Systematic Review of the Molecular Basis for Cavernous Sinus Invasion in Somatotropinomas

Somatotropinomas are a subtype of pituitary adenomas that have a particular predilection to invade the cavernous sinus. The objective of this systematic review was to examine the evidence regarding the molecular basis for cavernous sinus invasion in somatotropinomas. This review was conducted in accordance with the 2020 PRISMA guidelines on the 13th of April 2025. Inclusion criteria were reports of associations between somatotropinoma molecular changes and cavernous sinus invasion in adult patients. Title/abstract screening and full text screening were performed, with studies assessed for risk of bias using the Newcastle-Ottawa scale. A total of 43 studies were identified, studying 1824 patients (724 invasive tumours). Overall, 33 studies identified molecules that were upregulated in invasive tumours, and 20 studies identified molecules that were downregulated. Few studies incorporated modern proteomic or transcriptomic techniques. Risk of bias was low with a mean Newcastle-Ottawa Scale score of 7.0 (± 0.6). Molecules associated with invasion were related to epithelial-mesenchymal transition (E-cadherin, ESRP1, Fascin 1 and MMP-9), cellular proliferation (PTTG,AIP, TCERG1, EIF2β, E2F1,Notch 2, STAT3, ARRB1, TGFB1, SMAD3, SOX9, SGK1, MAGEA6 DLL3, EGFL7 and pEGFR), hormonal signalling (GNAS, DRD5, DRD1, sst5TMD4, SSTR2 and SSTR5) and tumour angiogenesis (VEGF and Drp1). These molecular variations present a possible explanation for the proclivity of somatotropinomas for the cavernous sinus. Identified molecules represent options for novel targeted therapies or biomarkers that could inform prognostication. Modern proteomic and transcriptomic techniques and larger somatotropinoma datasets are required to further elucidate the molecular pathways responsible for cavernous sinus invasion in somatotropinomas.