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.
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.
Subscribe to Journal
Get full journal access for 1 year
only $4.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Melmed, S. Pituitary-tumor endocrinopathies. N. Engl. J. Med. 382, 937–950 (2020).
Saeger, W. et al. Pathohistological classification of pituitary tumors: 10 years of experience with the German pituitary tumor registry. Eur. J. Endocrinol. 156, 203–216 (2007).
Raverot, G. et al. Risk of recurrence in pituitary neuroendocrine tumors: a prospective study using a five-tiered classification. J. Clin. Endocrinol. Metab. 102, 3368–3374 (2017).
Raverot, G. et al. European Society of Endocrinology Clinical Practice Guidelines for the management of aggressive pituitary tumours and carcinomas. Eur. J. Endocrinol. 178, G1–G24 (2018).
Shimon, I. Metastatic Spread to the Pituitary. Neuroendocrinology 110, 805–808 (2020).
Osamura, R. Y., Lopes, M. B. S., Grossman, A., Kontogeorgos, G. & Trouillas, J. In WHO Classification of Tumours of Endocrine Organs Vol. 13, Ch. 1 (IARC Press, 2017).
Trouillas, J. et al. Are aggressive pituitary tumors and carcinomas two sides of the same coin? Pathologists reply to clinician’s questions. Rev. Endocr. Metab. Disord. 21, 243–251 (2020).
Asa, S. L. et al. From pituitary adenoma to pituitary neuroendocrine tumor (PitNET): an International Pituitary Pathology Club proposal. Endocr. Relat. Cancer 24, C5–C8 (2017).
Dekkers, O. M., Karavitaki, N. & Pereira, A. M. The epidemiology of aggressive pituitary tumors (and its challenges). Rev. Endocr. Metab. Disord. 21, 209–212 (2020).
Lloyd, R. V., Kovacs, K. & Young, W. F. In WHO Classification of Tumours. Pathology and Genetics of Tumours of Endocrine Organs (DeLellis, R.A., Lloyd, R.V., Heitz, P.U., Eng, C., Eds.) Chapter 1, 10–13 (IARC Press, 2004).
Neou, M. et al. Pangenomic classification of pituitary neuroendocrine tumors. Cancer Cell 37, 123–134.e5 (2020).
Ilie, M. D., Vasiljevic, A., Louvet, C., Jouanneau, E. & Raverot, G. Gonadotroph tumors show subtype differences that might have implications for therapy. Cancers 12, 1012 (2020).
Ilie, M. D., Vasiljevic, A., Raverot, G. & Bertolino, P. The microenvironment of pituitary tumors — biological and therapeutic implications. Cancers 11, 1605 (2019).
Marques, P., Grossman, A. B. & Korbonits, M. The tumour microenvironment of pituitary neuroendocrine tumours. Front. Neuroendocrinol. 58, 100852 (2020).
Ilie, M. D., Lasolle, H. & Raverot, G. Emerging and novel treatments for pituitary tumors. J. Clin. Med. 8, 1107 (2019).
Micko, A. S. G., Wöhrer, A., Wolfsberger, S. & Knosp, E. Invasion of the cavernous sinus space in pituitary adenomas: endoscopic verification and its correlation with an MRI-based classification. J. Neurosurg. 122, 803–811 (2015).
Serioli, S. et al. Pituitary adenomas and invasiveness from anatomo-surgical, radiological, and histological perspectives: a systematic literature review. Cancers 11, 1936 (2019).
Buchy, M. et al. Predicting early post-operative remission in pituitary adenomas: evaluation of the modified knosp classification. Pituitary 22, 467–475 (2019).
Imber, B. S. et al. Comparison of radiographic approaches to assess treatment response in pituitary adenomas: is RECIST or RANO good enough? J. Endocr. Soc. 3, 1693–1706 (2019).
Schwartz, L. H. et al. RECIST 1.1 — update and clarification: from the RECIST committee. Eur. J. Cancer 62, 132–137 (2016).
Eisenhauer, E. A. et al. New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). Eur. J. Cancer 45, 228–247 (2009).
Ilie, M. D., Jouanneau, E. & Raverot, G. Aggressive pituitary adenomas and carcinomas. Endocrinol. Metab. Clin. North Am. 49, 505–515 (2020).
