Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Aggressive pituitary adenomas—diagnosis and emerging treatments

Key Points

  • The WHO categorizes pituitary tumours as typical adenomas, atypical adenomas and pituitary carcinomas, although this classification does not cover the entire spectrum of histopathological findings or clinical behaviour

  • Pituitary adenomas are generally benign, but some display high rates of recurrence and/or resistance to conventional therapies—and are clinically defined as aggressive adenomas

  • Aggressive pituitary adenomas seem to represent a distinct entity requiring strict follow-up and early multimodal treatment, nonetheless, specific morphological, radiological and molecular diagnostic criteria should be identified

  • Pituitary carcinomas, by definition, are diagnosed only by demonstration of craniospinal dissemination or systemic metastases, although not all show cytological features of malignancy

  • Unlike pituitary carcinomas, aggressive pituitary adenomas do not give rise to metastases, but the two classes can share some histological features

  • Temozolomide might be useful in treating aggressive pituitary adenomas: anti-VEGF therapy, mTOR and tyrosine kinase inhibitors can also be used in selected patients

Abstract

The WHO categorizes pituitary tumours as typical adenomas, atypical adenomas and pituitary carcinomas, with typical adenomas constituting the major class. However, the WHO classification does not provide an accurate correlation between histopathological findings and clinical behaviour. Tumours lacking typical histological features are classified as atypical, but not all are clinically atypical or exhibit aggressive behaviour. Pituitary carcinomas, by definition, have craniospinal or systemic metastases, although not all display classical cytological features of malignancy. Aggressive pituitary adenomas, defined from a clinical perspective, have earlier and more frequent recurrences and can be resistant to conventional treatments. Specific biomarkers have not yet been identified that can distinguish between clinically aggressive and nonaggressive pituitary adenomas, although the antigen Ki-67 proliferation index might be of value. This Review highlights the need to develop new biomarkers to facilitate the early detection of clinically aggressive pituitary adenomas and discusses emerging markers that hold promise for their identification. Defining aggressiveness is of crucial importance for improving the management of patients by enhancing prognostic predictions and effectiveness of treatment. New drugs, such as temozolomide, have potential use in the management of these patients; anti-VEGF therapy, mTOR and tyrosine kinase inhibitors are also potentially useful in managing selected patients.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Proposed models of pituitary tumourigenesis.
Figure 2: Normal anatomy of the sellar and parasellar regions surrounding the pituitary gland.
Figure 3: Classification systems used to characterize pituitary adenomas.
Figure 4: Value of the Ki-67 labelling index (derived from MIB-1 antibody binding) for characterizing pituitary tumours.
Figure 5: Exemplary case of aggressive pituitary adenoma.

References

  1. Asa, S. L. & Ezzat, S. The pathogenesis of pituitary tumors. Annu. Rev. Pathol. 4, 97–126 (2009).

    Article  CAS  PubMed  Google Scholar 

  2. Aflorei, E. D. & Korbonits, M. Epidemiology and etiopathogenesis of pituitary adenomas. J. Neurooncol. http://dx.doi.org/10.1007/s11060-013-1354–1355.

  3. Scheithauer, B. W., Kovacs, K. T., Laws, E. R. Jr & Randall, R. V. Pathology of invasive pituitary tumors with special reference to functional classification. J. Neurosurg. 65, 733–744 (1986).

    Article  CAS  PubMed  Google Scholar 

  4. Thapar, K. et al. Proliferative activity and invasiveness among pituitary adenomas and carcinomas: an analysis using the MIB-1 antibody. Neurosurgery 38, 99–106 (1996).

    Article  CAS  PubMed  Google Scholar 

  5. Meij, B. P., Lopes, M. B., Ellegala, D. B., Alden, T. D. & Laws, E. R. Jr. The long-term significance of microscopic dural invasion in 354 patients with pituitary adenomas treated with transsphenoidal surgery. J. Neurosurg. 96, 195–208 (2002).

    Article  PubMed  Google Scholar 

  6. Kaltsas, G. A. et al. Diagnosis and management of pituitary carcinomas. J. Clin. Endocr. Metab. 90, 3089–3099 (2005).

    Article  CAS  PubMed  Google Scholar 

  7. Buchfelder, M. Management of aggressive pituitary adenomas: current treatment strategies. Pituitary 12, 256–260 (2009).

    Article  PubMed  Google Scholar 

  8. McCormack, A. I., Wass, J. A. & Grossman, A. B. Aggressive pituitary tumours: the role of temozolomide and the assessment of MGMT status. Eur. J. Clin. Invest. 41, 1133–1148 (2011).

