海南地区阴道自取样联合p16蛋白检测在宫颈癌人乳头瘤病毒分流筛查中的应用

Application of vaginal self-sampling test combined with p16 protein detection in HPV shunt screening for cervical cancer in Hainan Province

    摘要
  • 摘要:
    目的 构建海南地区阴道自取样人乳头瘤病毒（HPV）宫颈癌筛查模式，分析p16蛋白检测在HPV阳性及非HPV 16、18分流筛查中的应用。
    方法 琼海市人民医院于2019年1月—2022年9月采用随机数字表法在海南地区目标人群中随机选择200名女性进行阴道自取样HPV分型检测以筛查宫颈癌，并在阴道自取样后行宫颈细胞学取样进行细胞学p16蛋白检测。以术后病理检查为金标准。采用多因素logistic回归分析宫颈病变HPV阳性检出率的影响因素，并构建列线图模型，应用受试者操作特征（ROC）曲线和校准曲线对模型进行评价。记录自取样HPV阳性和HPV感染基因型分布差异，并分析p16蛋白检测在HPV阳性及非HPV16、18分流筛查中的应用。
    结果 年龄≥40岁、BMI≥28.00 kg·m-2、性伴侣数≥2、性生活频率≥10次·月-1、接触性出血、初次性生活年龄<22岁均为宫颈病变HPV阳性的危险因素（均P<0.001）。ROC曲线和校准曲线结果显示，ROC曲线下面积（AUC）为0.874（95%CI：0.823~0.907，P<0.05），灵敏度为0.835，特异度为0.847，约登指数为0.672，校准曲线显示模型拟合度良好。阴道自取样HPV检测结果显示，HPV阳性率为86.50%（173/200）。HPV高危感染型主要包括HPV16、18、31、33、35、39、45、52、56、58、59、68、73、82型。单一HPV感染者占95.95%（166/173），2型感染者占2.89%（5/173），3型及以上感染者占1.16%（2/173）。以阴道镜病理诊断作为金标准，结果显示，p16蛋白诊断宫颈癌的准确度为93.50%（187/200），灵敏度为96.53%（167/173），特异度为74.07%（20/27），阴性与阳性预测值分别为76.92%（20/26）、95.98%（167/174）。分流筛查结果显示，HPV16、18型及非HPV16或18型分别有80、79、41例，灵敏度分别为90.91%、90.32%、86.67%；特异度分别为71.43%、64.71%、72.73%；阴性预测值分别为62.50%、64.71%、66.67%；阳性预测值分别为93.75%、90.32%、89.66%；准确度分别为87.50%、84.81%、82.93%。p16阳性筛查宫颈癌的特异度与准确度均高于HPV阳性检测，假阳性率低于HPV阳性检测。HPV阳性、p16阳性及二者联合检出宫颈癌病变的AUC分别为0.603、0.822、0.907。
    结论 阴道自取样HPV检测是一种被广泛认可的宫颈癌筛查模式。宫颈细胞学p16蛋白检测对自取样HPV阳性及非HPV16、18型的分流筛查有重要意义。

     

    Abstract:
    Objective To establish a vaginal self-sampling HPV cervical cancer screening model in Hainan Province, to analyze the application of p16 protein detection in HPV positive and non-HPV16 /18 shunt screening.
    Methods From January 2019 to September 2022, a total of 200 women from the targeted population was randomly selected for vaginal self-sampling HPV typing test to screen cervical cancer using randomized numeric table method, followed by cervical cytology sampling for cytology p16 protein detection. Postoperative pathological examination was used as the gold standard. Multivariate logistic regression analysis was used to analyze the influencing factors of HPV positive detection rate in cervical lesions, and the nomogram model was constructed simultaneously. The receiver operating characteristic(ROC) curve and calibration curve were used for evaluating the accuracy of the nomogram model. Differences in the distribution of self-sampled HPV-positive and HPV infected genotypes were recorded, and the application of p16 protein detection in HPV-positive and non-HPV16/18 shunt screening was analyzed.
    Results Aged ≥40 years, BMI ≥28.00 kg·m-2, number of sexual partners ≥2, frequency of sexual life ≥10 times·month-1, bleeding from sexual intercourse, and age of first sexual intercourse <22 years were the risk factors for HPV positive of cervical lesions (all P<0.001). The results of ROC curve and calibration curve showed that the area under ROC curve (AUC) was 0.874 (95%CI: 0.823‒0.907, P<0.05), the sensitivity was 0.835, the specificity was 0.847, and the Youden index was 0.672, indicating a good fit of the model. Results of vaginal self-sampling HPV test showed that the positive rate of HPV was 86.50% (173/200). HPV high-risk infection types mainly included HPV16, 18, 31, 33, 35, 39, 45, 52, 56, 58, 59, 68, 73, and 82. Single HPV infection accounted for 95.95% (166/173), 2.89% (5/173) were infected with two types of HPV, and 1.16% (2/173) were infected with three or more types of HPV. Colposcopic pathologic diagnosis was used as the gold standard, and the results showed that the accuracy of p16 protein detection in the diagnosis of cervical cancer was 93.50% (187/200), with a sensitivity of 96.53% (167/173), and a specificity of 74.07% (20/27). The negative and positive predictive value were 76.92% (20/26) and 95.98% (167/174), respectively. The results of shunt screening showed that there were 80 cases infected with HPV16, 79 cases infected with HPV18 and 41 cases of non-HPV16/18, with a sensitivity of 90.91%, 90.32% and 86.67%, a specificity of 71.43%, 64.71% and 72.73%, a negative predictive value of 62.50%, 64.71% and 66.67%, a positive predictive value of 93.75%, 90.32% and 89.66%, and an accuracy of 87.50%, 84.81% and 82.93%, respectively. The specificity and accuracy of p16 positive screening for cervical cancer were significantly higher than that of HPV positive detection, but the false positive rate was significantly lower than that of HPV positive detection. The AUCs of HPV positive, p16 positive and combination of the two detection methods for cervical cancer were 0.603, 0.822 and 0.907, respectively.
    Conclusion Vaginal self-sampling HPV testing is a widely accepted mode for cervical cancer screening. Cervical cytology p16 protein detection is important for self-sampled HPV positive and shunt screening of non-HPV16/18.

     

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