Effect of S-Phase Kinase-Associated Protein 2 Expression on Distant Metastasis and Survival in Nasopharyngeal Carcinoma Patients

Purpose: The S-phase kinase-associated protein 2 (Skp2) oncoprotein is an E3 ubiquitin ligase targeting the p27Kip1 tumor suppressor for degradation. We evaluated the prognostic utility of Skp2 in nasopharyngeal carcinoma (NPC), with an emphasis on distant metastasis-free (DMF) survival. Methods and Materials: Immunohistochemical expression of Skp2 was assessed by H-score for 233 NPC patients without initial distant metastasis and correlated with the clinicopathologic features, therapeutic modalities, locoregional control rate, DMF survival, and overall survival (OS). No selection bias in essential parameters was shown between these and another 113 control patients. Results: Skp2 was detectable in most patients (95%) but displayed a wide range of expression. Despite no correlation between Skp2 and any clinicopathologic factor, greater Skp2 expression (H-score >80) significantly portended inferior DMF survival (p = 0.01) and OS (p = 0.02) when categorically dichotomizing the study cohort. The associations with DMF survival (p = 0.003) and OS (p = 0.003) became even stronger when the H-score was expressed as a continuous variable. In the multivariate model, greater Skp2 expression remained significantly predictive of poorer DMF survival and OS (p = 0.01 for both), along with T stage (p = 0.04 for DMF survival; p = 0.005 for OS), N stage (p = 0.008 for DMF survival; p = 0.02 for OS), and/or age (p = 0.001 for OS). In contrast, T stage (p = 0.01) was the single independent prognosticator of LCR. Conclusions: The results of our study have shown that Skp2 expression is frequent in NPC and has a wide range of distribution in H-score. Skp2 overexpression is significantly predictive of DMF survival and OS, independent of the T stage and/or older age. Therefore, Skp2 might represent a useful prognostic adjunct to risk stratify NPC patients for appropriate allocation of adjuvant therapy