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Perineural spread (PNS) refers to the propagation of tumor cells along the perineural space of nerves, often extending far beyond the primary tumor margins. It is a recognized pathway for local tumor dissemination and is distinct from direct invasion of nerve tissue (perineural invasion, PNI) seen histologically.

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Perineural invasion (PNI): Histologic phenomenon (microscopic tumor cells in nerve sheath).
Perineural spread (PNS): Radiologically evident, often subclinical, tumor tracking along nerves.

Etiopathogenesis

Tumor cells access the perineural or endoneural space, exploiting it as a low-resistance path.
Neurotrophic factors (e.g. NGF, GDNF), chemokines, and cell adhesion molecules facilitate migration.
PNS allows tumor to bypass anatomical barriers, resulting in:
- Tumor recurrence
- Poor surgical margins
- Delayed cranial neuropathies

Common Primary Tumors Associated with PNS

Tumor Type	Common Sites	Comments
‣	Minor salivary glands	High neurotropism
‣	Skin of face, oral cavity, nasopharynx	Especially high-risk cutaneous SCC
‣	Parotid gland	Less common but possible
Lymphoma, melanoma	Less commonly exhibit true PNS

Commonly Involved Nerves in Head & Neck

Nerve	Associated Route of Spread
Trigeminal nerve (CN V)	V2 and V3 most commonly; via foramen rotundum and foramen ovale
Facial nerve (CN VII)	Retrograde spread to geniculate ganglion and internal auditory canal
Auriculotemporal nerve	Connection between CN V3 and CN VII (notably parotid tumors)
Pterygopalatine ganglion	Central hub connecting CN V2, maxillary sinus, orbit, and nasal cavity

![Nerves affected by perineural invasion in oral cavity cancer. The oral cavity cancer site consists of several subsites: oral tongue (anterior 2/3), floor of mouth, hard palate, retromolar trigone, buccal mucosa, upper and lower mucosal lip, and gingiva. The oral tongue (anterior 2/3) receives taste innervation from the chorda tympani (CN VII). The posterior 1/3 of the oral tongue belongs to the oropharynx and receives taste and sensory innervations by the glossopharyngeal nerve (CN IX). Motor innervation of the tongue is primarily supplied by the hypoglossal nerves (CN XII). Sensory innervation of the oral cavity is supplied by the maxillary (CN V2) and mandibular (CN V3) nerves. Perineural invasion in oral cavity cancer may involve any of the aforementioned nerves.

Misztal CI, Green C, Mei C, Bhatia R, Velez Torres JM, Kamrava B, Moon S, Nicolli E, Weed D, Sargi Z, et al. Molecular and Cellular Mechanisms of Perineural Invasion in Oral Squamous Cell Carcinoma: Potential Targets for Therapeutic Intervention. Cancers. 2021; 13(23):6011. https://doi.org/10.3390/cancers13236011](attachment:12cfff56-3f3f-45e0-978b-025fd1c9f751:image.png)

Nerves affected by perineural invasion in oral cavity cancer. The oral cavity cancer site consists of several subsites: oral tongue (anterior 2/3), floor of mouth, hard palate, retromolar trigone, buccal mucosa, upper and lower mucosal lip, and gingiva. The oral tongue (anterior 2/3) receives taste innervation from the chorda tympani (CN VII). The posterior 1/3 of the oral tongue belongs to the oropharynx and receives taste and sensory innervations by the glossopharyngeal nerve (CN IX). Motor innervation of the tongue is primarily supplied by the hypoglossal nerves (CN XII). Sensory innervation of the oral cavity is supplied by the maxillary (CN V2) and mandibular (CN V3) nerves. Perineural invasion in oral cavity cancer may involve any of the aforementioned nerves.

Radiology

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PNS appears as nerve enhancement, thickening, and muscle denervation on MR imaging, particularly evident along CN V2 and V3 courses.

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Modality	Imaging features
MR	T1W post-contrast fat-saturated images are the most important sequence for PNS:
• Nerve enlargement
• Abnormal enhancement along the nerve (linear or nodular)
• Obliteration of fat planes around foramina (e.g., foramen ovale, rotundum, stylomastoid foramen)
• Asymmetric muscle denervation (atrophy and fatty infiltration in muscles of mastication or facial expression)
• Perineural extension into intracranial segments (Meckel's cave, cavernous sinus)
CT	Useful for detecting foraminal widening or bone erosion:
• Bony foraminal widening (e.g., foramen ovale, rotundum, stylomastoid)
• Erosion or sclerosis of adjacent bone
• Loss of normal fat around neural foramina

Sites & pathways of spread:

Pterygopalatine fossa (PPF) serves as a key crossroad for multiple routes of PNS due to its connections to orbit, nasal cavity, maxillary sinus, and cranial base.

Tumor Site	Nerve Pathway
Face (cutaneous SCC)	CN V2/V3 → PPF → cavernous sinus
Parotid gland	CN VII → stylomastoid foramen → facial canal
Oral cavity	CN V3 → mandibular canal/foramen ovale
Maxillary sinus	CN V2 → infraorbital nerve → PPF