Perineural Invasion in Oral Squamous Cell Carcinoma: A Review

Perineural Invasion (PNI) in cancer is a continuous, multistep process. PNI, generally understood as the invasion of cancer cells into or around nerves, is recognised as a high-risk pathological feature. The extent of tumour progression into nearby and distant lymph nodes, as well as the degree of invasiveness of the primary tumour, largely determines the prognosis of Head and Neck Squamous Cell Carcinoma (HNSCC). Among high-risk factors, PNI is strongly associated with the greatest risk of locoregional and distant metastasis. With rapid advancements in precision medicine and molecular biology, it has become evident that PNI does not result from a single causative factor. Instead, it is increasingly recognised as a significant pathological characteristic of several cancers, including those of the stomach, biliary tract, prostate, colon, rectum, pancreas, and head and neck. PNI is considered a hallmark of tumour invasion and metastasis and is associated with poor patient prognosis. Although the pathological description and clinical implications of PNI are well established, research into its molecular mechanisms is still evolving. Recent studies suggest that tumour migration and invasion into nerves may result from complex molecular interactions within the tumour-nerve microenvironment, involving various signalling molecules that promote both tumour cell invasion and neuronal growth. Historically, it was believed that PNI occurred because the anatomical region provided a path of low resistance. However, given its strong association with poor prognosis, advancing our understanding of PNI may help clarify mechanisms of tumour metastasis and recurrence, aid in improving staging systems, and lead to the development of novel therapeutic strategies and potentially new paradigms in patient management.