Cyclooxygenase-2 expression and angiogenesis in squamous cell carcinoma of the skin and its precursors: a paired immunohistochemical study of 35 cases

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Abstract
Background Cyclooxygenase (COX)‐2 expression and tumour‐induced angiogenesis appear to be increased in squamous cell carcinoma (SCC) of the skin. In other cancers, COX‐2 is a pro‐angiogenic factor. The association between angiogenesis and COX‐2 has not been studied in skin cancer. Objectives To assess the onset of increased COX‐2 expression and angiogenesis in the multistage carcinogenesis of SCC as well as the correlation between those two parameters. Patients/methods We performed a retrospective paired immunohistochemical analysis of normal skin, actinic keratosis (AK), Bowen's disease (BD) and SCC among 35 individuals. Specimens were considered COX‐2 immunopositive when 5% or more of the tumour cells showed clear evidence of immunostaining. To quantify active angiogenesis, we used a Ki‐67–CD34 double‐labelling immunohistochemical stain and calculated the fraction of proliferating endothelial cells. The Chalkley method was used to determine the microvessel density. To detect hypoxia, a carboanhydrase IX immunostain was used. Results Compared with normal epidermis (0%), AK (31%), BD (22%) and SCC (40%) were significantly more likely to be COX‐2 immunopositive (P < 0·01). The fraction of proliferating endothelial cells and the Chalkley scores paralleled multistage carcinogenesis (P < 0·05 between different stages). COX‐2 immunopositivity was fairly correlated with hypoxia and higher proliferating endothelial cell fractions but not with Chalkley counts. Conclusions Induction of COX‐2 expression and angiogenesis are both early events in the development of SCC. In addition to ultraviolet light, hypoxia and COX‐2 may be involved in skin tumour angiogenesis.