Abstract
Perineural invasion (PNI) is defined as the presence of neoplastic cells along nerves and/or within the different layers of nervous fibers: epineural, perineural and endoneural spaces. In pancreatic cancer—particularly in pancreatic ductal adenocarcinoma (PDAC)—PNI has a prevalence between 70 and 100%, surpassing any other solid tumor. PNI has been detected in the early stages of pancreatic cancer and has been associated with pain, increased tumor recurrence and diminished overall survival. Such an early, invasive and recurrent phenomenon is probably crucial for tumor growth and metastasis. PNI is a still not a uniformly characterized event; usually it is described only dichotomously (“present” or “absent”). Recently, a more detailed scoring system for PNI has been proposed, though not specific for pancreatic cancer. Previous studies have implicated several molecules and pathways in PNI, among which are secreted neurotrophins, chemokines and inflammatory cells. However, the mechanisms underlying PNI are poorly understood and several aspects are actively being investigated. In this review, we will discuss the main molecules and signaling pathways implicated in PNI and their roles in the PDAC.
Highlights
Pancreatic ductal adenocarcinoma (PDAC), the most common cancer of the exocrine pancreas, is known for its extreme aggressiveness with a 5–year survival rate below 10% [1] and it is estimated to become the second leading cause of death by 2030 [2,3].One of the pathological hallmarks of PDAC is perineural invasion (PNI)
Present in several solid tumors, PNI has its highest prevalence in PDAC [8], with a range varying between 70% and 98%
PNI is less frequent in Intraductal Papillary Mucinous Neoplasm (IPMNs) with invasive carcinoma and neuroendocrine tumors (NETs)—though it has been recently demonstrated that PNI in NETs is a strong predictor of aggressiveness [50]
Summary
Pancreatic ductal adenocarcinoma (PDAC), the most common cancer of the exocrine pancreas, is known for its extreme aggressiveness with a 5–year survival rate below 10% [1] and it is estimated to become the second leading cause of death by 2030 [2,3]. One of the pathological hallmarks of PDAC is perineural invasion (PNI). PNI is considered a more elaborate process and it is defined as the presence of cancer cells along nerves and/or within the epineural, perineural and endoneural spaces of the neuronal sheath, including cases in which the cells circumscribe at least 33% of the nerves [6,7]. PNI can be considered a characteristic and pervasive feature of PDAC [17] and such a widespread phenomenon probably has a role in supporting tumor growth. Understanding the mechanisms by which PNI spreads is critical for developing targeted strategies directed towards cancer cells and to the nerve microenvironment and possibly supporting cells, which likely have a crucial role in promoting tumor growth. We will highlight clinical–pathological features of neural invasion as well as recent developments in its molecular comprehension
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