Ronco Guglielmo, Giorgi-Rossi Paolo, Carozzi Francesca, Confortini Massimo, Dalla Palma Paolo, Del Mistro Annarosa, Gillio-Tos Anna, Minucci Daria, Naldoni Carlo, Rizzolo Raffaella, Schincaglia Patrizia, Volante Renza, Zappa Marco, Zorzi Manuel, Cuzick Jack, Segnan Nereo
Unit of Cancer Epidemiology, Centro per la Prevenzione Oncologica, Turin, Italy.
J Natl Cancer Inst. 2008 Apr 2;100(7):492-501. doi: 10.1093/jnci/djn065. Epub 2008 Mar 25.
In the first recruitment phase of a randomized trial of cervical cancer screening methods (New Technologies for Cervical Cancer Screening [NTCC] study), we compared screening with conventional cytology with screening by human papillomavirus (HPV) testing in combination with liquid-based cytology. HPV-positive women were directly referred to colposcopy if aged 35 or older; if younger, they were retested after 1 year.
In the second recruitment phase of NTCC, we randomly assigned women to conventional cytology (n = 24,661) with referral to colposcopy if cytology indicated atypical squamous cells of undetermined significance or more severe abnormality or to testing for high-risk HPV DNA alone by Hybrid Capture 2 (n = 24,535) with referral to colposcopy if the test was positive at a concentration of HPV DNA 1 pg/mL or greater. For the main endpoint of the study, histologic detection of cervical intraepithelial neoplasia of grade 2 or more (CIN2+), we calculated and compared sensitivity and positive predictive value (PPV) of the two screening methods using HPV DNA cutoffs of 1 pg/mL and 2 pg/mL. All statistical tests were two-sided.
For women aged 35-60 years, the relative sensitivity of HPV testing for detection of CIN2+ at a cutoff of 1 pg/mL vs conventional cytology was 1.92 (95% CI = 1.28 to 2.87) and the relative PPV was 0.80 (95% CI = 0.55 to 1.18). At a cutoff of 2 pg/mL HPV DNA, the relative sensitivity was 1.81 (95% CI = 1.20 to 2.72) and the relative PPV was 0.99 (95% CI = 0.67 to 1.46). In this age group, there was no evidence of heterogeneity between study phases. Among women aged 25-34 years, the relative sensitivity for detection of CIN2+ of HPV testing at a cutoff of 1 pg/mL vs cytology was 3.50 (95% CI = 2.11 to 5.82), statistically significantly larger (P = .019) than that observed in phase 1 at this age (1.58; 95% CI = 1.03 to 2.44).
For women aged 35-60 years, HPV testing with a cutoff of 2 pg/mL achieves a substantial gain in sensitivity over cytology with only a small reduction in PPV. Among women aged 25-34 years, the large relative sensitivity of HPV testing compared with conventional cytology and the difference between relative sensitivity during phases 1 and 2 suggests that there is frequent regression of CIN2+ that are detected by direct referral of younger HPV-positive women to colposcopy. Thus, triage test or repeat testing is needed if HPV is to be used for primary testing in this context.
在一项宫颈癌筛查方法的随机试验（宫颈癌筛查新技术[NTCC]研究）的首次招募阶段，我们将传统细胞学筛查与人类乳头瘤病毒（HPV）检测联合液基细胞学筛查进行了比较。HPV检测呈阳性的35岁及以上女性直接转诊至阴道镜检查；如果年龄较小，则在1年后重新检测。
在NTCC的第二个招募阶段，我们将女性随机分为接受传统细胞学检查组（n = 24,661），若细胞学检查显示意义不明确的非典型鳞状细胞或更严重异常则转诊至阴道镜检查；或仅接受杂交捕获2法检测高危HPV DNA组（n = 24,535），若HPV DNA浓度为1 pg/mL或更高且检测呈阳性则转诊至阴道镜检查。对于该研究的主要终点，即组织学检测到的2级或更高级别的宫颈上皮内瘤变（CIN2+），我们使用1 pg/mL和2 pg/mL的HPV DNA临界值计算并比较了两种筛查方法的敏感性和阳性预测值（PPV）。所有统计检验均为双侧检验。
对于35至60岁的女性，HPV检测在临界值为1 pg/mL时检测CIN2+的相对敏感性与传统细胞学检查相比为1.92（95%置信区间 = 1.28至2.87），相对PPV为0.80（95%置信区间 = 0.55至1.18）。在HPV DNA临界值为2 pg/mL时，相对敏感性为1.81（95%置信区间 = 1.20至2.72），相对PPV为0.99（95%置信区间 = 0.67至1.46）。在这个年龄组中，没有证据表明研究阶段之间存在异质性。在25至34岁的女性中，HPV检测在临界值为1 pg/mL时检测CIN2+的相对敏感性与细胞学检查相比为3.50（95%置信区间 = 2.11至5.82），在统计学上显著高于该年龄组在第一阶段观察到的结果（1.58；95%置信区间 = 1.03至2.44）（P = 0.019）。
对于35至60岁的女性，临界值为2 pg/mL的HPV检测在敏感性方面比细胞学检查有显著提高，而PPV仅略有降低。在25至34岁的女性中，与传统细胞学检查相比，HPV检测的相对敏感性较高，且第一阶段和第二阶段的相对敏感性存在差异，这表明通过将年轻HPV阳性女性直接转诊至阴道镜检查检测到的CIN2+常有消退。因此，在这种情况下，如果将HPV用于初次检测，则需要进行分流检测或重复检测。
