title: Evolution of an aggressive prolactinoma into a growth hormone secreting pituitary tumor coincident with GNAS gene mutation.
abstract: BACKGROUND
  Mixed PRL- and GH-secreting pituitary adenomas are relatively common because somatotrophs and lactotrophs share the common somato-mammotroph progenitor lineage. Conversely, the occurrence of a prolactinoma evolving into clinically and biochemically active acromegaly is a rare phenomenon.
  
  
  OBJECTIVE
  We report a patient with a prolactinoma who after 15 yr of disease control by bromocriptine became resistant to dopaminergic drugs and due to the rapid tumor growth was submitted to four neurosurgeries and two stereotactic radiotherapies in the subsequent 5 yr. Unexpectedly, in the last 1.5 yr, after the fourth neurosurgery and second gamma-knife, she complained of signs and symptoms of acromegaly that was biochemically confirmed. Histological examination of the surgical specimens revealed high Ki67 and p53 and low D2 receptor expression. Although samples from the initial surgery were positive for prolactin and negative for GH, about 10% of GH-positive cells were detected in tissue from the last surgery, consistent with the observed clinical shift to acromegaly. Molecular screening failed to find mutations in RAS, TP53, and BRAF hot spots, whereas Arg201His mutation in GNAS gene (gsp oncogene), absent in the previous surgical materials, was detected in the tumor from the last surgery, which was found to be monoclonal.
  
  
  CONCLUSIONS
  These observations suggest that 1)treatment of prolactinomas resistant to dopaminergic drugs is still a challenge, and 2) the appearance of gsp oncogene in a prolactinoma evolving into acromegaly might be the underlying mechanism of this rare transition, further confirming that this mutational change is associated with somatotroph growth and transformation.
authors.affiliation: Endocrinology and Diabetology Unit, Department of Medical Sciences,Fondazione Ospedale Maggiore Istituto di Ricovero e Cura a Carattere Scientifico, University of Milan, 20122 Milan, Italy.
authors.forename: Andrea G
authors.initials: AG
authors.lastname: Lania
authors.forename: Stefano
authors.initials: S
authors.lastname: Ferrero
authors.forename: Rosario
authors.initials: R
authors.lastname: Pivonello
authors.forename: Giovanna
authors.initials: G
authors.lastname: Mantovani
authors.forename: Erika
authors.initials: E
authors.lastname: Peverelli
authors.forename: Antonella
authors.initials: A
authors.lastname: Di Sarno
authors.forename: Paolo
authors.initials: P
authors.lastname: Beck-Peccoz
authors.forename: Anna
authors.initials: A
authors.lastname: Spada
authors.forename: Annamaria
authors.initials: A
authors.lastname: Colao
mesh_terms: D002864:Chromogranins; D004252:DNA Mutational Analysis; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics*; D049912:Growth Hormone-Secreting Pituitary Adenoma / Q000235:genetics* / Q000473:pathology*; D006801:Humans; D008875:Middle Aged; D009154:Mutation / Q000502:physiology; D009361:Neoplasm Invasiveness; D010911:Pituitary Neoplasms / Q000235:genetics / Q000473:pathology*; D015175:Prolactinoma / Q000235:genetics / Q000473:pathology*
chemical_list: D002864:Chromogranins; C406732:GNAS protein, human; D019205:GTP-Binding Protein alpha Subunits, Gs