Integrating Molecular and Imaging Insights: Ryanodine Receptor 2 (RyR2) Expression, CK18 Status, and Conventional MRI Findings in Pituitary Neuroendocrine Tumors.

Ryanodine receptor 2 (RyR2) has been increasingly recognized as an important regulator in cancer biology. Previous studies demonstrate that RyR2 expression is associated with patient survival, although its precise role in tumorigenesis remains unclear. Elevated RyR2 expression has been linked to poorer survival outcomes, while gene silencing or pharmacological inhibition (e.g., with S107) has been shown to reduce cancer cell metastasis in both in vitro and in vivo models. Cytokeratin 18 (CK18), a key epithelial marker, is associated with tumor differentiation, hormonal phenotype, and clinical behavior in pituitary neuroendocrine tumors (PitNETs), reflecting underlying cytoskeletal organization. Variations in CK18 expression have been linked to distinct adenoma subtypes and may provide insight into tumor aggressiveness. This exploratory study investigated associations between RyR2 expression, CK18 status, and conventional MRI findings of pituitary tumors. Quantitative T2-weighted signal intensity and radiomic features were not assessed. This exploratory observational study used prospective patient recruitment between January 2017 and January 2026, after ethics approval was obtained in December 2016. RyR2 expression in immunohistological samples was quantified using QuPath v0.6.0. CK18 immunostaining was performed with the Dako Omnis system according to the manufacturer's protocols. Conventional MRI findings were available for 24 patients and were retrospectively reviewed. Statistical analysis was conducted using SPSS/W 31.0. No statistically significant associations were observed between RyR2 expression and sex, hormonal activity, tumor size, invasiveness, recurrence, or the evaluated conventional MRI findings (all p > 0.05). The only statistically significant finding was higher RyR2 expression in CK18-negative than in CK18-positive tumors (median (IQR): 2.49% (18.36%) vs. 0.06% (0.39%); p = 0.006; r = 0.47). Higher RyR2 expression was observed in CK18-negative tumors. Given the exploratory design and limited sample size, this association should be considered hypothesis-generating and requires validation in larger independent cohorts.