Supplementary Material for: Perineural invasion for risk stratification in cutaneous squamous cell carcinoma: a scoping review

Introduction: Microscopic perineural invasion (mPNI) is a histopathological characteristic that can be found in cutaneous squamous cell carcinoma (cSCC). In the eight edition of the American Joint Committee on Cancer (AJCC), mPNI defined as the involvement of nerves ≥0.1mm and nerves deeper than the dermis is included in risk stratification of cSCC. The question remains whether other mPNI features are important for optimal cSCC staging. We aim to summarize the evidence from published studies on the independent association between various mPNI features and the risk of recurrence, metastasis and disease-specific death in patients with cSCC. Methods: Embase, PubMed, and Web of Science were searched from January 2023 to February 2024 to identify studies that reported the prognostic impact of mPNI features in patients ≥18 years with histopathologically verified cSCC. Data on study and tumour characteristics were extracted. Results: Nineteen studies met the inclusion criteria and evaluated one or more mPNI features in cSCC including nerve diameter, the extent of mPNI, the number of affected nerves, and depth of mPNI. Two studies provided evidence that ‘mPNI ≥0.1mm’ and ‘mPNI deeper than the dermis’ are significantly and independently associated with poor prognosis after correction for other mPNI features and high-risk factors. One of these studies additionally identified ‘involvement of ≥3 nerves’ as an independent and significant predictor of higher risk of local recurrence (HR, 2.17; 95% CI, 1.03-4.56; p=0.04). Conclusion: Besides ‘nerve diameter of ≥0.1mm’ and ‘depth of mPNI involvement’, ‘involvement of multiple nerves’ was found to be an independent risk factor for poor prognosis and should also be considered for appropriate risk stratification.