Advances in understanding and management of high-grade pancreatic neuroendocrine neoplasm: a comprehensive review

High-grade (HG) pancreatic neuroendocrine neoplasms (PAN-NENs) are aggressive and have a poor prognosis. Yet, our understanding and treatment approaches for these tumors have rapidly evolved in the past decade, despite a lack of prospective and randomized trials. It is essential to differentiate grade 3 (G3) neuroendocrine tumors (NETs) from neuroendocrine carcinomas (NECs) due to their different prognostic and treatment implications. The molecular landscape of HG PAN-NENs is complex, with mutations in key cancer-related genes, extensive genomic rearrangements, and chromosomal instability. Advanced studies have provided insights into the significant genetic heterogeneity of HG PAN-NENs and potential therapeutic targets. Several therapeutic strategies have emerged from molecular characterization studies. These include agents targeting the mammalian target of rapamycin (mTOR) pathway, DNA repair pathways, and epigenetic modifiers. Moreover, high programmed cell death ligand 1 (PD-L1) expression in some tumors indicates potential for immunotherapy. However, many challenges remain, with a deeper understanding of the genetic and epigenetic alterations in these tumors necessary to develop novel therapeutic strategies and improve patient outcomes. Treatment strategies for HG PAN-NENs vary. Looking to the future, many clinical trials are exploring novel therapies or combinations of known therapies to improve outcomes. It is evident that understanding the molecular landscape of PAN-NECs, alongside personalized therapeutic strategies, is crucial to developing effective treatment options and improving patient outcomes. In this discourse, our emphasis will be on the molecular landscape and available treatment strategies for HG PAN-NECs.