Aggressive prolactinomas: how to manage?



Aggressive prolactinomas are defined as radiologically invasive tumors which cannot be cured by surgery, and that have an unusually rapid rate of tumor growth despite dopamine agonist treatment and surgery. In some cases, metastasis occurs, defining prolactin carcinoma which is the second most frequent pituitary carcinoma.


A literature search was performed to review the available data on the treatment of aggressive pituitary prolactinomas or carcinomas.


When optimal standard therapies (high dose cabergoline, surgery and radiotherapy) failed, temozolomide, an alkylating drug, is currently the best option, allowing to control tumor growth in about 50% of treated prolactinomas and improving overall survival of these patients. However, long-term complete response occurs in a limited subgroup of tumors. Alternative drugs could be discussed in a subset of aggressive prolactinomas either before temozolomide (pasireotide, peptide receptor radionuclide therapy…) or after temozolomide failure.


Despite the significant improvement obtained with the use of temozolomide, a need for alternative drugs persists since a majority of these tumors are resistant or will recur during the follow-up. Patients suffering from such a rare condition should have access to clinical trials available for other types of rare cancers, such as tyrosine kinase inhibitors or immunotherapy.

This is a preview of subscription content, log in to check access.

Access options

Buy single article

Instant unlimited access to the full article PDF.

US$ 39.95

Price includes VAT for USA

Subscribe to journal

Immediate online access to all issues from 2019. Subscription will auto renew annually.

US$ 99

This is the net price. Taxes to be calculated in checkout.

Fig. 1
Fig. 2


  1. 1.

    Raverot G, Burman P, McCormack A et al (2018) European Society of Endocrinology Clinical Practice Guidelines for the management of aggressive pituitary tumours and carcinomas. Eur J Endocrinol 178:G1–G24.

  2. 2.

    Melmed S, Casanueva FF, Hoffman AR et al (2011) Diagnosis and treatment of hyperprolactinemia: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 96:273–288.

  3. 3.

    Maiter D (2019) Management of dopamine agonist-resistant prolactinoma. Neuroendocrinology 109:42–50.

  4. 4.

    Webster J, Piscitelli G, Polli A et al (1994) A comparison of cabergoline and bromocriptine in the treatment of hyperprolactinemic amenorrhea. Cabergoline Comparative Study Group. N Engl J Med 331:904–909.

  5. 5.

    Delgrange E, Maiter D, Donckier J (1996) Effects of the dopamine agonist cabergoline in patients with prolactinoma intolerant or resistant to bromocriptine. Eur J Endocrinol 134:454–456

  6. 6.

    Delgrange E, Daems T, Verhelst J et al (2009) Characterization of resistance to the prolactin-lowering effects of cabergoline in macroprolactinomas: a study in 122 patients. Eur J Endocrinol 160:747–752.

  7. 7.

    Delgrange E, Vasiljevic A, Wierinckx A et al (2015) Expression of estrogen receptor alpha is associated with prolactin pituitary tumor prognosis and supports the sex-related difference in tumor growth. Eur J Endocrinol 172:791–801.

  8. 8.

    Raverot G, Wierinckx A, Dantony E et al (2010) 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.

  9. 9.

    McCormack A, Dekkers OM, Petersenn S et al (2018) Treatment of aggressive pituitary tumours and carcinomas: results of a European Society of Endocrinology (ESE) survey 2016. Eur J Endocrinol 178:265–276.

  10. 10.

    Salenave S, Ancelle D, Bahougne T et al (2015) Macroprolactinomas in children and adolescents: factors associated with the response to treatment in 77 patients. J Clin Endocrinol Metab 100:1177–1186.

  11. 11.

    Philippon M, Morange I, Barrie M et al (2012) Long-term control of a MEN1 prolactin secreting pituitary carcinoma after temozolomide treatment. Ann Endocrinol 73:225–229.

  12. 12.