    Article  CAS  PubMed  Google Scholar 

  9. Raverot, G. et al. Pituitary carcinomas and aggressive pituitary tumours: merits and pitfalls of temozolomide treatment. Clin. Endocrinol. (Oxf.) 76, 769–775 (2012).

    Article  CAS  Google Scholar 

  10. Lloyd, R. V. et al. in Pathology and Genetics of Tumours of Endocrine Organs (eds DeLellis, R. A. et al.) 10–13 (IARC Press, 2004).

    Google Scholar 

  11. 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).

    Article  CAS  PubMed  Google Scholar 

  12. Zada, G. et al. Atypical pituitary adenomas: incidence, clinical characteristics, and implications. J. Neurosurg. 114, 336–344 (2011).

    Article  PubMed  Google Scholar 

  13. Scheithauer, B. W. et al. in Pituitary Carcinoma (eds DeLellis, R. A. et al.). 36–39 (IARC Press, 2004).

    Google Scholar 

  14. Melmed, S. Pathogenesis of pituitary tumors. Nat. Rev. Endocrinol. 7, 257–266 (2011).

    Article  CAS  PubMed  Google Scholar 

  15. Hardy, J. Transsphenoidal microsurgery of the normal and pathological pituitary. Clin. Neurosurg. 16, 185–217 (1969).

    Article  CAS  PubMed  Google Scholar 

  16. Campero, A., Martins, C., Yasuda, A. & Rhoton, A. L. Jr. Microsurgical anatomy of the diaphragm sellae and its role in directing the pattern of growth of pituitary adenomas. Neurosurgery 62, 717–723 (2008).

    Article  PubMed  Google Scholar 

  17. Di Ieva, A. et al. The subdiaphragmatic cistern: historic and radioanatomic findings. Acta Neurochir. (Wien) 154, 667–674 (2012).

    Article  Google Scholar 

  18. Knosp, E., Steiner, E., Kitz, K. & Matula, C. Pituitary adenomas with invasion of the cavernous sinus space: a magnetic resonance imaging classification compared with surgical findings. Neurosurgery 33, 610–617 (1993).

    CAS  PubMed  Google Scholar 

  19. Cusimano, M. D. et al. Outcomes of surgically treated giant pituitary tumours. Can. J. Neurol. Sci. 39, 446–457 (2012).

    Article  PubMed  Google Scholar 

  20. Delgrange, E., Trouillas, J., Maiter, D., Donckier, J. & Tourniaire, J. Sex-related difference in the growth of prolactinomas: a clinical and proliferation marker study. J. Clin. Endocrinol. Metab. 82, 2012–2107 (1997).

    Google Scholar 

  21. Heaney, A. P. Clinical review: pituitary carcinoma: difficult diagnosis and treatment. J. Clin. Endocrinol. Metab. 96, 3649–3660 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Delgrange, E., Sassolas, G., Perin, G. & Trouillas, J. M. Clinical and histological correlations in prolactinomas, with specific reference to bromocriptine resistence. Acta Neurochir. (Wien.) 147, 4721–4727 (2005).

    Article  Google Scholar 

  23. Colao, A., Grasso, L. F., Pivonello, R. & Lombardi, G. Therapy of aggressive pituitary tumors. Expert Opin. Pharmacother. 12, 1561–1570 (2011).

    Article  CAS  PubMed  Google Scholar 

  24. George, D. H. et al Crooke's cell adenoma of the pituitary: an aggressive variant of corticotroph adenoma. Am. J. Surg. Pathol. 27, 1330–1336 (2003).

    Article  PubMed  Google Scholar 

  25. Kovacs, K. et al. Prognostic indicators in an aggressive pituitary Crooke's cell adenoma. Can. J. Neurol. Sci. 32, 540–545 (2005).

    Article  CAS  PubMed  Google Scholar 

  26. Crooke, A. A change in the basophil cells of the pituitary gland common to conditions which exhibit the syndrome attributed to basophil adenoma. J. Pathol. Bacteriol. 41, 339–349 (1935).

    Article  Google Scholar 

  27. Scheithauer, B. W. et al. Clinically silent corticotroph tumors of the pituitary gland. Neurosurgery 47, 723–729 (2000).

    CAS  PubMed  Google Scholar 

  28. Jahangiri, A. et al. A comprehensive long-term retrospective analysis of silent corticotrophic adenomas versus hormone-negative adenomas. Neurosurgery 73, 8–17 (2013).

