Expression of ATRX, DAXX, PDX1, ARX, and somatostatin receptors in pancreatic neuroendocrine tumors: a clinicopathological study

Background: Recent studies have identified ATRX/DAXX and PDX1/ARX as biomarkers defining novel pancreatic neuroendocrine tumor (PanNET) subtypes, while the clinical significance of somatostatin receptors (SSTRs) remains incompletely understood. Methods: We retrospectively analyzed 58 surgically resected primary PanNET samples and performed immunohistochemical evaluation of ATRX, DAXX, ARX/PDX1, and SSTR2a/5. The primary goal was to assess associations between biomarker expression and clinicopathological parameters. Secondary analyses explored relationships with recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS). Quantitative expression scores were calculated, receiver operating characteristic (ROC) curve analysis was performed, and survival outcomes were assessed using Kaplan-Meier analysis. Results: The loss of DAXX or ATRX expression (86.3%) was more commonly observed in nonfunctional PanNETs cases compared to the functional PanNET group (13.7%) (p = 0.02). SSTR5 positive tumors were associated with longer median OS (73 vs. 7 months, p < 0.001) and RFS (36 vs. 6 months, p = 0.005). However, the difference in OS was not confirmed by Kaplan-Meier analysis (log-rank p = 0.078). In PanNETs ≥ 2 cm, a tumor size cutoff of 2.45 cm predicted ATRX/DAXX mutations with 96.9% sensitivity and 75% specificity (AUC 0.922, p = 0.007), in a cohort of 36 patients. Conclusions: ATRX/DAXX loss was more prevalent in nonfunctional PanNETs (p = 0.02). Although SSTR5-positive tumors were associated with longer median OS, this difference was not confirmed by Kaplan-Meier analysis. Furthermore, tumor size demonstrates predictive value for ATRX/DAXX loss in PanNETs ≥2 cm, highlighting the relationship between tumor morphology and molecular alterations, however, this finding remains hypothesis-generating and requires further validation.