p16/Ki-67双染细胞学检测HPV阳性女性的宫颈上皮内瘤变
p16/Ki-67 Dual Stain Cytology for Detection of Cervical Precancer in HPV-Positive Women.
作者信息
Wentzensen Nicolas, Fetterman Barbara, Castle Philip E, Schiffman Mark, Wood Shannon N, Stiemerling Eric, Tokugawa Diane, Bodelon Clara, Poitras Nancy, Lorey Thomas, Kinney Walter
机构信息
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD (NW, MS, SNW, CB); Kaiser Permanente TPMG Regional Laboratory, Berkeley, CA (BF, ES, DT, NP, TL); Global Coalition Against Cervical Cancer, Arlington, VA (PEC); Albert Einstein College of Medicine, Bronx, NY (PEC); Division of Gynecologic Oncology, Kaiser Permanente Medical Care Program, Oakland, CA (WK).
出版信息
J Natl Cancer Inst. 2015 Sep 15;107(12):djv257. doi: 10.1093/jnci/djv257. Print 2015 Dec.
BACKGROUND
Human papillomavirus (HPV)-based cervical cancer screening requires triage markers to decide who should be referred to colposcopy. p16/Ki-67 dual stain cytology has been proposed as a biomarker for cervical precancers. We evaluated the dual stain in a large population of HPV-positive women.
METHODS
One thousand five hundred and nine HPV-positive women screened with HPV/cytology cotesting at Kaiser Permanente California were enrolled into a prospective observational study in 2012. Dual stain cytology was performed on residual Surepath material, and slides were evaluated for dual stain-positive cells. Disease endpoints were ascertained from the clinical database at KPNC. We evaluated the clinical performance of the assay among all HPV-positive women and among HPV-positive, cytology-negative women. We used internal benchmarks for clinical management to evaluate the clinical relevance of the dual stain assay. We evaluated sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the dual stain compared with Pap cytology. All statistical tests were two-sided.
RESULTS
The dual stain had lower positivity (45.9%) compared with cytology at an ASC-US threshold (53.4%). For detection of CIN2+, the dual stain had similar sensitivity (83.4% vs 76.6%, P = .1), and statistically higher specificity (58.9% vs 49.6%, P < .001), PPV (21.0% vs 16.6%, P < .001), and NPV (96.4% vs 94.2%, P = .01) compared with cytology. Similar patterns were observed for CIN3+. Women with a positive test had high enough risk for referral to colposcopy, while the risk for women with negative tests was below a one-year return threshold based on current US management guidelines.
CONCLUSION
Dual stain cytology showed good risk stratification for all HPV-positive women and for HPV-positive women with normal cytology. Additional follow-up is needed to determine how long dual stain negative women remain at low risk of precancer.
背景
基于人乳头瘤病毒（HPV）的宫颈癌筛查需要分流标志物来决定哪些人应转诊至阴道镜检查。p16/Ki-67双重染色细胞学检查已被提议作为宫颈上皮内瘤变的生物标志物。我们在大量HPV阳性女性群体中评估了这种双重染色检查。
方法
2012年，1509名在加利福尼亚州凯撒医疗集团通过HPV/细胞学联合检测筛查出HPV阳性的女性被纳入一项前瞻性观察研究。对剩余的Surepath样本进行双重染色细胞学检查，并对玻片上的双重染色阳性细胞进行评估。疾病终点从凯撒医疗集团的临床数据库中确定。我们在所有HPV阳性女性以及HPV阳性、细胞学检查阴性的女性中评估了该检测方法的临床性能。我们使用临床管理的内部基准来评估双重染色检测的临床相关性。与巴氏细胞学检查相比，我们评估了双重染色的敏感性、特异性、阳性预测值（PPV）和阴性预测值（NPV）。所有统计检验均为双侧检验。
结果
在非典型鳞状细胞不能明确意义（ASC-US）阈值下，双重染色的阳性率（45.9%）低于细胞学检查的阳性率（53.4%）。对于检测高级别鳞状上皮内病变2级及以上（CIN2+），双重染色的敏感性相似（83.4%对76.6%，P = 0.1），特异性在统计学上更高（58.9%对49.6%，P < 0.001），PPV更高（21.0%对16.6%，P < 0.001），NPV更高（96.4%对94.2%，P = 0.01）。对于CIN3+也观察到类似模式。检测结果为阳性的女性有足够高的风险被转诊至阴道镜检查，而检测结果为阴性的女性的风险低于根据当前美国管理指南的一年复查阈值。
结论
双重染色细胞学检查对所有HPV阳性女性以及细胞学检查正常的HPV阳性女性显示出良好的风险分层。需要进一步随访以确定双重染色阴性的女性在多长时间内仍处于低级别上皮内瘤变风险状态。
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