Prognostic Factors and Impact of HPV/p16ink4a Status on Survival in Vulvar Cancer Patients Treated with Radiation Therapy

Abstract

Nodal disease and extent of resection margins are prognostic factors for outcome of women with vulvar cancer. Only few data exist on the role of HPV/p16 in vulvar cancer. Aim of this study was to evaluate prognostic markers and in particular the association of p16-overexpression and prevalence of HPV-DNA in vulvar squamous cell carcinomas and its prognostic significance in patients treated with radiotherapy. One hundred nineteen patients received radiotherapy for vulvar squamous cell carcinoma between 1999 and 2014 at one institution. Fifty-seven percent received radiotherapy after first diagnosis, 43% received radiotherapy for locally recurrent disease. Median age at time of first diagnosis was 67 years. Eighty-two percent were initially staged as T1 or T2, 16% were staged as T3 or T4. Forty-three percent had nodal disease at time of first diagnosis, 33% at time of recurrence. The p16 status was available for 58 of the 119 patients (49%). Twenty-two percent were p16-positive. HPV status was available for 40 patients (34%), 43% were positive for HPV. Nine patients were p16 and HPV-positive, 17 were p16 and HPV-negative. The rest was either positive for only p16 or HPV. Patient characteristics and patient outcomes (locoregional progression-free survival (LPFS) and overall survival (OS)) were assessed. Survival data were analyzed using the Kaplan-Meier method and log-rank test, categorical variables were analyzed with the chi-square method and Fisher’s exact test. Median follow-up from the date of first radiation treatment was 1.15 years (range 0.07-13.35 years). Estimated 3- and 5-year OS/LPFS was 46%/60% and 41%/58%, respectively. First diagnosis before the year 2006, first radiotherapy for recurrent disease, nodal disease at time of recurrence and BED ≤50 Gy were significant prognostic factors for worse OS and LPFS with P < 0.05. Women with p16 positive tumors had a significantly higher 5-year-LPFS (85% vs. 39%, P = 0.03) and showed a trend for a prolonged OS (P = 0.145) after radiotherapy. HPV-DNA positivity had no significant impact on LPFS or OS after radiotherapy. Patients who were diagnosed before 2006 were treated with lower doses than those diagnosed after 2006 (P = 0.053). Nodal disease is well known as a prognostic factor for worse outcomes in women with vulvar cancer, which could be confirmed in this study. The dose of radiation treatment (BED) should exceed 50 Gy to achieve best locoregional control rates and also longer OS. It is suggested that p16-overexpression correlates with the presence of HPV-DNA in anal or oropharyngeal cancer. A recent study with over 2000 patients with intraepithelial and invasive lesions of the vulva revealed substantial mismatch between p16-overexpression and HPV-status. In this study, women with p16 positive vulvar cancer showed significantly better locoregional control rates after radiotherapy and also a trend for a better overall survival. HPV-positivity had no influence on LPFS or OS. Our findings suggest that p16 immunostaining but not HPV-DNA-detection seem to be prognostic in vulvar cancer.