Ilie, M. D. & Raverot, G. Treatment options for gonadotroph tumors: current state and perspectives. J. Clin. Endocrinol. Metab. 105, dgaa497 (2020).
McCormack, A. et al. Treatment of aggressive pituitary tumours and carcinomas: results of a European Society of Endocrinology (ESE) survey 2016. Eur. J. Endocrinol. 178, 265–276 (2018).
Yoo, F., Kuan, E. C., Heaney, A. P., Bergsneider, M. & Wang, M. B. Corticotrophic pituitary carcinoma with cervical metastases: case series and literature review. Pituitary 21, 290–301 (2018).
Santos-Pinheiro, F. et al. Treatment and long-term outcomes in pituitary carcinoma: a cohort study. Eur. J. Endocrinol. 181, 397–407 (2019).
Dudziak, K., Honegger, J., Bornemann, A., Horger, M. & Müssig, K. Pituitary carcinoma with malignant growth from first presentation and fulminant clinical course — case report and review of the literature. J. Clin. Endocrinol. Metab. 96, 2665–2669 (2011).
Kasuki, L. & Raverot, G. Definition and diagnosis of aggressive pituitary tumors. Rev. Endocr. Metab. Disord. 21, 203–208 (2020).
Philippon, M. et al. Long-term control of a MEN1 prolactin secreting pituitary carcinoma after temozolomide treatment. Ann. Endocrinol. 73, 225–229 (2012).
Trouillas, J. et al. Clinical, pathological, and molecular factors of aggressiveness in lactotroph tumours. Neuroendocrinology 109, 70–76 (2019).
Trouillas, J. et al. How to classify pituitary neuroendocrine tumors (PitNET)s in 2020. Cancers 12, 514 (2020).
Trouillas, J. et al. A new prognostic clinicopathological classification of pituitary adenomas: a multicentric case–control study of 410 patients with 8 years post-operative follow-up. Acta Neuropathol. 126, 123–135 (2013).
Asioli, S. et al. Validation of a clinicopathological score for the prediction of post-surgical evolution of pituitary adenoma: retrospective analysis on 566 patients from a tertiary care centre. Eur. J. Endocrinol. 180, 127–134 (2019).
Lelotte, J. et al. Both invasiveness and proliferation criteria predict recurrence of non-functioning pituitary macroadenomas after surgery: a retrospective analysis of a monocentric cohort of 120 patients. Eur. J. Endocrinol. 178, 237–246 (2018).
Guaraldi, F. et al. A practical algorithm to predict postsurgical recurrence and progression of pituitary neuroendocrine tumours (PitNET)s. Clin. Endocrinol. 93, 36–43 (2020).
Trouillas, J. et al. Aggressive pituitary tumours and carcinomas: two sides of the same coin? Eur. J. Endocrinol. 178, C7–C9 (2018).
Thapar, K. et al. Proliferative activity and invasiveness among pituitary adenomas and carcinomas: an analysis using the MIB-1 antibody. Neurosurgery 38, 99–107 (1996).
Scheithauer, B. W. et al. Pathobiology of pituitary adenomas and carcinomas. Neurosurgery 59, 341–353 (2006).
McCormack, A. I., Wass, J. A. H. & Grossman, A. B. Aggressive pituitary tumours: the role of temozolomide and the assessment of MGMT status. Eur. J. Clin. Invest. 41, 1133–1148 (2011).
Hirohata, T. et al. DNA mismatch repair protein (MSH6) correlated with the responses of atypical pituitary adenomas and pituitary carcinomas to temozolomide: the National Cooperative Study by the Japan Society for Hypothalamic and Pituitary Tumors. J. Clin. Endocrinol. Metab. 98, 1130–1136 (2013).
Bengtsson, D. et al. Long-term outcome and MGMT as a predictive marker in 24 patients with atypical pituitary adenomas and pituitary carcinomas given treatment with temozolomide. J. Clin. Endocrinol. Metab. 100, 1689–1698 (2015).
Srirangam Nadhamuni, V. & Korbonits, M. Novel insights into pituitary tumorigenesis: genetic and epigenetic mechanisms. Endocr. Rev. 41, 821–846 (2020).
