High <scp>ROR1</scp> Expression Is Associated With Poor Differentiation and Perineural Invasion in Cutaneous Squamous Cell Carcinoma

Cutaneous squamous cell carcinoma (cSCC) is a common type of skin cancer, predominantly affecting elderly and immunosuppressed patients. Despite recent therapeutic advances, including the introduction of immune checkpoint inhibitors, outcomes for patients with metastatic or recurrent disease remain poor, underscoring the need for new therapeutic approaches and reliable biomarkers to identify patients at high risk of progression. In this context, receptor tyrosine kinase-like orphan receptor 1 (ROR1), previously associated with poor prognosis and targeted therapeutically in other malignancies, has not yet been investigated in cSCC. This study aimed to evaluate ROR1 expression in cSCC and investigate its potential role as a biomarker for tumour aggressiveness. ROR1 expression was analysed via immunofluorescence in a tissue microarray of 360 cSCC samples from a biobank cohort at the University Hospital Cologne. Fluorescence intensity was quantified and correlated with clinicopathologic features and patient outcomes. High ROR1 expression was detected in 42.5% of samples, predominantly localised at tumour invasive fronts. Elevated ROR1 levels were significantly associated with poor tumour differentiation (p < 0.001), lymph node metastasis (p = 0.007), and perineural invasion (p = 0.005). Although higher ROR1 expression correlated with worse progression-free and metastasis-free survival, these differences did not reach statistical significance. In conclusion, this study identifies ROR1 as a novel marker of aggressive cSCC, linked to poor differentiation, lymphatic spread and perineural invasion. ROR1 holds potential both as a prognostic biomarker and as a therapeutic target, encouraging future exploration of ROR1-directed therapies in advanced cSCC.