    Article  PubMed  Google Scholar 

  29. Asa, S. L., Ezzat, S., Watson, R. E., Lindell, E. P. & Horvath, E. in Tumors of Endocrine Organs (eds DeLellis, R. et al.) 30–32 (IARC Press, 2004).

    Google Scholar 

  30. Mete, O., Ezzat, S. & Asa, S. L. Biomarkers of aggressive pituitary adenomas. J. Mol. Endocrinol. 49, R69–R78 (2012).

    Article  CAS  PubMed  Google Scholar 

  31. Mete, O. & Asa, S. L. Clinicopathological correlations in pituitary adenomas. Brain Pathology 22, 443–453 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  32. Mete, O. & Asa, S. L. Therapeutic implications of accurate classification of pituitary adenomas. Semin. Diagn. Pathol. 30, 158–164 (2013).

    Article  PubMed  Google Scholar 

  33. Batisse, M. et al. Aggressive silent GH pituitary tumor resistant to multiple treatments, including temozolomide. Cancer Invest. 31, 190–196 (2013).

    Article  CAS  PubMed  Google Scholar 

  34. Vieira Neto, L. et al. The role of temozolomide in the treatment of a patient with a pure silent pituitary somatotroph carcinoma. Endocr. Pract. 19, e145–e149 (2013).

    Article  PubMed  Google Scholar 

  35. Asa, S. L. et al. A growth hormone receptor mutation impairs growth hormone autofeedback signaling in pituitary tumors. Cancer Res. 67, 7505–7511 (2007).

    Article  CAS  PubMed  Google Scholar 

  36. Sano, T., Ohshima, T. & Yamada, S. Expression of glycoprotein hormones and intracytoplasmic distribution of cytokeratin in growth hormone-producing pituitary adenomas. Pathol. Res. Pract. 187, 530–533 (1991).

    Article  CAS  PubMed  Google Scholar 

  37. Hagiwara, A. et al. Comparison of growth hormone-producing and non-growth hormone-producing pituitary adenomas: imaging characteristics and pathologic correlation. Radiology 228, 533–538 (2003).

    Article  PubMed  Google Scholar 

  38. Wierinckx, A. et al. A diagnostic marker set for invasion, proliferation, and aggressiveness of prolactin pituitary tumors. Endocr. Relat. Cancer 14, 887–900 (2007).

    Article  CAS  PubMed  Google Scholar 

  39. 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).

    Article  PubMed  Google Scholar 

  40. Raverot, G., Jouanneau, E. & Trouillas, J. Clinicopathological classification and molecular markers of pituitary tumours for personalized therapeutic strategies. Eur. J. Endocrinol. 170, R121–R132 (2014).

    Article  CAS  PubMed  Google Scholar 

  41. Monsalves, E. et al. Growth patterns of pituitary adenomas and histopathological correlates. J. Clin. Endocrinol. Metab. 99, 1330–1338 (2014).

    Article  CAS  PubMed  Google Scholar 

  42. Salehi, F. et al. Biomarkers of pituitary neoplasms: a review (Part II). Neurosurgery 67, 1790–1798 (2010).

    Article  PubMed  Google Scholar 

  43. Sav, A., Rotondo, F., Syro, L. V., Scheithauer, B. W. & Kovacs, K. Biomarkers of pituitary neoplasms. Anticancer Res. 32, 4639–4654 (2012).

    CAS  PubMed  Google Scholar 

  44. Salehi, F. et al. Ki-67 in pituitary neoplasms: a review (Part I). Neurosurgery 65, 429–437 (2009).

    Article  PubMed  Google Scholar 

  45. Chiloiro, S. et al. Radically resected pituitary adenomas: prognostic role of Ki 67 labeling index in a monocentric retrospective series and literature review. Pituitary http://dx.doi.org/10.1007/s11102-013-0500–0506.

  46. Kovacs, K. The 2004 WHO classification of pituitary tumors: comments. Acta Neuropathol. 111, 62–63 (2006).

    Article  PubMed  Google Scholar 

  47. Turner, H. E. & Wass, J. A. Are markers of proliferation valuable in the histological assessment of pituitary tumours? Pituitary 1, 147–151 (1999).

    Article  CAS  PubMed  Google Scholar 

  48. Thapar, K., Scheithauer, B. W., Kovacs, K., Pernicone, P. J. & Laws, E. R. Jr. p53 expression in pituitary adenomas and carcinomas: correlation with invasiveness and tumor growth fractions. Neurosurgery 38, 765–770 (1996).