Trouillas, J. et al. Pituitary tumors and hyperplasia in multiple endocrine neoplasia type 1 syndrome (MEN1): a case-control study in a series of 77 patients versus 2509 Non-MEN1 patients. Am. J. Surg. Pathol. 32, 534–543 (2008).
de Laat, J. M. et al. Long-term natural course of pituitary tumors in patients with MEN1: results from the DutchMEN1 Study Group (DMSG). J. Clin. Endocrinol. Metab. 100, 3288–3296 (2015).
Vergès, B. et al. Pituitary disease in MEN type 1 (MEN1): data from the France-Belgium MEN1 multicenter study. J. Clin. Endocrinol. Metab. 87, 457–465 (2002).
Bengtsson, D. et al. Corticotroph pituitary carcinoma in a patient with lynch syndrome (LS) and pituitary tumors in a nationwide LS cohort. J. Clin. Endocrinol. Metab. 102, 3928–3932 (2017).
Casar-Borota, O. et al. Corticotroph aggressive pituitary tumours and carcinomas frequently harbour ATRX mutations. J. Clin. Endocrinol. Metab. 106, 1183–1194 (2021).
Wierinckx, A. et al. A diagnostic marker set for invasion, proliferation, and aggressiveness of prolactin pituitary tumors. Endocr. Relat. Cancer 14, 887–900 (2007).
Raverot, G. et al. Prognostic factors in prolactin pituitary tumors: clinical, histological, and molecular data from a series of 94 patients with a long postoperative follow-up. J. Clin. Endocrinol. Metab. 95, 1708–1716 (2010).
Li, C. et al. Somatic SF3B1 hotspot mutation in prolactinomas. Nat. Commun. 11, 2506 (2020).
Lan, X. et al. Whole-exome sequencing identifies variants in invasive pituitary adenomas. Oncol. Lett. 12, 2319–2328 (2016).
Gao, H. et al. Lower PRDM2 expression is associated with dopamine-agonist resistance and tumor recurrence in prolactinomas. BMC Cancer 15, 272 (2015).
Xue, Y., Chen, R., Du, W., Yang, F. & Wei, X. RIZ1 and histone methylation status in pituitary adenomas. Tumour Biol. 39, 1010428317711794 (2017).
Miyake, Y. et al. TERT promoter methylation is significantly associated with TERT upregulation and disease progression in pituitary adenomas. J. Neurooncol. 141, 131–138 (2019).
Pease, M., Ling, C., Mack, W. J., Wang, K. & Zada, G. The role of epigenetic modification in tumorigenesis and progression of pituitary adenomas: a systematic review of the literature. PLoS One 8, e82619 (2013).
Roche, M. et al. Deregulation of miR-183 and KIAA0101 in aggressive and malignant pituitary tumors. Front. Med. 2, 54 (2015).
Vicchio, T. M. et al. MicroRNAs expression in pituitary tumors: differences related to functional status, pathological features, and clinical behavior. J. Endocrinol. Invest. 43, 947–958 (2020).
Stilling, G. et al. MicroRNA expression in ACTH-producing pituitary tumors: up-regulation of microRNA-122 and −493 in pituitary carcinomas. Endocrine 38, 67–75 (2010).
Bi, W. L. et al. Landscape of genomic alterations in pituitary adenomas. Clin. Cancer Res. 23, 1841–1851 (2017).
Hage, M. et al. Genomic alterations and complex subclonal architecture in sporadic GH-secreting pituitary adenomas. J. Clin. Endocrinol. Metab. 103, 1929–1939 (2018).
Song, Z.-J. et al. The genome-wide mutational landscape of pituitary adenomas. Cell Res. 26, 1255–1259 (2016).
Salomon, M. P. et al. The epigenomic landscape of pituitary adenomas reveals specific alterations and differentiates among acromegaly, Cushing’s disease and endocrine-inactive subtypes. Clin. Cancer Res. 24, 4126–4136 (2018).
Buch, H. N. et al. Prediction of recurrence of nonfunctioning pituitary tumours by loss of heterozygosity analysis. Clin. Endocrinol. 61, 19–25 (2004).
