DNA methylation testing for vulvar cancer risk stratification in patients with high-grade vulvar intraepithelial neoplasia: a population-based cohort study

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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.