Perineural invasion in pancreatic cancer: Current biological function in R status, prognosis, and pain

Pancreatic ductal adenocarcinoma (PDAC) is predicted to become the second leading cause of death in 2030 and it is characterized by poor prognosis, recurrence and resistance to therapies. Several factors contribute to the complexity of this disease, among those the invasion of nerves by PDAC cells. This condition, defined as perineural invasion (PNI), is responsible of PDAC progression and pain generation. To date, PNI emerges as a hallmark feature of PDAC, showing the same oncological weight of lymph node metastasis in terms of prognosis. Targeting PNI could help improve prognosis and pain relief in PDAC patients. Only recently, a severity scoring system has been proposed to quantify PNI in histological samples although prospective validation and standardization are strongly advocated. More information about peripancreatic soft tissue infiltration and a "true" curative surgery could be found in understanding the molecular mechanisms of PNI. The incorporation of PNI markers for grading mesopancreas and retroperitoneal invasion is required to overcome current limitations of the histological workup. We discuss the modern understanding of PNI in PDAC, and the state of the art in clinical setting. Although there are still a lot to learn about PDAC, PNI represents one of the biological detonators and an important focus of future research.