Yan Ping Bao

A new HPV-DNA test for cervical-cancer screening in developing regions: a cross-sectional study of clinical accuracy in rural China

BACKGROUND A new test (careHPV; QIAGEN, Gaithersburg, MD, USA) has been developed to detect 14 high-risk types of carcinogenic human papillomavirus (HPV) in about 2.5 h, to screen women in developing regions for cervical intraepithelial neoplasia (CIN). We did a cross-sectional study to assess the clinical accuracy of careHPV as a rapid screening test in two county hospitals in rural China. METHODS From May 10 to June 15, 2007, the careHPV test was done locally by use of self-obtained vaginal and provider-obtained cervical specimens from a screening population-based set of 2530 women aged 30 to 54 years in Shanxi province, China. All women were assessed by visual inspection with acetic acid (VIA), Digene High-Risk HPV HC2 DNA Test (HC2), liquid-based cytology, and colposcopy with directed biopsy and endocervical curettage as necessary. In 2388 women with complete data, 441 women with negative colposcopy, but unsatisfactory or abnormal cytology or who were positive on HC2 or the new careHPV test, were recalled for a second colposcopy, four-quadrant cervical biopsies, and endocervical curettage. An absence of independence between the tests was not adjusted for and the Bonferroni correction was used for multiple comparisons. FINDINGS Complete data were available for 2388 (94.4%) women. 70 women had CIN2+ (moderate or severe CIN or cancer), of whom 23 had CIN3+. By use of CIN2+ as the reference standard and area-under-the-curve analysis with a two-sided alpha error level of 0.0083, the sensitivities and specificities of the careHPV test for a cut-off ratio cut-point of 0.5 relative light units, were 90.0% (95% CI 83.0-97.0) and 84.2% (82.7-85.7), respectively, on cervical specimens, and 81.4% (72.3-90.5) and 82.4% (80.8-83.9), respectively, on vaginal specimens (areas under the curve not significantly different, p=0.0596), compared with 41.4% (29.9-53.0) and 94.5% (93.6-95.4) for VIA (areas under the curve significantly different, p=0.0001 and p=0.0031, for cervical and vaginal-specimen comparisons for the careHPV test, respectively). The sensitivity and specificity of HC2 for cervical specimens were 97.1% (93.2-100) and 85.6% (84.2-87.1), respectively (areas under the curve not significantly different from the careHPV test on cervical specimens, p=0.0163). INTERPRETATION The careHPV test is promising as a primary screening method for cervical-cancer prevention in low-resource regions.

Human papillomavirus infection in Shanxi Province, People's Republic of China: a population-based study

To investigate the prevalence of, and risk factors for, cervical infection with human papillomavirus (HPV) in the rural province of Shanxi, Peoples Republic of China, which has relatively high cervical cancer mortality rates, we interviewed and obtained cervical cell samples from 662 women aged 15–59 years. A total of 24 different HPV types were identified using a GP5+/6+-based PCR assay able to detect 44 different HPV types. Human papillomavirus prevalence was 14.8% overall and 9.6% among women without cervical abnormalities (14.2 and 8.9%, respectively, age standardised to the world standard population). Multiple-type infections accounted for 30.6% of all infections. By far the most commonly found type was HPV16 (5.7% of all women and 38.8% of HPV-positive women), followed by HPV 58, 52, 33 and 18. Unlike most previous studies published, HPV prevalence was lower among women younger than 35 years (8.7%) than those older than 35 years (17.8%). High-risk HPV types predominated in all age groups. Although low-risk HPV types were rare in young women, they became more common with increasing age. 92.3% of women with cervical intraepithelial neoplasia grade 3 were infected with high-risk HPV types, but none with low-risk types only. No significant difference in HPV positivity was observed by educational level, sexual habits, reproductive history or use of contraceptive methods in this rural low-income Chinese population.

A meta-analysis of human papillomavirus type-distribution in women from South Asia: implications for vaccination.

OBJECTIVE To determine human papillomavirus (HPV) prevalence and type-distribution in women from South Asia, with and without cervical lesions, in order to estimate the impact of an HPV 16/18 prophylactic vaccine in this region and to assess additional types that should be incorporated in new vaccines. METHODS A meta-analysis was conducted that included studies using polymerase chain reaction to detect HPV-16, -18, -6, -11 and at least one other HPV type, with a minimum of 20 cases in each grade of lesion. Total as well as type-specific prevalence of various HPV types were estimated, stratified by cervical lesion grade, using Stata 9.0 software package. RESULTS Nine studies from India fulfilled the inclusion criteria. A total of 558, 52, 52 and 3061 women, respectively with invasive cervical cancer (ICC), high-grade squamous intraepithelial lesions (HSIL), low-grade squamous intraepithelial lesions (LSIL) and normal cytology/histology were included. Overall HPV prevalence was 94.6%, 86.5%, 65.4% and 12.0% in women with ICC, HSIL, LSIL and normal cytology/histology, respectively. In ICC, HPV-16 was the predominant type (64.8%), followed by HPV-18, -45, -33, -35, -58, -59 and -31. The estimated HPV-16/18 positive fraction was 78.9% in women with ICC (87.7% in North and 77.2% in South India), 61.5% with HSIL, 30.8% with LSIL and 3.9% in women with normal cytology/histology. There was no difference in overall HPV prevalence in cervical cancer between North and South India (P=0.063). However, HPV-16 and -45 appeared to be more prevalent in North India (P=0.018 and 0.013, respectively), while HPV-35 appeared to be more prevalent in South India (P=0.033). CONCLUSION It is estimated that HPV-16/18 vaccines will provide over 75% protection against ICC in South Asia. HPV-45, -33, -35 and -58 account for an additional 20% of cervical cancer in this region. The addition of these additional HPV types in a second-generation vaccine could provide optimal cervical cancer prevention in this region.

