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.
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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. https://doi.org/10.1530/EJE-17-0796
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. https://doi.org/10.1210/jc.2010-1692
Maiter D (2019) Management of dopamine agonist-resistant prolactinoma. Neuroendocrinology 109:42–50. https://doi.org/10.1159/000495775
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. https://doi.org/10.1056/NEJM199410063311403
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
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. https://doi.org/10.1530/EJE-09-0012
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. https://doi.org/10.1530/EJE-14-0990
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. https://doi.org/10.1210/jc.2009-1191
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. https://doi.org/10.1530/EJE-17-0933
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. https://doi.org/10.1210/jc.2014-3670
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. https://doi.org/10.1016/j.ando.2012.03.001
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. https://doi.org/10.1186/s13633-015-0011-5
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. https://doi.org/10.1007/s11102-016-0723-4
Molitch ME (2014) Management of medically refractory prolactinoma. J Neurooncol 117:421–428. https://doi.org/10.1007/s11060-013-1270-8
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. https://doi.org/10.1530/eje.1.02339
Trouillas J, Delgrange E, Wierinckx A et al (2019) Clinical, pathological, and molecular factors of aggressiveness in lactotroph tumours. Neuroendocrinology 109:70–76. https://doi.org/10.1159/000499382
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
Cooper O, Mamelak A, Bannykh S et al (2014) Prolactinoma ErbB receptor expression and targeted therapy for aggressive tumors. Endocrine 46:318–327. https://doi.org/10.1007/s12020-013-0093-x
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. https://doi.org/10.1097/01.MP.0000039572.75188.1A
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. https://doi.org/10.1210/jcem.85.8.6754
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. https://doi.org/10.3389/fendo.2018.00706
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
Kaltsas GA, Nomikos P, Kontogeorgos G et al (2005) Clinical review: diagnosis and management of pituitary carcinomas. J Clin Endocrinol Metab 90:3089–3099. https://doi.org/10.1210/jc.2004-2231
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. https://doi.org/10.1007/s11102-005-5086-1
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. https://doi.org/10.1530/EJE-12-0236
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. https://doi.org/10.1530/EJE-11-1000
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. https://doi.org/10.1007/s11102-015-0658-1
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. https://doi.org/10.3171/jns.2000.93.supplement
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. https://doi.org/10.1016/j.rpor.2014.09.004
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
Lim S, Shahinian H, Maya MM et al (2006) Temozolomide: a novel treatment for pituitary carcinoma. Lancet Oncol 7:518–520. https://doi.org/10.1016/S1470-2045(06)70728-8
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. https://doi.org/10.1093/nop/npv059
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. https://doi.org/10.1530/ERC-18-0015
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. https://doi.org/10.1530/EJE-16-0979
Scaringi C, De Sanctis V, Minniti G, Enrici RM (2013) Temozolomide-related hematologic toxicity. Onkologie 36:444–449. https://doi.org/10.1159/000353752
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. https://doi.org/10.1210/jc.2012-2924
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. https://doi.org/10.1210/jc.2014-4350
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. https://doi.org/10.1210/jcem.83.12.5300
Petterson T, MacFarlane IA, MacKenzie JM, Shaw MD (1992) Prolactin secreting pituitary carcinoma. J Neurol Neurosurg Psychiatry 55:1205–1206. https://doi.org/10.1136/jnnp.55.12.1205
Pernicone PJ, Scheithauer BW, Sebo TJ et al (1997) Pituitary carcinoma: a clinicopathologic study of 15 cases. Cancer 79:804–812. https://doi.org/10.1002/(sici)1097-0142(19970215)79:4%3c804:aid-cncr18%3e3.0.co;2-3
Fusco A, Gunz G, Jaquet P et al (2008) Somatostatinergic ligands in dopamine-sensitive and -resistant prolactinomas. Eur J Endocrinol 158:595–603. https://doi.org/10.1530/EJE-07-0806
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. https://doi.org/10.1007/s11102-008-0162-y
Lasolle H, Vasiljevic A, Borson-Chazot F, Raverot G (2019) Pasireotide: a potential therapeutic alternative for resistant prolactinoma. Ann Endocrinol 80:84–88. https://doi.org/10.1016/j.ando.2018.07.013
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. https://doi.org/10.1530/EJE-19-0279
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. https://doi.org/10.1530/EJE-19-0359
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. https://doi.org/10.1097/RLU.0000000000000462
Priola SM, Esposito F, Cannavò S et al (2017) Aggressive pituitary adenomas: the dark side of the moon. World Neurosurg 97:140–155. https://doi.org/10.1016/j.wneu.2016.09.092
Giuffrida G, Ferrau F, Laudicella R et al (2019) Peptide receptor radionuclide therapy for aggressive pituitary tumors: a monocentric experience. Endocr Connect. https://doi.org/10.1530/EC-19-0065
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. https://doi.org/10.1007/s11102-013-0540-y
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. https://doi.org/10.1210/jc.2018-02461
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. https://doi.org/10.1158/1535-7163.MCT-15-0891
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. https://doi.org/10.2217/cns-2016-0011
Jouanneau E, Wierinckx A, Ducray F et al (2012) New targeted therapies in pituitary carcinoma resistant to temozolomide. Pituitary 15:37–43. https://doi.org/10.1007/s11102-011-0341-0
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. https://doi.org/10.1210/me.2010-0353
Cooper O, Bonert V, Rudnick J et al (2019) SUN-442 EGFR/ErbB2 targeted therapy for aggressive prolactinomas. J Endocr Soc 46:318–327. https://doi.org/10.1210/js.2019-SUN-442
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. https://doi.org/10.1186/s13046-014-0056-y
Ortiz LD, Syro LV, Scheithauer BW et al (2012) Anti-VEGF therapy in pituitary carcinoma. Pituitary 15:445–449. https://doi.org/10.1007/s11102-011-0346-8
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. https://doi.org/10.1016/j.wneu.2018.11.011
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. https://doi.org/10.1002/ijc.30628
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. https://doi.org/10.1210/jc.2018-01347
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. https://doi.org/10.1007/s11060-018-2844-2
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. https://doi.org/10.18632/oncotarget.12088
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.
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Lasolle, H., Ilie, M.D. & Raverot, G. Aggressive prolactinomas: how to manage?. Pituitary 23, 70–77 (2020). https://doi.org/10.1007/s11102-019-01000-7
- Pituitary tumor
- Aggressive pituitary tumor
- Pituitary carcinoma