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.

引言：微细神经侵犯（mPNI）是一种可在皮肤鳞状细胞癌（cSCC）中发现的组织病理学特征。在美国癌症联合委员会（AJCC）第八版中，mPNI被定义为神经受累≥0.1毫米以及神经侵犯深度超过真皮层的情形，这些均被纳入cSCC的风险分层。关于其他mPNI特征是否对cSCC的最佳分期具有重要意义的疑问仍悬而未决。本研究旨在总结已发表研究中关于不同mPNI特征与cSCC患者复发、转移及疾病特异性死亡风险之间独立关联的证据。

方法：自2023年1月至2024年2月，通过Embase、PubMed和Web of Science数据库检索了报告≥18岁、经组织病理学证实cSCC患者mPNI特征预后影响的研究。提取了关于研究和肿瘤特征的数据。

结果：共19项研究符合纳入标准，并评估了cSCC中一个或多个mPNI特征，包括神经直径、mPNI范围、受累神经数量及mPNI深度。两项研究提供了证据，表明在调整其他mPNI特征和高风险因素后，‘mPNI≥0.1毫米’和‘mPNI深度超过真皮层’与不良预后显著且独立相关。其中一项研究还额外确定了‘≥3条神经受累’作为独立且显著的局部复发高风险预测因子（HR，2.17；95% CI，1.03-4.56；p=0.04）。

结论：除了‘神经直径≥0.1毫米’和‘mPNI侵犯深度’外，‘多神经受累’也被发现是预后不良的独立风险因素，也应考虑纳入适当的风险分层。