title: A macroprolactinoma becoming resistant to cabergoline and developing atypical pathology.
abstract: Pituitary adenomas are a common intracranial neoplasm, usually demonstrating a benign phenotype. They can be classified according to pathological, radiological or clinical behaviour as typical, atypical or carcinomas, invasive or noninvasive, and aggressive or nonaggressive. Prolactinomas account for 40-60% of all pituitary adenomas, with dopamine agonists representing the first-line treatment and surgery/radiotherapy reserved for drug intolerance/resistance or in neuro-ophthalmological emergencies. We present the case of a 62-year-old man with an apparently indolent prolactin-secreting macroadenoma managed with partial resection and initially showing a biochemical response to cabergoline. Five years later, the tumour became resistant to cabergoline, despite a substantial increase in dosage, showing rapid growth and causing worsening of vision. The patient then underwent two further transsphenoidal operations and continued on high-dose cabergoline; despite these interventions, the tumour continued enlarging and prolactin increased to 107 269 U/L. Histology of the third surgical specimen demonstrated features of aggressive behaviour (atypical adenoma with a high cell proliferation index) not present in the tumour removed at the first operation. Subsequently, he was referred for radiotherapy aiming to control tumour growth.
  
  
  CONCLUSIONS
  The development of secondary resistance to dopamine agonists (DAs) is a serious sign as it may be associated with de-differentiation of the prolactinoma and thus of aggressive or malignant transformation.Significant de-differentiation of the adenoma documented on consecutive histologies suggests a possible transition to malignancy.A combination of histological 'alarm' features associated with persistent growth and escape from DAs treatment in recurrent adenomas should alert clinicians and demands close follow-up.A multidisciplinary approach by pathologists, endocrinologists and neurosurgeons is essential.
authors.affiliation: Department of Endocrinology, Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, University of Oxford, Oxford, UK; Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy.
authors.forename: Emilia
authors.initials: E
authors.lastname: Sbardella
authors.affiliation: Department of Endocrinology , Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, University of Oxford, Oxford , UK.
authors.forename: George
authors.initials: G
authors.lastname: Farah
authors.affiliation: Department of Endocrinology , Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, University of Oxford, Oxford , UK.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Fathelrahman
authors.affiliation: Department of Neurological Surgery.
authors.forename: Simon
authors.initials: S
authors.lastname: Cudlip
authors.affiliation: Department of Neuropathology , John Radcliffe Hospital, University of Oxford, Oxford , UK.
authors.forename: Olaf
authors.initials: O
authors.lastname: Ansorge
authors.affiliation: Institute of Metabolism and Systems Research , University of Birmingham and Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partner, Birmingham , UK.
authors.forename: Niki
authors.initials: N
authors.lastname: Karavitaki
authors.affiliation: Department of Endocrinology , Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, University of Oxford, Oxford , UK.
authors.forename: Ashley B
authors.initials: AB
authors.lastname: Grossman