At the Cutting Edge Neuroendocrinology 2019;109:57–69 Aggressive and Malignant Prolactinomas Nicoleta Cristina Olarescu a Luis G. Perez-Rivas b Federico Gatto c Thomas Cuny d Maria A. Tichomirowa e Gianluca Tamagno f, g Manuel D. Gahete h–k on behalf of EYRC (ENEA Young Researcher Committee) a Section of Specialized Endocrinology, Department of Endocrinology, Oslo University Hospital, Oslo, Norway; b Medizinische Klinik und Poliklinik IV, Klinikum der LMU, Ludwig-Maximilians-Universität München, Munich, Germany; c Endocrinology Unit, IRCCS Ospedale Policlinico San Martino, Genoa, Italy; d Service d’Endocrinologie, Hôpital de la Conception, Inserm U1251, Marseille Medical Genetics, APHM, Aix-Marseille University, Marseille, France; e Service d’Endocrinologie, Centre Hospitalier du Nord, Ettelbruck, Luxembourg; f Department of Endocrinology/Diabetes Mellitus, Mater Misericordiae University Hospital, Dublin, Ireland; g Department of Medicine, Wexford General Hospital, Wexford, Ireland; h Maimonides Institute for Biomedical Research of Cordoba (IMIBIC), Cordoba, Spain; i Universidad de Córdoba, Cordoba, Spain; j Reina Sofia University Hospital, Cordoba, Spain; k CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Cordoba, Spain Received: November 20, 2018 Accepted after revision: January 24, 2019 Published online: January 24, 2019 Manuel D. Gahete Ed. IMIBIC. Avda. Menéndez Pidal s/n ES–14004 Cordoba (Spain) E-Mail bc2gaorm@uco.es Nicoleta C. Olarescu Department of Specialized Endocrinology Oslo University Hospital, Rikshospitalet Box 4950, Nydalen, NO–0424 Oslo (Norway) E-Mail nicola@rr-research.no © 2019 S. Karger AG, Basel E-Mail karger@karger.com www.karger.com/nen DOI: 10.1159/000497205 Keywords Aggressiveness · Dopamine receptor · Dopamine agonists · Preclinical models Abstract Prolactin-secreting tumors (prolactinomas) represent the most common pituitary tumor type, accounting for 47–66% of func- tional pituitary tumors. Prolactinomas are usually benign and controllable tumors as they express abundant levels of dopa- mine type 2 receptor (D2), and can be treated with dopaminer- gic drugs, effectively reducing prolactin levels and tumor vol- ume. However, a proportion of prolactinomas exhibit aggres- sive features (including invasiveness, relevant growth despite adequate dopamine agonist treatment, and recurrence poten- tial) and few may exhibit metastasizing potential (carcinomas). In this context, the clinical, pathological, and molecular defini- tions of malignant and aggressive prolactinomas remain to be clearly defined, as primary prolactin-secreting carcinomas are similar to aggressive adenomas until the presence of metasta- ses is detected. Indeed, standard molecular and histological analyses do not reflect differences between carcinomas and adenomas at a first glance and have limitations in prediction of the aggressive progression of prolactinomas, wherein the causes underlying the aggressive behavior remain unknown. Herein we present a comprehensive, multidisciplinary review of the most relevant epidemiological, clinical, pathological, ge- netic, biochemical, and molecular aspects of aggressive and malignant prolactinomas. © 2019 S. Karger AG, Basel Introduction Prolactin (PRL)-secreting tumors or prolactinomas comprise the most common pituitary tumor type, ac- counting for 47–66% of all pituitary tumors [1, 2]. Prolac-