Wierinckx, A. et al. Integrated genomic profiling identifies loss of chromosome 11p impacting transcriptomic activity in aggressive pituitary PRL tumors. Brain Pathol. 21, 533–543 (2011).
Lasolle, H. et al. Chromosomal instability in the prediction of pituitary neuroendocrine tumors prognosis. Acta Neuropathol. Commun. 8, 190 (2020).
Xiao, J.-Q. et al. Correlations of pituitary tumor transforming gene expression with human pituitary adenomas: a meta-analysis. PLoS One 9, e90396 (2014).
Gruppetta, M. et al. Expression of cell cycle regulators and biomarkers of proliferation and regrowth in human pituitary adenomas. Pituitary 20, 358–371 (2017).
Filippella, M. et al. Pituitary tumour transforming gene (PTTG) expression correlates with the proliferative activity and recurrence status of pituitary adenomas: a clinical and immunohistochemical study. Clin. Endocrinol. 65, 536–543 (2006).
Noh, T.-W. et al. Predicting recurrence of nonfunctioning pituitary adenomas. J. Clin. Endocrinol. Metab. 94, 4406–4413 (2009).
Principe, M. et al. Immune landscape of pituitary neuroendocrine tumours reveals association between macrophages and gonadotroph-tumour invasion. J. Clin. Endocrinol. Metab. 105, dgaa520 (2020).
Lu, J.-Q. et al. Immune cell infiltrates in pituitary adenomas: more macrophages in larger adenomas and more T cells in growth hormone adenomas. Endocr. Pathol. 26, 263–272 (2015).
Sato, M. et al. Analysis of tumor angiogenesis and immune microenvironment in non-functional pituitary endocrine tumors. J. Clin. Med. 8, 695 (2019).
Yagnik, G., Rutkowski, M. J., Shah, S. S. & Aghi, M. K. Stratifying nonfunctional pituitary adenomas into two groups distinguished by macrophage subtypes. Oncotarget 10, 2212–2223 (2019).
Marques, P. et al. Chemokines modulate the tumour microenvironment in pituitary neuroendocrine tumours. Acta Neuropathol. Commun. 7, 172 (2019).
Marques, P. et al. Pituitary tumour fibroblast-derived cytokines influence tumour aggressiveness. Endocr. Relat. Cancer 26, 853–865 (2019).
Qiu, L. et al. The expression of interleukin (IL)-17 and IL-17 receptor and MMP-9 in human pituitary adenomas. Pituitary 14, 266–275 (2011).
Trouillas, J., Vasiljevic, A., Jouanneau, E. & Raverot, G. In Encyclopedia of Endocrine Diseases 176–184 (Elsevier, 2019).
Turner, H. et al. Angiogenesis in pituitary adenomas-relationship to endocrine function, treatment and outcome. J. Endocrinol. 165, 475–481 (2000).
Lin, A. L. et al. Approach to the treatment of a patient with an aggressive pituitary tumor. J. Clin. Endocrinol. Metab. 105, 3807–3820 (2020).
Bakhsheshian, J. et al. Surgical outcomes following repeat transsphenoidal surgery for nonfunctional pituitary adenomas: a retrospective comparative study. Oper. Neurosurg. 16, 127–135 (2019).
Graillon, T. et al. Transcranial approach in giant pituitary adenomas: results and outcome in a modern series. J. Neurosurg. Sci. 64, 25–36 (2020).
Verma, J., McCutcheon, I. E., Waguespack, S. G. & Mahajan, A. Feasibility and outcome of re-irradiation in the treatment of multiply recurrent pituitary adenomas. Pituitary 17, 539–545 (2014).
Castinetti, F. Radiation techniques in aggressive pituitary tumours and carcinomas. Rev. Endocr. Metab. Disord. 21, 287–292 (2020).
Wolf, A. et al. Risk of radiation-associated intracranial malignancy after stereotactic radiosurgery: a retrospective, multicentre, cohort study. Lancet Oncol. 20, 159–164 (2019).
Guerrero-Pérez, F. et al. Sarcomas of the sellar region: a systematic review. Pituitary 24, 117–129 (2021).
