Diagnostic and prognostic biomarkers for pancreatic neuroendocrine neoplasms.

This review examines the diagnostic and prognostic biomarkers for pancreatic neuroendocrine neoplasms (PanNENs), a heterogeneous group of tumors with expression of neuroendocrine markers. PanNENs include both well-differentiated pancreatic neuroendocrine tumors (PanNETs) and poorly differentiated pancreatic neuroendocrine carcinomas (PanNECs). The diagnosis is confirmed through markers such as chromogranin A, synaptophysin, and INSM1, which establish neuroendocrine differentiation. The World Health Organization classification categorizes PanNENs based on tumor differentiation and proliferative activity (Ki-67 and/or mitotic index) into well-differentiated PanNETs (grade 1 to grade 3) and poorly differentiated PanNECs. In most cases, the morphology and proliferation index are sufficient to distinguish PanNETs from PanNECs. However, distinguishing grade 3 PanNETs from PanNECs can be challenging on the basis of morphology and proliferative activity alone. Additional key diagnostic markers for distinguishing grade 3 PanNET from PanNEC include SSTR2A expression and molecular immunohistochemical markers such as p53, Rb1, menin, ATRX, and DAXX. PanNECs are by definition high-grade tumors with highly aggressive clinical behavior, while PanNETs have a variable prognosis that is difficult to predict using current biomarkers such as tumor grade and size. Several studies have shown that ATRX or DAXX loss is strongly associated with a higher risk of PanNET metastasis and recurrence. They are therefore key prognostic markers in PanNETs. In addition, chromosomal copy number variations can further help assess PanNET aggressiveness and prognosis. Molecular profiling is increasingly important for improving the diagnosis, treatment, and prognosis of PanNENs.