    Article  CAS  PubMed  Google Scholar 

  49. Kontogeorgos, G. Predictive markers of pituitary adenoma behavior. Neuroendocrinology 83, 179–188 (2006).

    Article  CAS  PubMed  Google Scholar 

  50. Gejman, R., Swearingen, B. & Hedley-Whyte, E. T. Role of Ki-67 proliferation index and p53 expression in predicting progression of pituitary adenomas. Hum. Pathol. 39, 758–766 (2006).

    Article  CAS  Google Scholar 

  51. Trouillas, J. et al. Polysialylated neural cell adhesion molecules expressed in human pituitary tumors and related to extrasellar invasion. J. Neurosurg. 98, 1084–1093 (2003).

    Article  CAS  PubMed  Google Scholar 

  52. Jaffe, C. A. & Barkan, A. L. Acromegaly. Recognition and treatment. Drugs 47, 425–445 (1994).

    Article  CAS  PubMed  Google Scholar 

  53. LeRiche, V. K., Asa, S. L & Ezzat, S. Epidermal growth factor and its receptors (EGF-R) in human pituitary adenomas: EGF-R correlates with tumor aggressiveness. J. Clin. Endocrinol. Metab. 81, 656–662 (1996).

    CAS  PubMed  Google Scholar 

  54. Mete, O. et al. The role of mediators of cell invasiveness, motility, and migration in the pathogenesis of silent corticotroph adenomas. Endocr. Pathol. 24, 191–198 (2013).

    Article  PubMed  Google Scholar 

  55. Asa, S. L. & Ezzat, S. Genetics and proteomics of pituitary tumors. Endocrine 28, 43–47 (2005).

    Article  CAS  PubMed  Google Scholar 

  56. Lloyd, R. V., Vidal, S., Horvath, E, Kovacs, K. & Scheithauer, B. Angiogenesis in normal and neoplastic pituitary tissues. Microsc. Res. Tech. 60, 244–250 (2003).

    Article  CAS  PubMed  Google Scholar 

  57. Jugenburg, M., Kovacs, K., Stefaneanu, L. & Scheithauer, B. W. Vasculature in non-tumorous hypophyses, pituitary adenomas, and carcinomas: a quantitative morphological study. Endocr. Pathol. 6, 115–124 (1995).

    Article  PubMed  Google Scholar 

  58. Turner, H. E. et al. Angiogenesis in pituitary adenomas—relationship to endocrine function, treatment and outcome. J. Endocrinol. 165, 475–481 (2000).

    Article  CAS  PubMed  Google Scholar 

  59. Vidal, S. et al. Microvessel density in pituitary adenomas and carcinomas. Virchows Arch. 438, 595–602 (2001).

    Article  CAS  PubMed  Google Scholar 

  60. Di Ieva, A. et al. Euclidean and fractal geometry of microvascular networks in normal and neoplastic pituitary tissue. Neurosurg. Rev. 31, 271–281 (2008).

    Article  PubMed  Google Scholar 

  61. Di Ieva, A. et al. Fractal dimension as a quantitator of the microvasculature of normal and adenomatous pituitary tissue. J. Anat. 211, 673–680 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  62. Di Ieva, A. et al. Microvascular morphometrics of the hypohysis and pituitary tumors: from bench to operating theatre. Microvasc. Res. 89, 7–14 (2013).

    Article  PubMed  Google Scholar 

  63. Zachary, I. VEGF signalling: integration and multi-tasking in endothelial cell biology. Biochem. Soc. Trans. 31, 1171–1177 (2003).

    Article  CAS  PubMed  Google Scholar 

  64. Carmeliet, P. & Jain, R. K. Molecular mechanisms and clinical applications of angiogenesis. Nature 473, 298–307 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Sánchez-Ortiga, R. et al. Over-expression of vascular endothelial growth factor in pituitary adenomas is associated with extrasellar growth and recurrence. Pituitary 16, 370–377 (2013).

    Article  PubMed  CAS  Google Scholar 

  66. Pan, L. X., Chen, Z. P., Liu, Y. S. & Zhao, J. H. Magnetic resonance imaging and biological markers in pituitary adenomas with invasion of the cavernous sinus space. J. Neurooncol. 74, 71–76 (2005).

    Article  PubMed  Google Scholar 

  67. Yarman, S. et al. Expression of Ki-67, p53 and vascular endothelial growth factor (VEGF) concomitantly in growth hormone-secreting pituitary adenomas: which one has a role in tumor behavior? Neuro. Endocrinol. Lett. 31, 823–828 (2010).