Ono, M. et al. Prospective study of high-dose cabergoline treatment of prolactinomas in 150 patients. J. Clin. Endocrinol. Metab. 93, 4721–4727 (2008).
Lasolle, H., Ilie, M. D. & Raverot, G. Aggressive prolactinomas: how to manage? Pituitary 23, 70–77 (2020).
Nieman, L. K. et al. Treatment of Cushing’s syndrome: an endocrine society clinical practice guideline. J. Clin. Endocrinol. Metab. 100, 2807–2831 (2015).
Fountas, A. et al. Outcomes of patients with Nelson’s syndrome after primary treatment: a multicenter study from 13 UK pituitary centers. J. Clin. Endocrinol. Metab. 105, dgz200 (2020).
Stupp, R. et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N. Engl. J. Med. 352, 987–996 (2005).
Lasolle, H. et al. Temozolomide treatment can improve overall survival in aggressive pituitary tumors and pituitary carcinomas. Eur. J. Endocrinol. 176, 769–777 (2017).
Ji, Y., Vogel, R. I. & Lou, E. Temozolomide treatment of pituitary carcinomas and atypical adenomas: systematic review of case reports. Neuro-Oncol. Pract. 3, 188–195 (2016).
Elbelt, U. et al. Efficacy of temozolomide therapy in patients with aggressive pituitary adenomas and carcinomas — a german survey. J. Clin. Endocrinol. Metab. 105, e660–e675 (2020).
Thearle, M. S. et al. Temozolomide (Temodar®) and capecitabine (Xeloda®) treatment of an aggressive corticotroph pituitary tumor. Pituitary 14, 418–424 (2011).
Whitelaw, B. C. How and when to use temozolomide to treat aggressive pituitary tumours. Endocr. Relat. Cancer 26, R545–R552 (2019).
Lizzul, L. et al. Long-course temozolomide in aggressive pituitary adenoma: real-life experience in two tertiary care centers and review of the literature. Pituitary 23, 359–366 (2020).
Lin, A. L., Sum, M. W. & DeAngelis, L. M. Is there a role for early chemotherapy in the management of pituitary adenomas? Neuro-Oncology 18, 1350–1356 (2016).
Woo, P. Y. M. et al. A multifaceted review of temozolomide resistance mechanisms in glioblastoma beyond O-6-methylguanine-DNA methyltransferase. Glioma 2, 68 (2019).
Nicolas, G. P., Morgenstern, A., Schottelius, M. & Fani, M. New developments in peptide receptor radionuclide therapy. J. Nucl. Med. 60, 167–171 (2019).
Gatto, F., Arvigo, M. & Ferone, D. Somatostatin receptor expression and patients’ response to targeted medical treatment in pituitary tumors: evidences and controversies. J. Endocrinol. Invest. 43, 1543–1553 (2020).
Øystese, K. A. et al. Estrogen receptor α, a sex-dependent predictor of aggressiveness in nonfunctioning pituitary adenomas: SSTR and Sex hormone receptor distribution in NFPA. J. Clin. Endocrinol. Metab. 102, 3581–3590 (2017).
Thodou, E. & Kontogeorgos, G. Somatostatin receptor profile in pituitary thyrotroph adenomas. Clin. Neurol. Neurosurg. 195, 105865 (2020).
Behling, F. et al. High expression of somatostatin receptors 2A, 3, and 5 in corticotroph pituitary adenoma. Int. J. Endocrinol. 2018, 1–12 (2018).
Novruzov, F., Aliyev, J. A., Jaunmuktane, Z., Bomanji, J. B. & Kayani, I. The Use of 68Ga DOTATATE PET/CT for diagnostic assessment and monitoring of 177Lu DOTATATE therapy in pituitary carcinoma. Clin. Nucl. Med. 40, 47–49 (2015).
Boertien, T. M. et al. 68Ga-DOTATATE PET imaging in clinically non-functioning pituitary macroadenomas. Eur. J. Hybrid Imaging 4, 4 (2020).
Novruzov, F. et al. Assessment of 68Ga-DOTATATE PET/CT in suspected pituitary tumours. J. Nucl. Med. 55, 1960 (2014).
