充分诊断人乳头状瘤病毒（HPV）相关的高级别鳞状上皮内病变（HSIL）和HPV非相关的阴道上皮内肿瘤（VIN）是至关重要的，但也具有一定的挑战性。我们对一个大型的基于人群的阴道病变系列进行了全面的表征，最初被报告为高级别VIN，并评估了癌症风险。按病理学复评、综合免疫组化（p16INK4a，p53，Ki-67）和HPV DNA检测结果对751名患者的基线高级别VIN进行了分类。综合分析结果显示88.4%的HPV相关病变（77.0%的HSIL，10.9%的低级别鳞状上皮内病变[LSIL]，0.4%的阴道鳞状细胞癌[VSCC]），10.9%的HPV非相关病变（6.1%的HPV非相关VIN，4.7%的非增生性病变，0.1%的VSCC）和1.1%的不确定性病变。HSIL中，p16INK4a呈阻断阳性在99.0%、Ki-67在≥2/3的上皮中增加在93.6%、HPV阳性在99.6%。在HSIL中，p53野生型中上皮染色模式常见（51.6%），而在HPV非相关病变中观察不到这种情况。HPV非相关VIN中，65.2%的细胞显示突变型p53模式，并且呈现了广泛的形态谱，从分化到非分化（“类HPV相关”41.3%）。Kaplan-Meier分析显示10年内HPV相关HSIL的癌症风险为8.0%、HPV非相关VIN/p53突变型为67.4%、HPV非相关VIN/p53野生型为27.8%。令人惊讶的是，10年内非分化（“类HPV相关”）形态的HPV非相关VIN的癌症风险为73.3%。p16INK4a和p53的免疫组化检测对于将VIN分类为HPV相关和HPV非相关至关重要，这在不同的癌症风险方面尤为重要。HPV非相关VIN的高癌症风险强调了手术治疗和密切随访的必要性，特别是在出现p53突变模式和/或非分化形态的情况下。© 2023年作者，经John Wiley & Sons Ltd. 出版的《组织病理学》发表。

Adequate diagnosis of human papillomavirus (HPV)-associated high-grade squamous intraepithelial lesion (HSIL) and HPV-independent vulvar intraepithelial neoplasia (VIN) is essential but can be challenging. We comprehensively characterized a large population-based series of vulvar lesions, originally reported as high-grade VIN, and assessed the cancer risk.Baseline high-grade VIN of 751 patients were categorized by histopathological reassessment, integrating the results of immunohistochemistry (p16INK4a , p53, Ki-67) and HPV DNA testing. Integrated analyses resulted in 88.4% HPV-associated lesions (77.0% HSIL, 10.9% low-grade SIL [LSIL], and 0.4% vulvar squamous cell carcinoma [VSCC]), 10.9% HPV-independent lesions (6.1% HPV-independent VIN, 4.7% nondysplastic lesions, and 0.1% VSCC) and 1.1% inconclusive lesions. HSIL demonstrated p16INK4a block-positivity in 99.0%, increased Ki-67 in ≥2/3rd of the epithelium in 93.6%, and HPV positivity in 99.6%. In HSIL, a p53 wildtype mid-epithelial staining pattern was common (51.6%) while this was not observed in HPV-independent lesions. HPV-independent VIN harboured mutant p53 patterns in 65.2% and showed a wide morphological spectrum, ranging from differentiated to nondifferentiated ('HPV-associated-like', in 41.3%). Kaplan-Meier analyses showed a 10-year cancer risk of 8.0% in HPV-associated HSIL, 67.4% in HPV-independent VIN/p53mutant, and 27.8% in HPV-independent VIN/p53wildtype. Strikingly, the 10-year cancer risk was 73.3% in HPV-independent VIN with nondifferentiated ('HPV-associated-like') morphology.Immunohistochemistry by p16INK4a and p53 is highly recommended for optimal categorization into HPV-associated and HPV-independent VIN, which is of utmost importance given the different cancer risk. The high cancer risk of HPV-independent VIN underscores the need for surgical treatment and close follow-up, especially in case of a p53 mutant pattern and/or nondifferentiated morphology.© 2023 The Authors. Histopathology published by John Wiley & Sons Ltd.