Inappropriate gold standard bias in cervical cancer screening studies

As acetic acid‐aided visual inspection (VIA) and colposcopic‐directed biopsy miss small ≥cervical intraepithelial neoplasia (CIN) 2, inflation of sensitivity of VIA may occur when colposcopic‐directed biopsy is the gold standard for ≥CIN 2. To determine whether such inflation occurs, we reviewed 375 women with ≥CIN 2 from the Shanxi Province Cervical Cancer Screening Study II. These women had positive self or physician‐collected tests for high‐risk human papillomavirus or abnormal cervical cytology and had VIA followed by colposcopy with directed biopsy and endocervical curettage (ECC). If a cervical quadrant had no lesion, a random biopsy at the squamocolumnar junction within that quadrant was obtained. Sensitivity of colposcopic‐directed biopsy was higher for ≥CIN 2 involving 3–4 cervical quadrants (81.3%) than for ≥CIN 2 involving 0–2 quadrants (49.0%, p < 0.001). Sensitivities of VIA, cytology of ≥ASC‐US, ≥LSIL, and ≥HSIL were higher for ≥CIN 2 involving 3–4 quadrants than for ≥CIN 2 involving 0–2 quadrants. When a colposcopic‐directed biopsy gold standard was compared with that of a 5‐biopsy standard (which included ≥CIN 2 from colposcopic‐directed biopsy, random biopsy, or ECC), the sensitivity for ≥CIN 2 of VIA was inflated by 20.0% (65.9% vs. 45.9%, p < 0.001). Sensitivities of other screening tests were not affected. Similar inflation of sensitivity of VIA was found with an endpoint of ≥CIN 3 (70.4% vs. 52.0%, p = 0.0013). Inflation of sensitivity of VIA depended upon agreement between colposcopic‐directed biopsy and the screening tests as measured by kappa. Studies of VIA that used colposcopic‐directed biopsy as the gold standard require reevaluation.

Epidemiology and Prevention of Human Papillomavirus and Cervical Cancer in China and Mongolia

To develop a comprehensive intervention policy for future management of cervical cancer in China and Mongolia, it is essential to review the prevalence of human papillomavirus (HPV) infection, cervical cancer incidence and mortality, status of cervical screening and issues related to prophylactic HPV vaccines. Invasive cervical cancer (ICC) remains an important health problem among women in both China and Mongolia. However, a significant proportion of the burden is observed in rural settings. In areas of China and Mongolia where data are available, HPV prevalence is relatively high, with sexual activity being the most important risk factor. Nationwide programs for cervical cancer screening do not exist, and the majority of women have never been screened. However, government and non-governmental organizations have been collaborating to establish demonstration centers in both high- and low-resource settings to provide screening and obtain geographic specific data. To date, the prophylactic HPV vaccines are not licensed in China or Mongolia, although with wide coverage, the HPV vaccine could potentially prevent as much as three quarters of ICC cases among Chinese and Mongolian women. Ultimately, the introduction of HPV vaccination will present specific challenges, as well as opportunities, for developing advocacy, information and communication strategies that will involve policymakers and the general public.

Human papillomavirus type-distribution in the cervix of Chinese women: a meta-analysis

Summary The aim of the study was to determine human papillomavirus (HPV) type-distribution in the cervix of Chinese women, and to estimate the potential future impact of HPV prophylactic vaccines for cervical cancer prevention in China. A total of 32 studies using polymerase chain reaction for HPV detection were included in the meta-analysis, including 2844 invasive cervical cancer (ICC), 820 high-grade squamous intraepithelial lesions (HSIL), 432 low-grade squamous intraepithelial lesions (LSIL) and 2902 women with normal cytology/histology. The overall and type-specific HPV prevalence of 18 HPV types (HPV 6, 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68, 70, 73 and 82 of different cervical stages) were estimated. Overall HPV prevalence was 83.7%, 66.2%, 61.3% and 11.2% in ICC, HSIL, LSIL and normal, respectively. HPV 16 was the predominant type in all cervical stages. Estimated HPV 16/18-positive fractions in ICC, HSIL, LSIL and normal were 69.7%, 45.5%, 32.23% and 4.6%, respectively. HPV-16/18 vaccine has the 69.7% potential prevention in ICC. HPV 58 and 52 were the priority HPV types in Chinese women.