Assadi, M. et al. An aggressive functioning pituitary adenoma treated with peptide receptor radionuclide therapy. Eur. J. Nucl. Med. Mol. Imaging 47, 1015–1016 (2020).
Brabander, T., Nonnekens, J. & Hofland, J. The next generation of peptide receptor radionuclide therapy. Endocr. Relat. Cancer 26, C7–C11 (2019).
Reubi, J. C. et al. Affinity profiles for human somatostatin receptor subtypes SST1-SST5 of somatostatin radiotracers selected for scintigraphic and radiotherapeutic use. Eur. J. Nucl. Med. Mol. Imaging 27, 273–282 (2000).
Tjörnstrand, A. et al. Lower 68Ga-DOTATOC uptake in nonfunctioning pituitary neuroendocrine tumours compared to normal pituitary gland — a proof-of-concept study. Clin. Endocrinol. 92, 222–231 (2020).
Taelman, V. F. et al. Upregulation of key molecules for targeted imaging and therapy. J. Nucl. Med. 57, 1805–1810 (2016).
Jugenburg, M., Kovacs, K., Stefaneanu, L. & Scheithauer, B. W. Vasculature in nontumorous hypophyses, pituitary adenomas, and carcinomas: a quantitative morphologic study. Endocr. Pathol. 6, 115–124 (1995).
Vidal, S. et al. Microvessel density in pituitary adenomas and carcinomas. Virchows Arch. 438, 595–602 (2001).
Lloyd, R. V. et al. Vascular endothelial growth factor (VEGF) expression in human pituitary adenomas and carcinomas. Endocr. Pathol. 10, 229–235 (1999).
Alshaikh, O. M., Asa, S. L., Mete, O. & Ezzat, S. An institutional experience of tumor progression to pituitary carcinoma in a 15-year cohort of 1055 consecutive pituitary neuroendocrine tumors. Endocr. Pathol. 30, 118–127 (2019).
Dutta, P. et al. Surgery, octreotide, temozolomide, bevacizumab, radiotherapy, and pegvisomant treatment of an AIP mutation-positive child. J. Clin. Endocrinol. Metab. 104, 3539–3544 (2019).
Xu, L. et al. Pituitary carcinoma: two case reports and review of literature. World J. Clin. Oncol. 11, 91–102 (2020).
Touma, W. et al. Successful treatment of pituitary carcinoma with concurrent radiation, temozolomide, and bevacizumab after resection. J. Clin. Neurosci. 41, 75–77 (2017).
Duhamel, C. et al. Immunotherapy in corticotroph and lactotroph aggressive tumors and carcinomas: two case reports and a review of the literature. J. Pers. Med. 10, 88 (2020).
Lamb, L. S., Sim, H.-W. & McCormack, A. I. Case report: a case of pituitary carcinoma treated with sequential dual immunotherapy and vascular endothelial growth factor inhibition therapy. Front. Endocrinol. 11, 576027 (2020).
Jiao, Q. et al. Advances in studies of tyrosine kinase inhibitors and their acquired resistance. Mol. Cancer 17, 36 (2018).
Ben-Shlomo, A. & Cooper, O. Role of tyrosine kinase inhibitors in the treatment of pituitary tumours: from bench to bedside. Curr. Opin. Endocrinol. Diabetes Obes. 24, 301–305 (2017).
Wang, Y. et al. Apatinib (YN968D1) and temozolomide in recurrent invasive pituitary adenoma: case report and literature review. World Neurosurg. 124, 319–322 (2019).
Cooper, O. et al. EGFR/ErbB2 targeting lapatinib therapy for aggressive prolactinomas. J. Clin. Endocrinol. Metab. 106, e917–e925 (2021).
Musat, M. Enhanced protein kinase B/Akt signalling in pituitary tumours. Endocr. Relat. Cancer 12, 423–433 (2005).
Dworakowska, D. & Grossman, A. B. The pathophysiology of pituitary adenomas. Best Pract. Res. Clin. Endocrinol. Metab. 23, 525–541 (2009).
Sajjad, E. A. et al. mTOR is frequently active in GH-secreting pituitary adenomas without influencing their morphopathological features. Endocr. Pathol. 24, 11–19 (2013).