    CAS  PubMed  Google Scholar 

  68. Bisht, S., Feldmann, G. & Brossart, P. Pharmacokinetics and pharmacodynamics of sunitinib for the treatment of advanced pancreatic neuroendocrine tumors. Expert Opin. Drug Metab. Toxicol. 9, 777–788 (2013).

    Article  CAS  PubMed  Google Scholar 

  69. Barroso-Sousa, R. et al. Complete resolution of hypercortisolism with sorafenib in a patient with advanced medullary thyroid carcinoma and ectopic ACTH syndrome. Thyroid http://dx.doi.org/10.1089/thy.2013.0571.

  70. Jia, W. et al. Vascular endothelial growth inhibitor (VEGI) is an independent indicator for invasion in human pituitary adenomas. Anticancer Res. 33, 3815–3822 (2013).

    PubMed  Google Scholar 

  71. Kaur, B. et al. Hypoxia and the hypoxia-factor pathway in glioma growth and angiogenesis. Neuro. Oncol. 7, 134–153 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Scherpereel, A. et al. Overexpression of endocan induces tumor formation. Cancer Res. 63, 6084–6089 (2003).

    CAS  PubMed  Google Scholar 

  73. Maurage, C. A. et al. Endocan expression and localization in human glioblastomas. J. Neuropathol. Exp. Neurol. 68, 633–641 (2009).

    Article  CAS  PubMed  Google Scholar 

  74. Sarrazin, S. et al. Endocan or endothelial cell specific molecule-1 (ESM-1): a potential novel endothelial cell marker and a new target for cancer therapy. Biochim. Biophys. Acta 1765, 25–37 (2006).

    CAS  PubMed  Google Scholar 

  75. Cornelius, A. et al. Endothelial expression of endocan is strongly associated with tumor progression in pituitary adenoma. Brain Pathol. 22, 757–764 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. McCabe, C. J. et al. Vascular endothelial growth factor, its receptor KDR/FLK-1, and pituitary transforming gene in pituitary tumors. J. Clin. Endocrinol. Metab. 87, 4238–4244 (2002).

    Article  CAS  PubMed  Google Scholar 

  77. Minematsu, T. et al. PTTG overexpression is correlated with angiogenesis in human pituitary adenomas. Endocr. Pathol. 17, 143–153 (2006).

    Article  CAS  PubMed  Google Scholar 

  78. Chesnokova, V. & Melmed, S. Pituitary tumour-transforming gene (PTTG) and pituitary senescence. Horm. Res. 71 (Suppl. 2), 82–87 (2009).

    CAS  PubMed  Google Scholar 

  79. Chesnokova, V. & Melmed, S. Pituitary senescence: the evolving role of PTTG. Mol. Cell Endocrinol. 326, 55–59 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Karga, H. J., Alexander, J. M., Hedley-Whyte, E. T., Klibanski, A. & Jameson, J. L. Ras mutations in human pituitary tumors. J. Clin. Endocr. Metab. 74, 914–919 (1992).

    Article  CAS  PubMed  Google Scholar 

  81. Cai, W. Y. et al. Ras mutations in human prolactinomas and pituitary carcinomas. J. Clin. Endocrinol. Metab. 78, 89–93 (1994).

    CAS  PubMed  Google Scholar 

  82. Pei, L., Melmed, S., Scheithauer, B., Kovacs, K. & Prager, D. H-ras mutations in human pituitary carcinoma metastases. J. Clin. Endocrinol. Metab. 78, 842–846 (1994).

    CAS  PubMed  Google Scholar 

  83. Rickert, C. H. et al. Increased chromosomal imbalances in recurrent pituitary adenomas. Acta Neuropathol. 102, 615–620 (2001).

    Article  CAS  PubMed  Google Scholar 

  84. Pack, S. D. et al. Common genetic changes in hereditary and sporadic pituitary adenomas detected by comparative genomic hybridization. Genes Chromosomes Cancer 43, 72–82 (2005).

    Article  CAS  PubMed  Google Scholar 

  85. 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).

    Article  CAS  PubMed  Google Scholar 

  86. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Zemmoura, I. et al. Aggressive and malignant prolactin pituitary tumors: pathological diagnosis and patient management. Pituitary 16, 515–522 (2013).

    Article  CAS  PubMed  Google Scholar 

  88. Thapar, K. et al. Overexpression of the growth-hormone-releasing hormone gene in acromegaly-associated pituitary tumors. An event associated with neoplastic progression and aggressive behavior. Am. J. Pathol. 151, 769–784 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Gadelha, M. R., Trivellin, G., Hernandez Ramirez, L. C. & Korbonits, M. Genetics of pituitary adenomas. Front. Horm. Res. 41, 111–140 (2013).

