Abstract
BackgroundThe cyclin-dependent kinase inhibitors p15INK4b and p57KIP2 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 p15INK4b and p57KIP2 in the pathogenesis of vulvar carcinoma, and the prognostic impact is still unknown. In our current study, we examined the expression of p15INK4b and p57KIP2 in a large series of vulvar squamous cell carcinomas to elucidate the prognostic impact.MethodsExpression of p15INK4b and p57KIP2 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.ResultsCompared to the high levels of p15INK4b and p57KIP2 in normal vulvar squamous epithelium, low levels of p15INK4b and p57KIP2 were found in 82% and 44% of vulvar carcinomas, respectively. Low levels of p15INK4b and p57KIP2 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 p15INK4b and p57KIP2 levels could not be identified as prognostic markers, combined analysis of p14ARF/p15INK4b/p16INK4a 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).ConclusionsWe show for the first time that p15INK4b and p57KIP2 may be involved in the progression of vulvar carcinomas and the combined p14ARF/p15INK4b/p16INK4a status was a statistically independent prognostic factor.
Highlights
Vulvar carcinoma is a rare female genital malignancy with an incidence ranging from 1 to 2 per 100 000 person-years worldwide [1,2]
In 36 cases of normal vulvar squamous epithelium, nuclear staining for p15INK4b and p57KIP2 was identified in basal, parabasal, middle and top layers with a score of 9 (Figure 1A and B)
Low expression of p15INK4b and p57KIP2 were significantly correlated with large tumor diameter (p = 0.03 and p = 0.001, respectively) and deep invasion (p = 0.003 and p = 0.04, respectively)
Summary
Vulvar carcinoma is a rare female genital malignancy with an incidence ranging from 1 to 2 per 100 000 person-years worldwide [1,2]. It is important to make individualized treatment procedures in order to reduce negative effects for patients with a good prognosis. The identification of new biomarkers could possibly improve the prediction of clinical outcome and may be important for development of better treatment strategies. Cyclin-dependent kinase inhibitors (CDKI), the major inhibitors of the cell cycle, are divided into the INK4 and CIP/KIP family. The cyclin-dependent kinase inhibitors p15INK4b and p57KIP2 are important regulators of the cell cycle, and their abnormal expression has been detected in various tumors. Little is known about the role of p15INK4b and p57KIP2 in the pathogenesis of vulvar carcinoma, and the prognostic impact is still unknown. We examined the expression of p15INK4b and p57KIP2 in a large series of vulvar squamous cell carcinomas to elucidate the prognostic impact
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