Skip to main content

Free Content Perineural Invasion and Its Interrelationship with Neural Repair: A Review

The impact of perineural invasion and perineural spread on survival and the MR imaging of this tumor spread have been well documented in the literature. What has not been addressed in the radiology literature is the mechanics that are behind perineural invasion. Perineural invasion is not the result of a passive invasion of a nerve by tumor, a common misconception. Because there are no lymphatics within a nerve, perineural invasion is not mediated by a direct lymphatic extension. Rather, perineural invasion is the result of complex molecular interactions between a nerve and an adjacent cancer. Once the cancer has entered a nerve, it can travel in the spaces between fascicles, which explains how such perineural invasion can appear at great distances from the primary tumor. This article reviews the current concepts regarding the mechanisms of perineural invasion and the relationship to peripheral nerve regeneration. Perineural invasion is diagnosed by histology, whereas perineural spread can be identified on imaging.

Learning Objective: The reader will learn the intimate relationship between a tumor and its adjacent nerves that lead to perineural invasion. This process is the result of a series of molecular pathways, in part related to nerve regeneration.

Keywords: ARIA = acetylcholine receptor‐inducing activity; Akt = protein kinase B (also known as PKB); BDNF = brain-derived neurotrophic factor; BFABP = brain fatty acid binding protein, regulates the activity of an enzyme, fatty acid synthase, which has a potent influence on the regulation of the hypothalamus, potentially influencing the activity of regulation of neurones; CCL2 = stromal-derived C-C motif chemokine ligand 2; CD74 = plays an essential role in antigen presentation by mediating assembly and subcellular trafficking of the MHCII complex (major histocompatibility complex II); CNTF = ciliary neurotrophic factor; COX = cyclooxygenase, officially known as prostaglandin-endoperoxide synthase (PTGS), is an enzyme that is responsible for formation of prostanoids including prostaglandins; CX3CL1 = a C-X3-C motif chemokine ligand 1; CX3CR1 = a fractalkine receptor or G protein-coupled receptor 13; CXCL13 = a C-X-C (a chemokine family of proteins) motif chemokine ligand 13; DHH = desert hedgehog; Egr2 = early growth response 2; ErbB =; FGF = fibroblast growth factor, a family of cell signaling proteins that are involved in a wide variety of processes, most notably as crucial elements for normal development; GAL = galanin; GALR = galanin receptor; GDNF = glial cell line-derived neurotrophic factor; GLUT-1 = glucose transporter 1; GSK3 = glycogen synthase kinase-3; IGF = insulinlike growth factor; JAM = a family of junctional adhesion molecules; Krox20 = zinc-finger transcription factor Krox20 (Krox20 is also known as Egr-1 is an early growth response gene); LIF (leukaemia inhibitory factor) = an interleukin 6 class cytokine that affects cell growth by factor-inhibiting differentiation; MAG = myelin-associated glycoprotein is a transmembrane protein of both the CNS and the peripheral nervous system; MALT1 = mucosa-associated lymphoid tissue is a protease that plays an important role in T-cell antigen receptor-induced integrin adhesion; MAPK = mitogen-associated protein kinase; MBP = mannan binding protein; MCP-1 = monocyte chemotactic protein 1; MMP = metalloproteinase; N-cadherin = is involved in cell-cell adhesion, differentiation, embryogenesis, invasion, and signaling; NCAM = neural cell adhesion molecule; NDF = neu-differentiation factor regulates Schwann cell lineage; NFATC2 = a nuclear factor of activated T-cells; NFATC4 = nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent-4; NGF = nerve growth factor; NRG1 (type I and III) = neuregulin I is a cell adhesion molecule that, in humans, is expressed in excitatory and inhibitory neurons; NRTN = neurturin a protein of the GDNF family; NT = neurotrophin (3, 4/5); Oct6 = a transcription factor controlling myelination, and it is a marker for active nerve regeneration; P0 = peripheral nerve stimulating proteins are the dominant protein in peripheral nervous system myelin; PGE2 = prostaglandin E2 = a potent inflammatory mediator; PI3 = phosphoinositide 3; PNI = perineural invasion; PNS = perineural spread; Sox10 = SRY (sex related region)-related HMGbox (homeobox)-10; TNFα = tumor necrosis factor α; TRAF = tumor necrosis factor receptor-associated factor; TrkA = tropomyosin receptor kinase A; VEGF = vascular endothelial growth factor; ZO-1 = zonula occludens-1, a peripheral membrane protein and part of a family of ZO proteins (ie, ZO-2); artemin = a neurotrophic factor in the glial cell line‐derived neurotrophic factor family of ligands; cAMP = adenylate cyclase‐cAMP (cyclic adenosine monophosphate) protein kinase is an important mediator in determining the response of a cell to external stimuli; calpain = calpain is an intracellular Ca2+-dependent (calcium dependent) cysteine protease; claudins = function as major constituents of the tight junction complexes that regulate the permeability of epithelia; collagen IV = a type of collagen found primarily in the basal lamina; connexin = connexins or gap junction proteins are structurally related transmembrane proteins that assemble to form vertebrate gap junctions; erythropoietin (retrovirus-associated DNA sequences) = a hormone produced by the kidney that promotes the formation of red blood cells by the bone marrow; fractalkine = a transmembrane chemokine that releases an extracellular soluble fragment of CXC3L1; heregulin = stimulates axon-induced mitogenesis; interleukins (IL) = a class of glycoproteins produced by leukocytes for regulating immune responses; laminins = glycoprotein components of connective tissue basement membranes that promote cell adhesion; mRNA = messenger RNA is a large family of RNA molecules that convey genetic information from DNA to the ribosome, where they specify the amino acid sequence of the protein products of gene expression; occludin = a protein that, in humans, is an integral plasma-membrane protein located at the tight junctions; p44/42 MAPK pathway = mitigen-associated (activated) protein kinase signaling pathway; p75NTR = neurotrophin receptor p75 affects the binding affinity and specificity of Trk (tropomyosin receptor kinase) receptor activation by neurotrophins; pleiotrophin = secreted growth factor that induces neurite outgrowth and that is mitogenic for fibroblasts, epithelial, and endothelial cells

Document Type: Research Article

Publication date: October 1, 2019

  • Access Key
  • Free content
  • Partial Free content
  • New content
  • Open access content
  • Partial Open access content
  • Subscribed content
  • Partial Subscribed content
  • Free trial content