阴道镜下隐匿子宫颈上皮内瘤变Ⅲ级病变的HPV亚型感染特征及鳞状上皮厚度分析

Characteristics of invisible cervical intraepithelial neoplasia Ⅲ under colposcopy

目的探讨阴道镜下隐匿子宫颈上皮内瘤变Ⅲ级（CINⅢ）病变的HPV亚型感染特征及鳞状上皮厚度。方法对2009--2010年期间进行的深圳子宫颈癌筛查项目Ⅱ（SHENCCAST1I）研究中有完整资料、病理诊断为CINⅢ的93例患者的169个象限的CINⅢ组织的石蜡标本采用“三明治”法重新制作6张连续切片，其中第l张和最后1张行HE染色以明确病理诊断并确保其间的切片中含有同样级别的病变，第3～5张（第2张用于其他研究）共3张白片用于行基质辅助激光解吸电离飞行时间质谱（MALDI—TOF—MS）法HPV分型检测，并在显微镜下（×10）对CIN Ⅲ病变部位的鳞状上皮厚度进行测量。其中，由阴道镜指示对可见病灶进行活检发现的CINm定为“可见CINⅢ”，通过子宫颈随机多点活检发现的CINⅢ定为“隐匿CIN Ⅲ”。结果（1）169个象限中，43个象限为隐匿CINⅢ、126个象限为可见CIN Ⅲ，其HPV16型阳性率分别为37．2％（16／43）和55．6％（70／126），两者比较，差异有统计学意义（x2=4．318，P=0．038）。93例CINⅢ患者中，HPV16型阳性和非HPV16型阳性患者分别为49和44例，其中年龄≥45岁患者所占比例分别为20．4％（10／49）和40．9％（18／44），两者比较，差异有统计学意义（x2=4．630，P=0．031）；CINⅢ病灶〉1个象限患者所占比例分别为79．6％（39／49）和52．3％（23／44），两者比较，差异也有统计学意义（x2=7．786，P=0．005）。（2）阴道镜下可见CINⅢ病变的鳞状上皮厚度为（161±9）μm，较隐匿CINⅢ病变者[（140±12）μm]厚，两者比较，差异有统计学意义（t=4．383，P=0．038）。HPV16型阳性与非HPV16型阳性患者的CINⅢ病变的鳞状上皮厚度分别为（172±11）和（130±10）μm，两者比较，差异有统计学意义（t=4．784，P=0．031）。结论阴道镜下隐匿CINⅢ不易识别，可能与非HPV16型阳性、病灶范围小、病灶的鳞状上皮较薄有关。对非HPV16型阳性及年龄偏大者行阴道镜检查时，通过在子宫颈转化区域行病灶活检及多点随机活检，可提高CINⅢ的检出率，减少漏诊率。

Objective To explore the human papilomavirus （HPV） genotypes and epithelial thickness of invisible cervical intraepithelial neoplasia Ⅲ （CIN Ⅲ ） under colposeopy. Methods One hundred and sixty-nine biopsies from 93 patients with a final diagnosis of CIN Ⅲ were extracted from the Shenzhen cervical cancer screening trial Ⅱ （SHENCCAST Ⅱ ）. The SHENCCAST Ⅱ was conducted from 2009 to 2010. All the cervical blocks from these patients were re-cut and placed on 6 slides, i.e. sandwich model, with the top and bottom sections being stained with HE, the top second be processed for other studies, 3 sections for HPV genotypes by matrix-assisted laser desorption ionization-time of flight-mass spectrometry （MALDI-TOF-MS） assay. The thickness of squamous epithelium of CIN Ⅲ was measured by a microscope （×10） after re-cut. Colposcope directed CIN Ⅲ biopsies positively was defined as visible CIN Ⅲ, while random CIN Ⅲ biopsies positively was defined as invisible CIN Ⅲ. Results HPV16 positivity was 37.2% （16/43） and 55.6% （70/126） between invisible and visible CIN Ⅲ biopsies, respectively （X2=4.318, P=0.038）. Forty-nine cases of the 93 CIN Ⅲ patients were HPV16 positive, while 44 of them non-HPV16 positive. The proportion of patients with ≥45 years of age for other non-HPV16 positive 40.9% （18/44） was significantly higher than that HPV16 positive 20.4% （10/49; X2=4.630, P= 0.031 ）. Patients with HPV16 positive were more likely to have lesions ≥1 quadrant （X2=7.786, P=0.005） than other non-HPV16 positive. Compared the average epithelium thickness of invisible CIN m tissue （140±12） μm, the average epithelium thickness of visible CIN m tissue （161±9） μm was thicker. There was statistical difference between two groups （t=4.383, P=0.038）. The mean average epithelial thickness of CIN m with HPV16 positive （172±11） μm was thicker than that the mean average epithelial thickness of CIN Ⅲ with non-HPV16 positive （130±10）μm （t=4.784, P=0.031）. Conclusions Invisible lesions is difficult to identify under colposcopy and is related to non-HPVI 6 positive, small lesion size and thinner squamous epithelium. For non-HPV16 positive or older women should be performed colposcope directed biopsies and randomly multi-sites biopsies by colopscopy, which may be helpful to improve the detection of CIN Ⅲ and to reduce miss diagnosis.