Expanding histopathological assessment may provide limited prognostic value for metastatic cutaneous squamous cell carcinoma: insights from two nationwide nested case–control studies

BACKGROUND: Although multiple refined histopathological variables have been proposed to improve risk stratification of patients with cutaneous squamous cell carcinoma (CSCC), evidence of their added value over conventional clinicopathological variables such as depth of invasion or differentiation grade is limited. OBJECTIVES: To evaluate the association between refined histopathological variables and metastasis in CSCC and their value relative to routinely available variables. METHODS: We conducted two nested case-control (NCC) studies using data from the Netherlands Cancer Registry and nationwide pathology registry with over 10 years of follow-up (n = 19 120 patients). The first NCC study included a population-based set of 195 primary CSCCs of metastatic cases matched to 195 primary CSCCs of nonmetastatic controls based on follow-up time. The second NCC study included a metastatic risk-matched set, matching 250 cases with 250 controls based on calculated metastatic risk. Pathologists reviewed all primary CSCCs, including the refined variables: morphological subtype, solar elastosis, peritumoral infiltrate, tumour budding and mitosis. Analyses were conducted using conditional logistic regression. RESULTS: In the population-based set, multivariable analyses showed no significant associations between refined histopathological variables and metastasis. In the risk-matched set, extensive [odds ratio (OR) 0.28, 95% confidence interval (CI) 0.09-0.87] and moderate (OR 0.20, 95% CI 0.07-0.56) solar elastosis were negatively associated with metastasis. CONCLUSIONS: Most refined histopathological variables may not provide additional prognostic value beyond conventional risk factors for metastasis in patients with CSCC. The observed inverse association between solar elastosis and metastasis warrants further research.