    Gan H-W, Bulwer C, Jeelani O et al (2015) Treatment-resistant pediatric giant prolactinoma and multiple endocrine neoplasia type 1. Int J Pediatr Endocrinol 2015:15.

  13. 13.

    Shimon I, Sosa E, Mendoza V et al (2016) Giant prolactinomas larger than 60 mm in size: a cohort of massive and aggressive prolactin-secreting pituitary adenomas. Pituitary 19:429–436.

  14. 14.

    Molitch ME (2014) Management of medically refractory prolactinoma. J Neurooncol 117:421–428.

  15. 15.

    Gürlek A, Karavitaki N, Ansorge O, Wass JAH (2007) What are the markers of aggressiveness in prolactinomas? Changes in cell biology, extracellular matrix components, angiogenesis and genetics. Eur J Endocrinol 156:143–153.

  16. 16.

    Trouillas J, Delgrange E, Wierinckx A et al (2019) Clinical, pathological, and molecular factors of aggressiveness in lactotroph tumours. Neuroendocrinology 109:70–76.

  17. 17.

    Lloyd RV, Scheithauer BW, Kuroki T et al (1999) Vascular endothelial growth factor (VEGF) expression in human pituitary adenomas and carcinomas. Endocr Pathol 10:229–235

  18. 18.

    Cooper O, Mamelak A, Bannykh S et al (2014) Prolactinoma ErbB receptor expression and targeted therapy for aggressive tumors. Endocrine 46:318–327.

  19. 19.

    Qian ZR, Li CC, Yamasaki H, et al. (2002) Role of E-cadherin, alpha-, beta-, and gamma-catenins, and p120 (cell adhesion molecules) in prolactinoma behavior. Mod Pathol Off J US Can Acad Pathol Inc 15:1357–1365.

  20. 20.

    Turner HE, Nagy Z, Esiri MM et al (2000) Role of matrix metalloproteinase 9 in pituitary tumor behavior. J Clin Endocrinol Metab 85:2931–2935.

  21. 21.

    Wierinckx A, Delgrange E, Bertolino P et al (2018) Sex-related differences in lactotroph tumor aggressiveness are associated with a specific gene-expression signature and genome instability. Front Endocrinol 9:706.

  22. 22.

    Finelli P, Pierantoni GM, Giardino D et al (2002) The High Mobility Group A2 gene is amplified and overexpressed in human prolactinomas. Cancer Res 62:2398–2405

  23. 23.

    Kaltsas GA, Nomikos P, Kontogeorgos G et al (2005) Clinical review: diagnosis and management of pituitary carcinomas. J Clin Endocrinol Metab 90:3089–3099.

  24. 24.

    Hamilton DK, Vance ML, Boulos PT, Laws ER (2005) Surgical outcomes in hyporesponsive prolactinomas: analysis of patients with resistance or intolerance to dopamine agonists. Pituitary 8:53–60.

  25. 25.

    Vroonen L, Jaffrain-Rea M-L, Petrossians P et al (2012) Prolactinomas resistant to standard doses of cabergoline: a multicenter study of 92 patients. Eur J Endocrinol 167:651–662.

  26. 26.

    Primeau V, Raftopoulos C, Maiter D (2012) Outcomes of transsphenoidal surgery in prolactinomas: improvement of hormonal control in dopamine agonist-resistant patients. Eur J Endocrinol 166:779–786.

  27. 27.

    Cohen-Inbar O, Xu Z, Schlesinger D et al (2015) Gamma Knife radiosurgery for medically and surgically refractory prolactinomas: long-term results. Pituitary 18:820–830.

  28. 28.

    Pan L, Zhang N, Wang EM et al (2000) Gamma knife radiosurgery as a primary treatment for prolactinomas. J Neurosurg 93(Suppl 3):10–13.

  29. 29.

    Minniti G, Clarke E, Scaringi C, Enrici RM (2016) Stereotactic radiotherapy and radiosurgery for non-functioning and secreting pituitary adenomas. Rep Pract Oncol Radiother J Gt Cancer Cent Poznan Pol Soc Radiat Oncol 21:370–378.

