Center for Cervical Cancer Prevention, Department of Research, Buddhist Tzu Chi General Hospital, Hualien, Republic of China.
Am J Obstet Gynecol. 2011 Jan;204(1):21.e1-7. doi: 10.1016/j.ajog.2010.07.036. Epub 2010 Sep 15.
Management of equivocal Papanicolaou smear result remains to be challenging even with the aid of human papillomavirus test. Recently, 3 novel methylation-silenced genes, PAX1, WT1, and PCDH10, have been found to be specifically associated with cervical cancer. We compared the performances of methylation test of these genes with human papillomavirus tests in triage of equivocal Papanicolaou smear result.
Two hundred twenty-two women with Papanicolaou smear results of atypical cells of undetermined significance nested to a multicenter, nation-wide cohort (the T1899 cohort) were studied. Status of cervical neoplasm was diagnosed with colposcopic biopsy. Status of gene methylation was determined by methylation-specific polymerase chain reaction. High-risk human papillomavirus DNA was detected by polymerase chain reaction-reverse line blot hybridization and Hybrid Capture 2.
Cervical intraepithelial neoplasm 1, cervical intraepithelial neoplasm 2, cervical intraepithelial neoplasm 3, carcinoma in situ, carcinoma, and normal cervix were diagnosed in 58, 17, 14, 10, 1, and 120 women, respectively. Methylation of PCDH10, WT1, and PAX1 was highly associated with the severity of cervical neoplasm (P < 10⁻⁹, < 10⁻⁷, and < 10⁻⁵, respectively). In comparison with a negative test result, the odds ratio (95% confidence intervals) for cervical intraepithelial neoplasm 3 or more severe neoplasms for women tested positive for methylation of these 3 genes were 26.4 (9.0-77.3), 18.1 (6.9-47.2), and 10.3 (4.1-25.9), respectively; whereas those positive for human papillomavirus polymerase chain reaction and Hybrid Capture 2 were 10.5 (3.5-31.9) and 5.6 (2.3-21.4). In triage for atypical cells of undetermined significance, each methylation test had less colposcopy referral and false-positive rates, but higher false-negative rate than the human papillomavirus tests. With a combination test of PCDH10 or WT1 methylation, a comparable false-negative rate (P = .62) but much less false-positive rate (P = .002) and colposcopy referral rate (P < 10⁻⁶) were achieved.
In triage of atypical cells of undetermined significance Papanicolaou smear results, methylation test of WT1 and PCDH10 is superior to human papillomavirus test in this multicenter cohort. Comparing to current human papillomavirus triage, the new test has only one third of false positivity and half of colposcopy referral, with no compromise of the sensitivity in diagnosis of cervical intraepithelial neoplasm 3 or more severe neoplasms.
即使有人类乳头状瘤病毒（HPV）检测的辅助，对意义不明确的巴氏涂片结果的管理仍然具有挑战性。最近，3 种新型甲基化沉默基因（PAX1、WT1 和 PCDH10）已被发现与宫颈癌特异性相关。我们比较了这些基因的甲基化检测与 HPV 检测在意义不明确的巴氏涂片结果中的应用。
对嵌套于多中心全国性队列（T1899 队列）的 222 例巴氏涂片结果为不典型意义不明的细胞的妇女进行了研究。宫颈病变的状态通过阴道镜活检来诊断。通过甲基化特异性聚合酶链反应（PCR）确定基因甲基化状态。采用聚合酶链反应-反向线杂交和杂交捕获 2 法检测高危型 HPV DNA。
58、17、14、10、1 和 120 例妇女分别诊断为宫颈上皮内瘤变 1 级、宫颈上皮内瘤变 2 级、宫颈上皮内瘤变 3 级、原位癌、癌和正常宫颈。PCDH10、WT1 和 PAX1 的甲基化与宫颈病变的严重程度高度相关（P<10⁻⁹、<10⁻⁷ 和<10⁻⁵）。与阴性检测结果相比，这些基因检测结果阳性的妇女中宫颈上皮内瘤变 3 级或更严重病变的优势比（95%置信区间）为 26.4（9.0-77.3）、18.1（6.9-47.2）和 10.3（4.1-25.9），而 HPV 聚合酶链反应和杂交捕获 2 阳性的妇女分别为 10.5（3.5-31.9）和 5.6（2.3-21.4）。在不典型意义不明的巴氏涂片结果的分流中，每种甲基化检测的阴道镜转诊率和假阳性率较低，但假阴性率较高，而 HPV 检测则较低。采用 PCDH10 或 WT1 甲基化的联合检测，可获得相当的假阴性率（P=0.62），但假阳性率（P=0.002）和阴道镜转诊率（P<10⁻⁶）明显降低。
在意义不明确的巴氏涂片结果的分流中，与 HPV 检测相比，WT1 和 PCDH10 的甲基化检测在多中心队列中具有优势。与目前的 HPV 分流相比，新检测的假阳性率仅为其三分之一，阴道镜转诊率为一半，而对宫颈上皮内瘤变 3 级或更严重病变的诊断敏感性无任何降低。
