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Review
. 2023 Sep 30;30(10):8948-8972.
doi: 10.3390/curroncol30100647.

Unraveling the Mysteries of Perineural Invasion in Benign and Malignant Conditions

Hisham F Bahmad  1 , Samantha Gogola  2 , Michael Rejzer  2 , Kalin Stoyanov  2 , Aaron S Gomez  2 , Ann-Katrin Valencia  2 , Adonicah Cummings  2 , Timothy Skerry  2 , Ferial Alloush  1 , Abed A Aljamal  3 , Arunima Deb  1 , Sarah Alghamdi  1   4 , Robert Poppiti  1   4
Affiliations
Review

Unraveling the Mysteries of Perineural Invasion in Benign and Malignant Conditions

Hisham F Bahmad et al. Curr Oncol. .

Abstract

Perineural invasion (PNI) is defined as the dissemination of neoplastic cells within the perineural space. PNI can be a strong indicator of malignancy and is linked to poor prognosis and adverse outcomes in various malignant neoplasms; nevertheless, it can also be seen in benign pathologic conditions. In this review article, we discuss various signaling pathways and neurotrophic factors implicated in the development and progression of PNI. We also describe the methodology, benefits, and limitations of different in vitro, ex vivo, and in vivo models of PNI. The spectrum of presentation for PNI can range from diffuse spread within large nerves ("named" nerves) all the way through localized spread into unnamed microscopic nerves. Therefore, the clinical significance of PNI is related to its extent rather than its mere presence or absence. In this article, we discuss the guidelines for the identification and quantification of PNI in different malignant neoplasms based on the College of American Pathologists (CAP) and World Health Organization (WHO) recommendations. We also describe benign pathologic conditions and neoplasms demonstrating PNI and potential mimics of PNI. Finally, we explore avenues for the future development of targeted therapy options via modulation of signaling pathways involved in PNI.

Keywords: College of American Pathologists; TNM classification; World Health Organization; perineural invasion; staging.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
The anatomy of the nerve sheath. Created with BioRender.com (2023).
Figure 2
Figure 2
Outline three major cell signaling cascades implicated with the induction of perineural invasion. Created with BioRender.com (2023).
Figure 3
Figure 3
Nerve growth factor (NGF) mechanism of action. NGF dimer binds to its receptor TrkA to activate the PI3K, Ras, and PLC pathways to promote cell survival, neurite outgrowth, and neuronal differentiation. Created with BioRender.com (2023).
Figure 4
Figure 4
Microscopic image shows a focus on perineural entrapment in a sclerosing polycystic adenoma of the parotid gland. Image was taken at 400× magnification.
See this image and copyright information in PMC

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