BACKGROUND: Cadherin switch in melanoma, with loss of E-cadherin and up-regulation of N-cadherin, is believed to underlie melanoma cell detachment from the epidermis and promotion of dermal and vascular melanoma invasion. The tumour suppressor PTEN has been suggested as a potential regulator of this cadherin switch. OBJECTIVES: To study the biological and clinical implications of cadherin switch and PTEN expression in melanoma progression. METHODS: We constructed tissue microarrays from primary tumour samples from 393 formalin-fixed paraffin-embedded melanomas diagnosed between 2001 and 2006. Median follow-up was ten years. Tissue microarray sections were stained by immunohistochemistry for E-cadherin, N-cadherin, and PTEN, and expression was analysed semi-quantitatively. RESULTS: Breslow thickness correlated strongly with reduced/absent PTEN expression (p<0.0001), low E-cadherin expression (p<0.0001), high N-cadherin expression (p<0.0001) and the combination of low E-cadherin and high N-cadherin expression (cadherin switch profile; p=0.001). There was a significant association between reduced/absent PTEN expression and the presence of the cadherin switch profile (p=0.03). In univariate analyses, a low E-cadherin expression significantly predicted an adverse overall-relapse-free (p=0.04), melanoma-specific (p=0.03), and distant-metastasis-free (p=0.01) survival; reduced/absent PTEN predicted an adverse overall-relapse-free survival (p=0.006), and the cadherin switch profile predicted an adverse melanoma-specific (p=0.005), and distant-metastasis-free (p=0.01) survival. In multivariate analysis, the cadherin switch profile was an independent prognostic marker of melanoma-specific (p=0.04) and distant-metastasis-free survival (p=0.02). CONCLUSIONS: Cadherin switch and reduced/absent PTEN expression are associated in melanoma, and both factors may play important roles in the progression of melanoma. This article is protected by copyright. All rights reserved.