From Resistant to Aggressive and Malignant Prolactinomas: A Translational Approach

Prolactinomas are the most frequent pituitary adenomas. Most are successfully treated with Dopamine-Agonists (DA) and Cabergoline (CAB) is recommended as a first line therapeutic option. However, up to 20% may present primary or secondary DA/CAB resistance. Primary resistance is more frequent in macro- and/or invasive prolactinomas, in males and in the presence of inherited genetic predisposition to pituitary adenomas. Secondary resistance develops during follow-up, possibly indicating a change in tumour behaviour. Whereas partial resistance can be frequently overcome by increasing the weekly CAB dose above the labelled dose, severe resistance is typically associated with more aggressive features, often requiring a multimodal approach. Surgery may be indicated to improve neurological symptoms, before pregnancy, or to reduce pharmacological requirement. Because highly aggressive and malignant prolactinomas are life-threatening diseases, a panel of clinical, pathological and molecular features may be considered in order to achieve an early diagnosis and plan an adeguate follow-up and treatment. In addition to surgery and/or radiotherapy, Temozolomide (TMZ) currently represents the best option for highly aggressive/malignant prolactinomas. However, up to 30-40% of these tumours may not respond satisfactorily to TMZ and require innovative and personalized therapeutic approaches, such as molecular or radionuclide therapies targeted upon further characterization of the tumour. Increasing knowledge about the pathways involved in severe DA resistance and the aggressive behaviour of prolactinomas should help improve the clinical outcome of such patients.