    Article  CAS  PubMed  Google Scholar 

  90. 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).

    Article  PubMed  Google Scholar 

  91. Syro, L. V. et al. Pituitary tumors in patients with MEN1 syndrome. Clinics 67 (Suppl. 1), 43–48 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  92. Toledo, S. P., Lourenco, D. M. Jr & Toledo, R. A. A differential diagnosis of inherited endocrine tumors and their tumor counterparts. Clinics (Sao Paulo) 68, 1039–1056 (2013).

    Article  Google Scholar 

  93. Beckers, A., Aaltonen, L. A., Daly, A. F. & Karhu, A. Familial isolated pituitary adenomas (FIPA) and the pituitary adenoma predisposition due to mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene. Endocr. Rev. 34, 239–277 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Pivonello, R. et al. Dopamine receptor expression and function in human normal adrenal gland and adrenal tumors. J. Clin. Endocrinol. Metab. 89, 4493–4502 (2004).

    Article  CAS  PubMed  Google Scholar 

  95. Gagliano, T. et al. Cabergoline reduces cell viability in non functioning pituitary adenomas by inhibiting vascular endothelial growth factor secretion. Pituitary 16, 91–100 (2013).

    Article  CAS  PubMed  Google Scholar 

  96. Molitch, M. E. Management of medically refractory prolactinoma. J. Neurooncol. http://dx.doi.org/10.1007/s11060-013-1270–1278.

  97. Gillam, M. P., Molitch, M. P., Lombardi, G. & Colao, A. Advances in the treatment of prolactinomas. Endocr. Rev. 27, 485–534 (2006).

    Article  CAS  PubMed  Google Scholar 

  98. Oh, M. C. & Aghi, M. K. Dopamine agonist-resistant prolactinomas. J. Neurosurg. 114, 1369–1379 (2011).

    Article  CAS  PubMed  Google Scholar 

  99. Melmed, S. Acromegaly pathogenesis and treatment. J. Clin. Invest. 119, 3189–3202 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Kreutzer, J., Vance, M. L., Lopes, M. B. & Laws, E. R. Jr. Surgical management of GH-secreting pituitary adenomas: an outcome study using modern remission criteria. J. Clin. Endocrinol. Metab. 86, 4072–4077 (2001).

    Article  CAS  PubMed  Google Scholar 

  101. Wilson, T. J., McKean, E. L., Barkan, A. L., Chandler, W. F. & Sullivan, S. E. Repeat endoscopic transsphenoidal surgery for acromegaly: remission and complications. Pituitary 16, 459–464 (2013).

    Article  CAS  PubMed  Google Scholar 

  102. Melmed, S. et al. Acromegaly Consensus Group. Guidelines for acromegaly management: an update. J. Clin. Endocrinol. Metab. 94, 1509–1517 (2009).

    Article  CAS  PubMed  Google Scholar 

  103. Gola, M., Bonadonna, S., Mazziotti, G., Amato, G. & Giustina, A. Resistance to somatostatin analogs in acromegaly: an evolving concept? J. Endocrinol. Invest. 29, 86–93 (2006).

    Article  CAS  PubMed  Google Scholar 

  104. Colao, A., Auriemma, R. S., Lombardi, G. & Pivonello, R. Resistance to somatostatin analogs in acromegaly. Endocr. Rev. 32, 247–271 (2011).

    Article  CAS  PubMed  Google Scholar 

  105. Fougner, S. L., Casar-Borota, O., Heck, A., Berg, J. P. & Bollerslev, J. Adenoma granulation pattern correlates with clinical variables and effect of somatostatin analogue treatment in a large series of patients with acromegaly. Clin. Endocrinol. 76, 96–102 (2012).

    Article  CAS  Google Scholar 

  106. Kato, M. et al. Differential expression of genes related to drug responsiveness between sparsely and densely granulated somatotroph adenomas. Endocr. J. 59, 221–228 (2012).

    Article  CAS  PubMed  Google Scholar 

  107. Kopchick, J. J., Parkinson, C., Stevens, E. C. & Trainer, P. J. Growth hormone receptor antagonists: discovery, development and use in patients with acromegaly. Endocr. Rev. 23, 623–646 (2002).

    Article  CAS  PubMed  Google Scholar 

  108. Parkinson, C. & Trainer, D. J. The place of pegvisomant in the management of acromegaly. Endocrinologist 13, 408–416 (2003).