  30. 30.

    O’Reilly SM, Newlands ES, Glaser MG et al (1990) (1993) Temozolomide: a new oral cytotoxic chemotherapeutic agent with promising activity against primary brain tumours. Eur J Cancer Oxf Engl 29A:940–942

  31. 31.

    Lim S, Shahinian H, Maya MM et al (2006) Temozolomide: a novel treatment for pituitary carcinoma. Lancet Oncol 7:518–520.

  32. 32.

    Ji Y, Vogel RI, Lou E (2016) Temozolomide treatment of pituitary carcinomas and atypical adenomas: systematic review of case reports. Neuro-Oncol Pract 3:188–195.

  33. 33.

    Syro LV, Rotondo F, Ortiz LD, Kovacs K (2018) 65 YEARS OF THE DOUBLE HELIX: Treatment of pituitary tumors with temozolomide: an update. Endocr Relat Cancer 25:T159–T169.

  34. 34.

    Lasolle H, Cortet C, Castinetti F et al (2017) Temozolomide treatment can improve overall survival in aggressive pituitary tumors and pituitary carcinomas. Eur J Endocrinol 176:769–777.

  35. 35.

    Scaringi C, De Sanctis V, Minniti G, Enrici RM (2013) Temozolomide-related hematologic toxicity. Onkologie 36:444–449.

  36. 36.

    Hirohata T, Asano K, Ogawa Y et al (2013) 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.

  37. 37.

    Bengtsson D, Schrøder HD, Andersen M et al (2015) 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.

  38. 38.

    Kaltsas GA, Mukherjee JJ, Plowman PN et al (1998) The role of cytotoxic chemotherapy in the management of aggressive and malignant pituitary tumors. J Clin Endocrinol Metab 83:4233–4238.

  39. 39.

    Petterson T, MacFarlane IA, MacKenzie JM, Shaw MD (1992) Prolactin secreting pituitary carcinoma. J Neurol Neurosurg Psychiatry 55:1205–1206.

  40. 40.

    Pernicone PJ, Scheithauer BW, Sebo TJ et al (1997) Pituitary carcinoma: a clinicopathologic study of 15 cases. Cancer 79:804–812.;2-3

  41. 41.

    Fusco A, Gunz G, Jaquet P et al (2008) Somatostatinergic ligands in dopamine-sensitive and -resistant prolactinomas. Eur J Endocrinol 158:595–603.

  42. 42.

    Fusco A, Lugli F, Sacco E et al (2011) Efficacy of the combined cabergoline and octreotide treatment in a case of a dopamine-agonist resistant macroprolactinoma. Pituitary 14:351–357.

  43. 43.

    Lasolle H, Vasiljevic A, Borson-Chazot F, Raverot G (2019) Pasireotide: a potential therapeutic alternative for resistant prolactinoma. Ann Endocrinol 80:84–88.

  44. 44.

    Coopmans EC, van Meyel SWF, Pieterman KJ et al (2019) Excellent response to pasireotide therapy in an aggressive and dopamine-resistant prolactinoma. Eur J Endocrinol.

  45. 45.

    Raverot G, Vasiljevic A, Jouanneau E, Lasolle H (2019) Excellent response to pasireotide therapy in an aggressive and dopamine-resistant prolactinoma—commentary. Eur J Endocrinol.

  46. 46.

    Xiao J, Zhu Z, Zhong D et al (2015) Improvement in diagnosis of metastatic pituitary carcinoma by 68Ga DOTATATE PET/CT. Clin Nucl Med 40:e129–131.

  47. 47.

    Priola SM, Esposito F, Cannavò S et al (2017) Aggressive pituitary adenomas: the dark side of the moon. World Neurosurg 97:140–155.

  48. 48.

    Giuffrida G, Ferrau F, Laudicella R et al (2019) Peptide receptor radionuclide therapy for aggressive pituitary tumors: a monocentric experience. Endocr Connect.