Gorshtein, A. et al. Mammalian target of rapamycin inhibitors rapamycin and RAD001 (everolimus) induce anti-proliferative effects in GH-secreting pituitary tumor cells in vitro. Endocr. Relat. Cancer 16, 1017–1027 (2009).
Chanal, M. et al. Differential effects of PI3K and dual PI3K/mTOR inhibition in rat prolactin-secreting pituitary tumors. Mol. Cancer Ther. 15, 1261–1270 (2016).
Monsalves, E. et al. The PI3K/AKT/mTOR pathway in the pathophysiology and treatment of pituitary adenomas. Endocr. Relat. Cancer 21, R331–R344 (2014).
Lee, M. et al. Targeting PI3K/mTOR signaling displays potent antitumor efficacy against nonfunctioning pituitary adenomas. Clin. Cancer Res. 21, 3204–3215 (2015).
Pivonello, C. et al. Effect of combined treatment with a pan-PI3K inhibitor or an isoform-specific PI3K inhibitor and everolimus on cell proliferation in GH-secreting pituitary tumour in an experimental setting. Endocrine 62, 663–680 (2018).
Anderson, E., Heller, R. S., Lechan, R. M. & Heilman, C. B. Regression of a nonfunctioning pituitary macroadenoma on the CDK4/6 inhibitor palbociclib: case report. Neurosurg. Focus. 44, E9 (2018).
Hewedi, I. H., Osman, W. M. & El Mahdy, M. M. Differential expression of cyclin D1 in human pituitary tumors: relation to MIB-1 and p27/Kip1 labeling indices. J. Egypt. Natl Cancer Inst. 23, 171–179 (2011).
Jordan, S., Lidhar, K., Korbonits, M., Lowe, D. & Grossman, A. Cyclin D and cyclin E expression in normal and adenomatous pituitary. Eur. J. Endocrinol. 143, R1–R6 (2000).
Mei, Y. et al. Increased expression of programmed death ligand 1 (PD-L1) in human pituitary tumors. Oncotarget 7, 76565–76576 (2016).
Wang, P. et al. The expression profile of PD-L1 and CD8+ lymphocyte in pituitary adenomas indicating for immunotherapy. J. Neurooncol. 139, 89–95 (2018).
Kemeny, H. R. et al. Targeting PD-L1 initiates effective antitumor immunity in a murine model of cushing disease. Clin. Cancer Res. 26, 1141–1151 (2020).
Lin, A. L. et al. Marked response of a hypermutated ACTH-secreting pituitary carcinoma to ipilimumab and nivolumab. J. Clin. Endocrinol. Metab. 103, 3925–3930 (2018).
Sol, B. et al. Immune checkpoint inhibitor therapy for ACTH-secreting pituitary carcinoma: a new emerging treatment? Eur. J. Endocrinol. 184, K1–K5 (2021).
Majd, N. et al. Efficacy of pembrolizumab in patients with pituitary carcinoma: report of four cases from a phase II study. J. Immunother. Cancer 8, e001532 (2020).
Wilky, B. A. Immune checkpoint inhibitors: The linchpins of modern immunotherapy. Immunol. Rev. 290, 6–23 (2019).
Deng, L. et al. Irradiation and anti–PD-L1 treatment synergistically promote antitumor immunity in mice. J. Clin. Invest. 124, 687–695 (2014).
Rahma, O. E. & Hodi, F. S. The intersection between tumor angiogenesis and immune suppression. Clin. Cancer Res. 25, 5449–5457 (2019).
Ramjiawan, R. R., Griffioen, A. W. & Duda, D. G. Anti-angiogenesis for cancer revisited: Is there a role for combinations with immunotherapy? Angiogenesis 20, 185–204 (2017).
Wang, Z. et al. The immune profile of pituitary adenomas and a novel immune classification for predicting immunotherapy responsiveness. J. Clin. Endocrinol. Metab. 105, e3207–e3223 (2020).
de Baere, T. et al. GEP-NETS update: Interventional radiology: role in the treatment of liver metastases from GEP-NETs. Eur. J. Endocrinol. 172, R151–R166 (2015).
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.
Peer review information
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.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
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