Expression of p15INK4b and p57KIP2 and Relationship with Clinicopathological Features and Prognosis in Patients with Vulvar Squamous Cell Carcinoma

Background The cyclin-dependent kinase inhibitors p15 INK4b and p57 KIP2 are important regulators of the cell cycle, and their abnormal expression has been detected in various tumors. However, little is known about the role of p15 INK4b and p57 KIP2 in the pathogenesis of vulvar carcinoma, and the prognostic impact is still unknown. In our current study, we examined the expression of p15 INK4b and p57 KIP2 in a large series of vulvar squamous cell carcinomas to elucidate the prognostic impact. Methods Expression of p15 INK4b and p57 KIP2 were examined in 297 vulvar squamous cell carcinomas using immunohistochemistry. Both uni- and multivariate analysis of prognostic factors were performed, and correlations with clinicopathologic parameters were examined. Results Compared to the high levels of p15 INK4b and p57 KIP2 in normal vulvar squamous epithelium, low levels of p15 INK4b and p57 KIP2 were found in 82% and 44% of vulvar carcinomas, respectively. Low levels of p15 INK4b and p57 KIP2 correlated significantly with malignant features, including large tumor diameter ( p  = 0.03 and p  = 0.001, respectively) and increased invasiveness ( p  = 0.003 and p  = 0.04, respectively). Although p15 INK4b and p57 KIP2 levels could not be identified as prognostic markers, combined analysis of p14 ARF /p15 INK4b /p16 INK4a showed that patients whose tumors expressed low levels of two or three of these INK4 proteins had a worse prognosis than those with only low levels of one or no protein (univariate analysis p  = 0.02). The independent prognostic significance of these INK4 proteins was confirmed by multivariate analysis ( p  = 0.008). Conclusions We show for the first time that p15 INK4b and p57 KIP2 may be involved in the progression of vulvar carcinomas and the combined p14 ARF /p15 INK4b /p16 INK4a status was a statistically independent prognostic factor.