Perineural Invasion in Adenoid Cystic Carcinoma of the Salivary Glands: Where We Are and Where We Need to Go

Abstract

Adenoid cystic carcinoma of the salivary gland (SACC) is a rare malignant tumors of the head and neck region, but it is one of the most common malignant tumors that are prone to perineural invasion (PNI) of the head and neck. The prognosis of patients with SACC is strongly associated with the presence of perineural spread (PNS). Although many contributing factors have been reported, the mechanisms underlying the preferential destruction of the blood-nerve barrier (BNB) by tumors and the infiltration of the tumor microenvironment by nerve fibers in SACC, have received little research attention. This review summarizes the current knowledge concerning the characteristics of SACC in relation to the PNI, and then highlights the interplay between components of the tumor microenvironment and perineural niche, as well as their contributions to the PNI. Finally, we provide new insights into the possible mechanisms underlying the pathogenesis of PNI, with particular emphasis on the role of extracellular vesicles that may serve as an attractive entry point in future studies.

Keywords: adenoid cystic carcinoma; perineural invasion; perineurium barrier; salivary glands; tumor microenvironment.

Figure 1

The perineural niche and tumor microenvironment in PNI. (A) Diagram showing the architecture and main cellular components of a normal axon. The perineurium that composed of several layers of perineurial cells protects the axon. The perineurium that surrounds individual Schwann cell, micro-vessel, fibroblast. (B) Diagram showing the brief structure of tumor derived-exosomes(TDE). TDE contains mRNA, miRNA, protein and other substances, which can be transferred to their target cells, directly or indirectly changing the biological function of recipient cells. (C) Diagram showing the architecture and main cellular components of an axon while tumor invades the nerve. After the effect of multiple factors, such as chemokines, GDNF family, NGF family, MMPs and PNI-related cells, the tight connections between the perineurial cells the and the tumor invades the nerve. (D) Diagram show the corresponding H&E-stained image of normal nerve. (E) Diagram show the corresponding H&E-stained image of tumor infiltrating nerve by the adenoid cystic carcinoma.