高危型HPV阳性妇女子宫颈脱落细胞HPV L1蛋白检测的临床意义

Clinical significance of HPV L1 capsid protein detection in cervical exfoliated cells in high-risk HPV positive women

目的：探讨高危型HPV阳性妇女子宫颈脱落细胞HPV L1蛋白检测的临床意义。方法收集2012年11月-2013年6月间，在浙江省湖州市妇幼保健院和浙江大学医学院附属妇产科医院就诊的符合入组条件[包括既往无子宫颈上皮内瘤变（CIN）史及恶性肿瘤史，无子宫颈手术史，年龄为30-65岁，非妊娠期妇女]的高危型HPV阳性妇女。收集子宫颈脱落细胞，分别行液基薄层细胞学检查（TCT）和免疫细胞化学染色检测HPV L1蛋白。所有高危型HPV阳性妇女均行阴道镜检查，并对可疑病变部位行阴道镜活检病理检查。比较不同组织学诊断妇女的子宫颈脱落细胞中HPV L1蛋白的表达情况，评估子宫颈脱落细胞HPV L1蛋白检测在子宫颈病变筛查中的价值。结果符合入组条件的高危型HPV阳性妇女共386例，其组织学诊断为：正常子宫颈162例，低度鳞状上皮内病变（LSIL）94例，高度鳞状上皮内病变（HSIL）128例，子宫颈鳞癌（SCC）2例。HSIL和SCC妇女的HPV L1蛋白阳性表达率显著低于LSIL和正常子宫颈者[分别为19.2%（25/130）和66.4%（170/256）；P=0.000]。在高危型HPV阳性妇女中，子宫颈脱落细胞HPV L1蛋白检测预测组织学诊断≥HSIL病变（包括HSIL和SCC）的敏感度（分别为80.77%、50.77%）和阴性预测值（分别为87.18%、76.47%）均显著高于细胞学检查（P〈0.01），但其特异度（分别为66.41%、81.25%）显著低于细胞学检查（P〈0.01）；而两者的阳性预测值（分别为54.97%、57.89%）比较，差异则无统计学意义（P=0.619）。在高危型HPV阳性、细胞学检查正常的妇女中，HPV L1蛋白检测预测组织学诊断≥HSIL时的敏感度和阴性预测值分别为87.50%和94.12%，特异度和阳性预测值分别为61.54%和41.18%；而在高危型HPV阳性、细胞学检查结果为未明确诊断意义的不典型鳞状上皮细胞（ASCUS）的妇女中，HPV L1蛋白检测用于预测的敏感度、特异度、阳性预测值和阴性预测值分别为80.00%、86.36%、80.00%和86.36%。结论子宫颈脱落细胞HPV L1蛋白检测在高危型HPV阳性妇女的子宫颈病变筛查中具有一定的价值，可能成为高危型HPV阳性，而细胞学检查正常或ASCUS妇女的一种合适的分流方法。

Objective To explore the clinical significance of human papillomavirus L1 capsid protein detection in cervical exfoliated cells in high-risk HPV positive women. Methods From November 2012 to June 2013,386 high-risk HPV positive （detected by hybrid capture Ⅱ） cases were enrolled as eligible women from Huzhou Maternity＆Child Care Hospital and Women′s Hospital,School of Medicine, Zhejiang University. All eligible women underwent liquid-based cytology （ThinPrep） followed by colposcopy. Biopsies were taken if indicated. Cervical exfoliated cells were collected for HPV L1 capsid protein detection by immunocytochemistry. Expression of HPV L1 capsid protein in groups with different histological diagnosis were compared, and the role of HPV L1 capsid protein detection in cervical exfoliated cells in cervical lesions screening was accessed. Results Total 386 enrolled eligible women were finally diagnosed histologically as follwed：162 normal cervix, 94 low-grade squamous intraepithelial lesion （LSIL）, 128 high-grade squamous intraepithelial lesion （HSIL） and 2 squamous cervical cancer （SCC）. The positive expression rate of HPV L1 in HSIL＋（HSIL or worse） group was significantly lower than that in LSIL-（LSIL or better） group （19.2% vs 66.4%,P=0.000）. While identifying HSIL＋ in HPV positive cases and compared with cytology, HPV L1 detection resulted in significant higher sensitivity （80.77%vs 50.77%,P=0.000） and negative predictive value （NPV;87.18% vs 76.47%,P=0.004）, significant lower specificity （66.41% vs 81.25%,P=0.000）,and comparable positive predictive value （PPV;54.97% vs 57.89%, P=0.619）. To identify HSIL＋in HPV-positive/cytology-negative women, the sensitivity, specificity, PPV, and NPV of HPV L1 detection were 87.50%, 61.54%, 41.18%, and 94.12%respectively, while 80.00%, 86.36%, 80.00%and 86.36%respectively in HPV-positive/atypical squamous cell of undetermined significance（ASCUS）women. Conclusions HPV L1 capsid detection in cervical exfoliated cells have a role in cervical lesions screening in high-risk HPV positive women, and may be a promising triage for high-risk HPV-positive/cytology-negative or ASCUS women.