Expression of p15INK⁴b and p57KIP² and relationship with clinicopathological features and prognosis in patients with vulvar squamous cell carcinoma

Abstract

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.

Figure 1. Immunohistochemical staining of p15^INK4b and p57^KIP2 protein in vulvar squamous epithelium.

High nuclear expression of p15^INK4b (A) and p57^KIP2 (B) in normal vulvar epithelium. High nuclear expression of p15^INK4b (C) and p57^KIP2 (D) and low nuclear expression of p15^INK4b (E) and p57^KIP2 (F) in vulvar carcinomas.

Figure 2. Survival curves using the Kaplan-Meier method.

The Kaplan-Meier curve of disease-specific survival in relation to the 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 (p = 0.02).

Figure 3. Survival curves using the Kaplan-Meier method for a subgroup of patients obtained surgical radicality (no rest tumor).

The Kaplan-Meier curve of disease-specific survival in relation to the 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 (p = 0.06).