Cyclin D1 Overexpression Predicts Poor Disease-Specific Survival in HPV-independent Vulvar Squamous Cell Carcinoma.

Abstract

The amplification of CCND1 is associated with the development and progression of various cancers. In a recent study, we showed that almost all adverse outcomes in vulvar squamous cell carcinomas (VSCC) occurred in patients with human papillomavirus (HPV)-independent, TP53 mutated tumors harboring CCND1 gains. In this study, we analyzed the association between CCND1 gain, cyclin D1 immunohistochemistry (IHC), and disease-specific survival (DSS) in a series of patients with HPV-independent VSCC. All patients who underwent primary surgery for VSCC at the Hospital Clinic of Barcelona, Spain, from 1975 to 2023 were recruited ("overall" cohort, n=139). IHC for p53 and cyclin D1 was performed in all cases. In a subset of patients, we performed DNA sequencing to evaluate CCND1 copy number variations ("sequencing" cohort, n=54). Cyclin D1 IHC overexpression (≥50% of tumor cells) had 94% sensitivity and 67% specificity as a surrogate marker of CCND1 gain. In the "sequencing" cohort, only CCND1 gains were significantly associated with impaired DSS in the multivariate analysis (HR=4.15, 95%confidence interval (CI): 1.08-5.40; p=0.032), whereas stage or mutant TP53 status did not reach statistical significance. In the "overall" cohort, advanced stage (HR=2.41, 95%CI: 1.08-5.39; p=0.032) and cyclin D1 IHC overexpression (HR=4.89, 95%CI: 1.77-18.5; p=0.001) were associated with worse DSS in the multivariate analysis, whereas abnormal p53 IHC was not (HR=5.06, 95%CI: 0.68-647; p=0.138). In conclusion, cyclin D1 overexpression is an acceptable surrogate for CCND1 gain and has a much stronger adverse prognostic impact than altered p53 IHC in patients with HPV-independent VSCC.