Thuijs Nikki B, Voss Féline O, van Beurden Marc, Duin Sylvia, de Vries Dominique C, Steenbergen Renske D M, Berkhof Johannes, Bleeker Maaike C G
Amsterdam UMC location Vrije Universiteit Amsterdam, Pathology, De Boelelaan 1117, Amsterdam, The Netherlands.
Cancer Center Amsterdam, Imaging and Biomarkers, Amsterdam, The Netherlands.
Br J Dermatol. 2025 Jul 26. doi: 10.1093/bjd/ljaf302.
High-grade vulvar intraepithelial neoplasia (VIN) is the precursor of vulvar cancer and is divided into 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, reduced quality of life and reduced sexual function, which has a major impact on quality of life. To optimize clinical management, accurate biomarkers providing information on the cancer risk of high-grade VIN are needed.
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.
From a population-based cohort of patients diagnosed with high-grade VIN, patients with a histopathological confirmed diagnosis of HSIL (n=578) and dVIN (n=46) were selected. All lesions were tested for a three-gene methylation panel including genes ZNF582, SST, and miR124-2. The vulvar cancer risk and the prognostic value of methylation, age, HPV genotype, p53 immunohistochemistry status, and presence of lichen sclerosus were estimated by Kaplan-Meier and Cox regression, respectively.
Vulvar cancer developed in 26/578 (4.5%) HSIL patients and in 21/46 (45.7%) dVIN patients within five years. In patients with HSIL, a positive methylation status was identified as the only prognostic factor for vulvar cancer development (HR 4.87; 95%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 patients with dVIN, p53 status was the sole prognostic risk factor for progression to cancer (HR 7.67; 95% CI 1.78-33.08).
Despite wide confidence intervals, 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 improve quality of life.
高级别外阴上皮内瘤变（VIN）是外阴癌的前驱病变，分为人乳头瘤病毒（HPV）相关的高级别鳞状上皮内病变（HSIL）和HPV非依赖性VIN，后者临床上常称为分化型VIN（dVIN），与外阴皮肤病有关，通常为硬化性苔藓。高级别VIN的手术治疗常导致生殖器畸形、生活质量下降和性功能减退，对生活质量有重大影响。为优化临床管理，需要准确的生物标志物来提供高级别VIN癌症风险的信息。
研究三基因甲基化标志物组合及其他潜在风险因素对HSIL和dVIN患者进展为癌症风险的预后价值。
从以人群为基础的诊断为高级别VIN的患者队列中，选择经组织病理学确诊为HSIL（n = 578）和dVIN（n = 46）的患者。对所有病变进行三基因甲基化检测，包括ZNF582、SST和miR124 - 2基因。分别采用Kaplan - Meier法和Cox回归分析评估外阴癌风险以及甲基化、年龄、HPV基因型、p53免疫组化状态和硬化性苔藓的存在情况的预后价值。
5年内，26/578（4.5%）的HSIL患者和21/46（45.7%）的dVIN患者发生了外阴癌。在HSIL患者中，甲基化状态阳性被确定为外阴癌发生的唯一预后因素（HR 4.87；95%CI 1.20 - 21.45）。在选择未接受根治性手术切除作为主要治疗方法的患者时，甲基化的预后价值依然存在。在这组患者中，甲基化阳性的HSIL患者5年癌症风险为7.7%，甲基化阴性的HSIL患者为1.4%（p = 0.008）。在dVIN患者中，p53状态是进展为癌症的唯一预后风险因素（HR 7.67；95%CI 1.78 - 33.08）。
尽管置信区间较宽，但三基因甲基化检测对外阴HSIL患者的癌症风险分层是一种有前景的预后工具。甲基化阴性的HSIL患者癌症风险较低，可采用更保守的管理策略。这种方法可能有助于避免过度治疗，降低发病率并提高生活质量。
