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Aims: Myoepithelial salivary gland tumours are uncommon and follow an unpredictable biological course. The aim was to examine their molecular background to acquire a better understanding of their clinical behaviour. Methods and results: Expression of protein (E2F1, p16INK4a, p53, cyclin D1, Ki67 and Polycomb group proteins BMI-1, MEL-18 and EZH2) was investigated in 49 benign and 30 primary malignant myoepithelial tumours and five histologically benign recurrences by immunohistochemistry and the findings correlated with histopathological characteristics. Benign tumours showed a higher percentage of cells with expression of p16INK4a pathway members [p16INK4a and E2F1 (both P < 0.001), and cyclin D1, P = 0.002] compared with normal salivary gland. Furthermore, malignant tumours expressed p53 ( P = 0.003) and EZH2 ( P = 0.09) in a higher percentage. Recurrences displayed more p53 + tumour cells ( P = 0.02) than benign primaries. Amongst the benign tumours, the clear cell type had the highest proliferation fraction ( P = 0.05) and a higher percentage of EZH2 was detected in the plasmacytoid cell type ( P = 0.002). Conclusions: This study is the first to demonstrate that deregulation of the p16INK4a senescence pathway is involved in the development of myoepithelial tumours. We propose that additional inactivation of p53 in malignant primaries and benign recurrences contributes to myoepithelial neoplastic transformation and aggressive tumour growth. [ABSTRACT FROM AUTHOR]