p62/SQSTM1 Accumulation Defines an Epithelial-Mesenchymal Transition (EMT)/Twist1-Associated Infiltrative Phenotype...

Pancreatic neuroendocrine tumors (PNETs) lack clinically validated biomarkers for risk stratification and treatment selection. p62 (also known as SQSTM1)-a multifunctional adaptor protein degraded by autophagy-has been associated with adverse outcomes, but its correlation with invasion and metastasis in PNETs remains unclear. We retrospectively analyzed 194 PNETs resected between January 1994 and December 2022. The expression of p62, LC3B, E-cadherin, and Twist1 was evaluated using immunohistochemistry, and targeted transcriptomic profiling (nCounter) was performed to compare p62-high and p62-low groups. High p62 expression was associated with shorter overall survival and disease-free survival and higher frequencies of lymph node metastasis and an infiltrating growth pattern. In tumors with an infiltrating growth pattern, p62 expression was higher at the invasive front than in the tumor center, supporting a spatial association with histopathologic invasion. Transcriptomic profiling showed enrichment of epithelial-mesenchymal transition (EMT) pathways in the p62-high group, including upregulation of TWIST1, a key EMT-related transcription factor. Consistently, p62-high tumors showed reduced membranous E-cadherin and increased cytoplasmic and nuclear Twist1 expression. In a subgroup of small tumors (≤20 mm), p62-high status was not associated with significantly different survival, but it remained associated with infiltrative histopathologic features. Collectively, high p62 expression was associated with an aggressive, infiltrative PNET phenotype and an EMT/Twist1-associated signature, suggesting that p62 may capture a biologic state characterized by infiltrative behavior and complement risk stratification within current World Health Organization frameworks.