    Article  Google Scholar 

  109. Paisley, A. N. & Drake, W. H. Treatment of pituitary tumors. Pegvisomant. Endocrine 28, 111–114 (2005).

    Article  CAS  PubMed  Google Scholar 

  110. Kovacs, K. & Horvath, E. Effects of medical therapy on pituitary tumors. Ultrastruct. Pathol. 29, 163–167 (2005).

    Article  PubMed  Google Scholar 

  111. Drake, W. M., Berney, D. M., Kovacs, K. & Monson, J. P. Markers of cell proliferation in a GH-producing adenoma of a patient treated with pegvisomant. Eur. J. Endocrinol. 153, 203–205 (2005).

    Article  CAS  PubMed  Google Scholar 

  112. Horvath, E. & Kovacs, K. Pathology of acromegaly. Neuroendocrinology 83, 161–165 (2006).

    Article  CAS  PubMed  Google Scholar 

  113. Van der Lely et al. Long-term safety of pegvisomant in patients with acromegaly: comphrensive review of 1288 subjects in ACROSTUDY. J. Clin. Endocrinol. Metab. 97, 1589–1597 (2012).

    Article  CAS  PubMed  Google Scholar 

  114. Fleseriu, M. & Petersen, S. Medical management of Cushing's disease: what is the future? Pituitary 15, 330–341 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Colao, A., Boscaro, M., Ferone, D. & Casanueva, F. F. Managing Cushing's disease: the state of the art. Endocrine http://dx.doi.org/10.1007/s12020-013-0129–0122.

  116. Pollock, B. E. & Young, W. F. Jr. Stereotactic radiosurgery for patients with ACTH-producing pituitary adenomas after prior adrenalectomy. Int. J. Radiat. Oncol. Biol. Phys. 54, 839–841 (2002).

    Article  PubMed  Google Scholar 

  117. Vik-Mo, E. O. et al. γ knife stereotactic radiosurgery of Nelson syndrome. Eur. J. Endocrinol. 160, 143–148 (2009).

    Article  CAS  PubMed  Google Scholar 

  118. Petit, J. H. et al. Proton stereotactic radiotherapy for persistent adrenocorticotropin-producing adenomas. J. Clin. Endocrinol. Metab. 93, 393–399 (2008).

    Article  CAS  PubMed  Google Scholar 

  119. Banasiak, M. J. & Malek, A. R. Nelson syndrome: comprehensive review of pathophysiology, diagnosis, and management. Neurosurg. Focus 23, E13 (2007).

    Article  PubMed  Google Scholar 

  120. Wagenmakers, M. A. et al. Endoscopic transsphenoidal pituitary surgery: a good and safe primary treatment option for Cushing's disease, even in case of macroadenomas or invasive adenomas. Eur. J. Endocrinol. 169, 329–337 (2013).

    Article  CAS  PubMed  Google Scholar 

  121. Pereira, A. M. & Biermasz, N. R. Treatment of nonfunctioning pituitary adenomas: what were the contributions of the last 10 years? A critical view. Ann. Endocrinol. (Paris) 73, 111–116 (2012).

    Article  Google Scholar 

  122. Ding, D., Starke, R. M. & Sheehan, J. P. Treatment paradigms for pituitary adenomas: defining the roles of radiosurgery and radiation therapy. J. Neurooncol. http://dx.doi.org/10.1007/s11060-013-1262–1268.

  123. Castinetti, F. et al. Outcome of γ knife radiosurgery in 82 patients with acromegaly: correlation with initial hypersecretion. Clin. Endocrinol. Metab. 90, 4483–4488 (2005).

    Article  CAS  Google Scholar 

  124. Prasad, D. Clinical results of conformal radiotherapy and radiosurgery for pituitary adenoma. Neurosurg. Clin. N. Am. 17, 129–141 (2006).

    Article  PubMed  Google Scholar 

  125. 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 http://dx.doi.org/10.1007/s11102-013-0541-x.

  126. Castinetti, F., Regis, J., Dufour, H. & Brue, T. Role of stereotactic radiosurgery in the management of pituitary adenomas. Nat. Rev. Endocrinol. 6, 214–223 (2010).

    Article  PubMed  Google Scholar 

  127. Minniti, G. et al. Risk of second brain tumor after conservative surgery and radiotherapy for pituitary adenoma: update after an additional 10 years. J. Clin. Endocrinol. Metab. 90, 800–804 (2005).