  49. 49.

    Maclean J, Aldridge M, Bomanji J et al (2014) Peptide receptor radionuclide therapy for aggressive atypical pituitary adenoma/carcinoma: variable clinical response in preliminary evaluation. Pituitary 17:530–538.

  50. 50.

    Zhang D, Way JS, Zhang X et al (2019) Effect of everolimus in treatment of aggressive prolactin-secreting pituitary adenomas. J Clin Endocrinol Metab 104:1929–1936.

  51. 51.

    Chanal M, Chevallier P, Raverot V et al (2016) Differential effects of PI3K and dual PI3K/mTOR inhibition in rat prolactin-secreting pituitary tumors. Mol Cancer Ther 15:1261–1270.

  52. 52.

    Donovan LE, Arnal AV, Wang S-H, Odia Y (2016) Widely metastatic atypical pituitary adenoma with mTOR pathway STK11(F298L) mutation treated with everolimus therapy. CNS Oncol 5:203–209.

  53. 53.

    Jouanneau E, Wierinckx A, Ducray F et al (2012) New targeted therapies in pituitary carcinoma resistant to temozolomide. Pituitary 15:37–43.

  54. 54.

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

  55. 55.

    Cooper O, Bonert V, Rudnick J et al (2019) SUN-442 EGFR/ErbB2 targeted therapy for aggressive prolactinomas. J Endocr Soc 46:318–327.

  56. 56.

    Wang Y, Li J, Tohti M et al (2014) The expression profile of Dopamine D2 receptor, MGMT and VEGF in different histological subtypes of pituitary adenomas: a study of 197 cases and indications for the medical therapy. J Exp Clin Cancer Res CR 33:56.

  57. 57.

    Ortiz LD, Syro LV, Scheithauer BW et al (2012) Anti-VEGF therapy in pituitary carcinoma. Pituitary 15:445–449.

  58. 58.

    Rotman LE, Vaughan TB, Hackney JR, Riley KO (2019) Long-term survival after transformation of an adrenocorticotropic hormone-secreting pituitary macroadenoma to a silent corticotroph pituitary carcinoma. World Neurosurg 122:417–423.

  59. 59.

    Chauvet N, Romanò N, Lafont C et al (2017) Complementary actions of dopamine D2 receptor agonist and anti-vegf therapy on tumoral vessel normalization in a transgenic mouse model. Int J Cancer 140:2150–2161.

  60. 60.

    Lin AL, Jonsson P, Tabar V et al (2018) Marked response of a hypermutated ACTH-secreting pituitary carcinoma to ipilimumab and nivolumab. J Clin Endocrinol Metab 103:3925–3930.

  61. 61.

    Wang P-F, Wang T-J, Yang Y-K et al (2018) The expression profile of PD-L1 and CD8+ lymphocyte in pituitary adenomas indicating for immunotherapy. J Neurooncol 139:89–95.

  62. 62.

    Mei Y, Bi WL, Greenwald NF et al (2016) Increased expression of programmed death ligand 1 (PD-L1) in human pituitary tumors. Oncotarget 7:76565–76576.

Download references

Author information

Correspondence to Gérald Raverot.

Ethics declarations

Conflict of interest

Gérald Raverot has received research Grants from Novartis Pharma and IPSEN; speaker honorarium from Novartis Pharma and IPSEN, consultant for Pfizer, Ipsen and Novartis. Mirela Diana Ilie and Hélène Lasolle declare they have no conflict of interest.

Research involving human participants and animals rights

This article does not contain any studies with human participants or animals performed by any of the authors.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Lasolle, H., Ilie, M.D. & Raverot, G. Aggressive prolactinomas: how to manage?. Pituitary 23, 70–77 (2020).

Download citation


  • Pituitary tumor
  • Prolactinoma
  • Temozolomide
  • Pasireotide
  • Aggressive pituitary tumor
  • Pituitary carcinoma