and F.C. reviewed/edited the manuscript before submission.

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Correspondence to Thierry Brue.

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G.R. received research grants and consulting fees from Ipsen, Novartis, Pfizer and Recordati Rare Diseases. F.C. received research grants and consulting fees from HRA Pharma Rare Diseases, Ipsen, Novartis, Pfizer and Recordati Rare Diseases. T.B. received consultant/speaker fees or research grants from Advanz Pharma, Corcept, Ipsen Pharma, Merck-Serono, Novartis Pharma SAS, Novo-Nordisk, Pfizer SAS, Recordati Rare Diseases, and Sandoz. The other authors declare no competing interests.

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Nature Reviews Endocrinology thanks E. Laws, who co-reviewed with A. Montaser; A. Grossman; and C. Boguszewski for their contribution to the peer review of this work.

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Raverot, G., Ilie, M.D., Lasolle, H. et al. Aggressive pituitary tumours and pituitary carcinomas. Nat Rev Endocrinol (2021). https://doi.org/10.1038/s41574-021-00550-w

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