DNA methylation testing for vulvar cancer risk stratification in patients with high-grade vulvar intraepithelial neoplasia: a population-based cohort study
Abstract
Background
High-grade vulvar intraepithelial neoplasia (VIN) is the precursor of vulvar cancer. The main variants are human papillomavirus (HPV)-associated high-grade squamous intraepithelial lesion (HSIL) and HPV-independent VIN, often clinically referred to as differentiated VIN (dVIN) and associated with vulvar dermatoses, usually lichen sclerosus. Surgical treatment of high-grade VIN often leads to genital deformity, impaired sexual function and reduced quality of life. To optimize clinical management, accurate biomarkers providing information on the cancer risk of high-grade VIN are needed.
Objectives
To investigate the prognostic value of a three-gene methylation marker panel and other potential risk factors for the risk of progression to cancer in patients with HSIL and dVIN.
Methods
From a population-based cohort of patients diagnosed with high-grade VIN, patients with a histopathologically confirmed diagnosis of HSIL (n = 578) and dVIN (n = 46) were selected. All lesions were tested by a three-gene methylation panel including the genes ZNF582, SST and miR124-2. The vulvar cancer risk and the prognostic value of methylation status, age, HPV genotype, wild-type vs. mutant p53 immunohistochemistry status and presence of lichen sclerosus were estimated by Kaplan–Meier and Cox regression, respectively.
Results
Vulvar cancer developed in 26 of 578 patients with HSIL (4.5%) and in 21 of 46 with dVIN (46%) within 5 years. In HSIL, positive methylation status was identified as the only prognostic factor for vulvar cancer development [hazard ratio (HR) 4.87, 95% confidence interval (CI) 1.20–21.45]. The prognostic value of methylation remained present when selecting patients who did not receive radical surgical excision as their primary treatment. In this group, the 5-year cancer risk was 7.7% in methylation-positive HSIL and 1.4% in methylation-negative HSIL (P = 0.008). In dVIN, mutant p53 status was the sole prognostic risk factor for progression to cancer (HR 7.67, 95% CI 1.78–33.08).
Conclusions
Despite wide CIs, the three-gene methylation test serves as a promising prognostic tool for cancer risk stratification in patients with vulvar HSIL. Patients with methylation-negative HSIL carry a low cancer risk, allowing for more conservative management strategies. This approach may help avoid overtreatment, reducing morbidity and improving quality of life.