hormone–releasing hormone (GHRH) receptor, to intracellular effectors (e.g., adenyl cyclase), which then generate second messengers (e.g., cAMP). G-proteins are heterotrimeric proteins, composed of a specific α-subunit that binds guanine nucleotides and interacts with both cell surface receptors and intracellular effectors (
Fig. 20.3 ); the β-and γ-subunits are noncovalently bound to the α-subunit. Gs is a stimulatory G protein that has a pivotal role in signal transduction in several endocrine organs, including the pituitary. The α-subunit of Gs (Gsα) is encoded by the GNAS gene. In the basal state, Gs exists in an inactive state, with guanosine diphosphate (GDP) bound to the guanine nucleotide-binding site of Gsα. On interaction with the ligand-bound cell surface receptor, GDP dissociates, and guanosine triphosphate (GTP) binds to Gsα, activating the G protein. The activation of Gsα results in the generation of cAMP, which is a potent mitogenic stimulus in several endocrine cells (e.g., pituitary somatotrophs and corticotrophs, thyroid follicular cells, parathyroid cells), promoting cellular proliferation and hormone synthesis and secretion. Normally, Gsα activation is transient because of an intrinsic GTPase activity in the α-subunit, which hydrolyzes GTP into GDP. Approximately 40% of somatotroph cell adenomas bear GNAS mutations that abrogate the GTPase activity of Gsα, leading to constitutive activation of Gsα, persistent generation of cAMP, and unchecked cellular proliferation. GNAS mutations also have been described in a minority of corticotroph adenomas; but are absent in thyrotroph, lactotroph, and gonadotroph adenomas, which arise from cells whose hypothalamic release hormones do not signal via cAMP-dependent pathways.
Approximately 5% of pituitary adenomas arise as a result of an inherited predisposition. Four genes have been identified thus far as a cause of familial pituitary adenomas: MEN1, CDKN1B, PRKAR1A, and AIP. These genes regulate transcription and the cell cycle. Of note, somatic mutations of these four genes are rarely encountered in sporadic pituitary adenomas.
Molecular abnormalities associated with aggressive behavior include aberrations in cell cycle checkpoint genes, such as overexpression of cyclin D1, mutations of TP53, and epigenetic silencing of the retinoblastoma gene (RB). In addition, activating mutations of the RAS oncogene are observed in rare pituitary carcinomas. The functions of these genes were discussed in Chapter 6.
MORPHOLOGYTheusualpituitaryadenomaisawell-circumscribed,softlesion.Smalltumorsmaybeconfinedtothesellaturcica,whilelargerlesionsmaycompresstheopticchiasmandadjacentstructures(
Fig.20.4 ),erodethesellaturcicaandanteriorclinoidprocesses,andextendlocallyintothecavernousandsphenoidalsinuses.Inasmanyas30%ofcases,theadenomasarenonencapsulatedandinfiltrateadjacentbone,dura,and(uncommonly)brain.Fociofhemorrhageand/ornecrosisarecommoninlargeradenomas.
Pituitaryadenomasarecomposedofrelativelyuniform,polygonalcellsarrayedinsheets,cords,orpapillae.Supportingconnectivetissue,orreticulin,issparse.Thenucleioftheneoplasticcellsmaybeuniformorpleomorphic.Thiscellularmonomorphismandtheabsenceofasignificantreticulinnetworkdistinguishpituitaryadenomasfromnon-neoplasticanteriorpituitaryparenchyma(