    Article  CAS  PubMed  Google Scholar 

  128. MacLean, J., Aldridge, M., Bomanji, J., Short, S. & Fersht, N. Peptide receptor radionuclide therapy for aggressive atypical pituitary adenoma/carcinoma: variable clinical response in preliminary evaluation. Pituitary http://dx.doi.org/10.1007/s11102-013-0540-y.

  129. Mrugala, M. M. & Chamberlain, M. C. Mechanisms of disease: temozolomide and glioblastoma—look to the future. Nat. Clin. Pract Oncol. 5, 476–486 (2008).

    Article  CAS  PubMed  Google Scholar 

  130. Stupp, R., van den Bent, M. J. & Hegi, M. E. Optimal role of temozolomide in the treatment of malignant gliomas. Curr. Neurol. Neurosci. Rep. 5, 198–206 (2005).

    Article  CAS  PubMed  Google Scholar 

  131. Salehi. F. et al. O-6 methylguanine-DNA methyltransferase (MGMT) immunohistochemical expression in pituitary cortocotroph adenomas. Neurosurgery 70, 491–496 (2012).

    Article  PubMed  Google Scholar 

  132. Kovacs, K. et al. MGMT immunoexpression predicts responsiveness of pituitary tumors to temozolomide therapy. Acta Neuropathol. 115, 261–262 (2008).

    Article  PubMed  Google Scholar 

  133. Ortiz, L. D. et al. Temozolomide in aggressive pituitary adenomas and carcinomas. Clinics (Sao Paulo) 67 (Suppl. 1), 119–123 (2012).

    Article  Google Scholar 

  134. Syro, L. V. et al. Antitumour effects of temozolomide in a man with a large, invasive prolactin-producing pituitary neoplasm. Clin. Endocrinol. (Oxf.) 65, 552–553 (2006).

    Article  Google Scholar 

  135. Kovacs, K. et al. Temozolomide therapy in a man with an aggressive prolactin-secreting pituitary neoplasm: morphological findings. Hum. Pathol. 38, 185–189 (2007).

    Article  CAS  PubMed  Google Scholar 

  136. Syro, L. V. et al. Treatment of pituitary neoplasms with temozolomide: a review. Cancer 117, 454–462 (2011).

    Article  CAS  PubMed  Google Scholar 

  137. Moshkin, O. et al. Aggressive silent corticotroph adenoma progressing to pituitary carcinoma: the role of temozolomide therapy. Hormones (Athens) 10, 162–167 (2011).

    Article  Google Scholar 

  138. Ortiz, L. D. et al. Anti-VEGF therapy in pituitary carcinoma. Pituitary 15, 445–449 (2012).

    Article  PubMed  Google Scholar 

  139. Bode, H. et al. SOM230 (pasireotide) and temozolomide achieve sustained control of tumour progression and ACTH secretion in pituitary carcinoma with widespread metastases. Exp. Clin. Endocrinol. Diabetes 118, 760–763 (2010).

    Article  CAS  PubMed  Google Scholar 

  140. Zacharia, B. E. et al. High response rates and prolonged survival in patients with corticotroph pituitary tumors and refractory Cushing's disease from capecitabine and temozolomide (CAPTEM): a case series. Neurosurgery 74, E447–E455 (2014).

    Article  PubMed  Google Scholar 

  141. Jouanneau, E. et al. New targeted therapies in pituitary carcinoma resistant to temozolomide. Pituitary 15, 37–43 (2012).

    Article  CAS  PubMed  Google Scholar 

  142. Fukuoka, H. et al. EGFR as a therapeutic target for human, canine, and mouse ACTH-secreting pituitary adenomas. J. Clin. Invest. 121, 4712–4721 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Fukuoka, H. et al. HER2/ErbB2 receptor signaling in rat and human prolactinoma cells: strategy for targeted prolactinoma therapy. Mol. Endocrinol. 25, 92–103 (2011).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors are grateful to the Jarislowsky and Lloyd Carr-Harris Foundations for their generous support.

Author information

Authors and Affiliations

Authors

Contributions

A.D.I., F.R. and L.V.S. researched data for the article. A.D.I. and K.K. made substantial contributions to discussions of the content. A.D.I. and L.V.S. wrote the article. A.D.I., F.R., L.V.S., M.D.C. and K.K. reviewed and edited the manuscript before submission.

Corresponding author

Correspondence to Antonio Di Ieva.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Di Ieva, A., Rotondo, F., Syro, L. et al. Aggressive pituitary adenomas—diagnosis and emerging treatments. Nat Rev Endocrinol 10, 423–435 (2014). https://doi.org/10.1038/nrendo.2014.64

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrendo.2014.64

This article is cited by

Search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer