Perineural invasion
PNI; perineural tumour spread; nerve-sheath invasion
Perineural invasion is the histological identification of tumour cells around or within a nerve. It is a major adverse feature across many skin cancers, particularly cutaneous squamous cell carcinoma (where it contributes to the BWH T-classification), basal cell carcinoma, adenoid cystic carcinoma and microcystic adnexal carcinoma. PNI is sub-classified by the calibre of the involved nerve, the depth of invasion, and whether a named nerve is involved — distinctions that have direct implications for MRI imaging, surgical planning and adjuvant radiotherapy. The BWH cSCC T-staging PNI risk factor is nerve calibre ≥ 0.1 mm only; depth beyond the dermis and named-nerve involvement are separate AJCC 8 / TNM 8 high-risk descriptors rather than the BWH factor.
Definition
- Tumour cells around (perineural) or within (intraneural) a nerve sheath, identified on H&E.
- Single tumour cells in close proximity to a nerve without sheath invasion is often called "perineural invasion" but more rigorous reporting distinguishes "perineural tumour spread" (within the perineurium) from incidental proximity.
- Recorded as present / absent in the pathology dataset, with sub-classification by calibre, depth and named-nerve involvement.
Sub-classification (BAD 2020 / TNM 8 for cSCC)
- BWH PNI risk factor — the PNI criterion in the BWH cSCC T-staging system is nerve calibre ≥ 0.1 mm ONLY; meeting this counts as one BWH risk factor.
- Additional AJCC 8 / TNM 8 high-risk PNI descriptors (separate from the BWH calibre factor):
- PNI extending deep to / beyond the dermis (into subcutis or deeper).
- PNI of a named nerve.
- Incidental PNI — small-calibre PNI within the dermis only, in an otherwise low-risk lesion — does not by itself trigger adjuvant RT or aggressive workup.
Role in cSCC (BWH / AJCC 8)
- BWH cSCC T-staging uses four risk factors — diameter ≥ 2 cm, poorly differentiated, PNI (high-risk), invasion beyond subcutaneous fat. Bone invasion is automatic T3.
- BWH T1 = 0 factors; T2a = 1; T2b = 2–3; T3 = 4 or bone.
- High-risk PNI alone (without other risk factors) is a BWH T2a tumour.
- AJCC 8 — PNI of a named nerve, of a deep nerve, of a nerve calibre ≥ 0.1 mm, or with nerve involvement to / beyond the dermis is an adverse feature contributing to T-classification.
- Implications — consider baseline MRI to assess perineural spread, MDT discussion for adjuvant RT, baseline imaging for nodal basin and brain (CN involvement).
Imaging in high-risk PNI
- MRI of the affected region with gadolinium contrast — identify perineural spread along V1 / V2 / V3 (trigeminal) or VII (facial) for head and neck PNI cSCC.
- Look for nerve thickening, enhancement, denervation atrophy of muscles innervated by the affected nerve (e.g. masticator atrophy in V3 PNI).
- CT for bony foramen / canal involvement.
- PET-CT for distant disease in advanced PNI cases.
Management
- High-risk PNI in cSCC — surgical excision with negative margins (Mohs preferred for resectable head-and-neck disease); MDT discussion for adjuvant RT.
- Named-nerve or extensive PNI — adjuvant RT to the primary site, neural pathway and regional nodal basin per local protocol.
- Cemiplimab (TA802) — for unresectable / metastatic cSCC; selected cases of locally advanced PNI cSCC.
- Surveillance — clinical and imaging follow-up tailored to risk; cranial nerve symptoms (numbness, weakness) warrant prompt re-imaging.
- Outside cSCC — high-risk PNI in BCC / MAC / adenoid cystic / DFSP / melanoma similarly warrants MDT discussion of adjuvant RT and imaging.
References
- Jambusaria-Pahlajani A et al. Evaluation of AJCC tumor staging for cutaneous squamous cell carcinoma — proposed alternative staging system (BWH). JAMA Dermatol; 2013.
- Keohane SG et al. British Association of Dermatologists guidelines for the management of people with cutaneous squamous cell carcinoma 2020. Br J Dermatol. 2021;184(3):401-414.
- Amin MB, Edge SB, Greene FL et al., eds. AJCC Cancer Staging Manual. 8th ed. New York: Springer; 2017.
- Williams LS et al. Perineural invasion in cutaneous squamous cell carcinoma — MRI features. Am J Neuroradiol; 2007.
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