p16INK4A immunohistochemical staining and predictive value for progression of cervical intraepithelial neoplasia grade 1: a prospective study in China.

p16INK4A is strongly expressed in tissues diagnosed as cervical intraepithelial neoplasia (CIN) and cancer in women infected with human papillomavirus (HPV), but few prospective studies have evaluated p16INK4A as a marker for the risk of low‐grade CIN (CIN1) progression. We investigated the prevalence of p16INK4A immunostaining by CIN grade and whether overexpression of p16INK4A in CIN1 predicts future risk for high‐grade CIN in Chinese women. 6,557 Chinese women aged 30–49 years were screened from 2003 to 2005 using cytology and carcinogenic HPV test. Colposcopy was performed on women with any abnormal result. p16INK4A Immunostaining was performed on biopsies from all women with CIN1, as well as randomly selected women with normal or CIN grade 2 and worse (CIN2+) biopsies. Women with CIN1 were followed up without treatment. Colposcopy was performed on all untreated women at a 2‐year interval. The prevalence of p16INK4A staining was 2.7%, 42.7%, 75.5%, 79.6% and 100% among women with normal, CIN1, 2, 3 and cancer biopsies, respectively (p < 0.001). HPV positivity was strongly associated with p16INK4A staining [odds ratios (OR) = 12.8; 95% confidence intervals (CI): 5.2–31.6]. p16INK4A staining of CIN1 biopsies at baseline was associated with an increased risk of finding high‐grade CIN over 2 years of follow‐up (OR = 1.43; 95% CI: 0.52–3.91). The two‐year cumulative incidence of CIN2+ for p16INK4A positive women was higher at 10.71% than for p16INK4A negative women at 1.30% (crude RR = 8.25, 95% CI: 1.02–66.62). p16INK4A overexpression is strongly associated with grade of CIN and risk of progression to high‐grade CIN in women with low‐grade lesions.

Use of an expanded gold standard to estimate the accuracy of colposcopy and visual inspection with acetic acid

We estimate the accuracy of colposcopy and visual inspection with acetic acid (VIA) while minimizing the effects of misclassification bias, and maximizing ascertainment of disease. VIA was performed by experienced physicians on a population‐based sample of women aged 30 to 49 years in rural Shanxi province, China. Each woman received VIA, liquid‐based cytology (LBC) and hybrid capture 2 (hc2, QIAGEN, Gaithersburg, MD; formerly Digene Corporation). Any woman who tested positive on any test had colposcopy, endocervical curettage (ECC) with directed biopsies as necessary and 4‐quadrant random biopsies from normal‐appearing areas of the cervix. A standard diagnosis based on colposcopy and directed biopsy, and an expanded diagnosis including ECC and 4‐quadrant random biopsy were generated for each woman. In 1,839 women, use of the expanded versus the standard diagnostic criteria increased the prevalence of histologically confirmed high‐grade cervical intraepithelial neoplasia and cancer (CIN2+) from 3.2% (59/1,839) to 4.2% (77/1,839) and decreased the sensitivity of VIA for CIN2+ from 69.5% (95% CI: 56.8–79.8) to 58.4% (95% CI: 47.3–68.8%) with little change in specificity of approximately 89%. Compared with the expanded diagnostic criterion, the sensitivity of a visual diagnosis of high‐grade CIN or cancer by a colposcopist was 49.4% (95% CI: 38.2–60.5). The use of an expanded diagnostic criterion in this study yielded more conservative estimates of the sensitivity of VIA and colposcopy.

Comparison of ThinPrep and SurePath Liquid-Based Cytology and Subsequent Human Papillomavirus DNA Testing in China

Liquid‐based cytology (LBC) has been compared with conventional cytology in numerous studies. In the current study of 2 LBC systems, the accuracy, rates of unsatisfactory cytology, and sufficiency of residual LBC specimens for Hybrid Capture 2 (HC2) HPV DNA testing were compared.

Distribution of cervical intraepithelial neoplasia 2, 3 and cancer on the uterine cervix.

Objective To determine the distribution of cervical intraepithelial neoplasia 2 or 3 on the uterine cervix. Materials and Methods During two screening studies, 5,060 women underwent colposcopy with biopsy. If a cervical quadrant had no lesion, a random biopsy at the squamocolumnar junction was obtained. Results Cervical intraepithelial neoplasia 2 or worse was more common on the posterior (426/806; 52.9%) than on the anterior (380/806; 47.2%) cervix (p < .05) and was equally likely on the right (411/806; 51.0%) and left (395/806; 49.0%) sides of the cervix. More quadrants with colposcopically detected lesions of human papillomavirus or worse came from the anterior (1,338; 57.5%) than posterior (991; 42.6%) cervix (p < .05), whereas similar numbers of these lesions were found on the left (1,163) and right (1,166) sides of the cervix. Conclusions Cervical intraepithelial neoplasia 2 or worse is slightly more common on the posterior cervix. Using colposcopically detected lesions as a surrogate for cervical intraepithelial neoplasia 2 or worse inflates the prevalence of cervical intraepithelial neoplasia on the anterior cervix.