Evolution of an aggressive prolactinoma into a growth hormone secreting pituitary tumor coincident with GNAS gene mutation

Context: 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 and Results: 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 γ-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.