Should we worry about high-grade pancreatic neuroendocrine tumor progression and alkylating agents?^†

Predicting metachronous metastases in localized pancreatic neuroendocrine tumors (PanNETs) and improving survival of patients with advanced disease are some of the most important goals in PanNET research. Both are addressed by a study published recently in this journal. First, the results suggest that heterozygous DAXX mutations are already present in tumor cells but only become potentiated after a single massive chromosomal event that causes loss of heterozygosity and biallelic loss of DAXX. Second, the significant finding that the alkylating agent streptozocin may also induce a hypermutator phenotype with aggressive high-grade progression is further explored. The literature on temozolomide and peptide receptor radionuclide therapy-induced and spontaneous high-grade PanNET progression shows that the cause of high-grade progression is likely multifactorial. High-grade progressed PanNETs may show histopathological features normally seen in neuroendocrine carcinomas. Although it is not clear how often alkylating treatment induces progression, increasing evidence suggests that after an initial response, some patients indeed progress due to streptozocin or temozolomide. © 2025 The Pathological Society of Great Britain and Ireland.