Pooled analysis of the accuracy of five cervical cancer screening tests assessed in eleven studies in Africa and India

Cervical cancer is the main cancer among women in sub-Saharan Africa, India and other parts of the developing world. Evaluation of screening performance of effective, feasible and affordable early detection and management methods is a public health priority. Five screening methods, naked eye visual inspection of the cervix uteri after application of diluted acetic acid (VIA), or Lugol's iodine (VILI) or with a magnifying device (VIAM), the Pap smear and human papillomavirus testing with the high-risk probe of the Hybrid Capture-2 assay (HC2), were evaluated in 11 studies in India and Africa. More than 58,000 women, aged 25-64 years, were tested with 2-5 screening tests and outcome verification was done on all women independent of the screen test results. The outcome was presence or absence of cervical intraepithelial neoplasia (CIN) of different degrees or invasive cervical cancer. Verification was based on colposcopy and histological interpretation of colposcopy-directed biopsies. Negative colposcopy was accepted as a truly negative outcome. VIA showed a sensitivity of 79% (95% CI 73-85%) and 83% (95% CI 77-89%), and a specificity of 85% (95% CI 81-89%) and 84% (95% CI 80-88%) for the outcomes CIN2+ or CIN3+, respectively. VILI was on average 10% more sensitive and equally specific. VIAM showed similar results as VIA. The Pap smear showed lowest sensitivity, even at the lowest cutoff of atypical squamous cells of undetermined significance (57%; 95% CI 38-76%) for CIN2+ but the specificity was rather high (93%; 95% CI 89-97%). The HC2-assay showed a sensitivity for CIN2+ of 62% (95% CI 56-68%) and a specificity of 94% (95% CI 92-95%). Substantial interstudy variation was observed in the accuracy of the visual screening methods. Accuracy of visual methods and cytology increased over time, whereas performance of HC2 was constant. Results of visual tests and colposcopy were highly correlated. This study was the largest ever done that evaluates the cross-sectional accuracy of screening tests for cervical cancer precursors in developing countries. The merit of the study was that all screened subjects were submitted to confirmatory investigations avoiding to verification bias. A major finding was the consistently higher sensitivity but equal specificity of VILI compared with VIA. Nevertheless, some caution is warranted in the interpretation of observed accuracy measures, since a certain degree of gold standard misclassification cannot be excluded. Because of the correlation between visual screening tests and colposcopy and a certain degree of over-diagnosis of apparent CIN2+ by study pathologists, it is possible that both sensitivity and specificity of VIA and VILI were overestimated. Gold standard verification error could also explain the surprisingly low sensitivity of HC2, which contrasts with findings from other studies.     

Evaluation of Several Screening Approaches for Detection of Cervical Lesions in Rural Shandong,China

Purpose: The study was designed to: (1) investigate the prevalence of high-risk human papillomavirus (HRHPV)infection and cervical neoplasia; and (2) evaluate clinical performance of visual inspection with aceticacid/ Lugol’s iodine (VIA /VILI), Pap smear, high-risk human papillomavirus (HR-HPV) DNA test for detectingcervical intraepithelial neoplasia grade 2 or worse (CIN2+) and (3) explore appropriate screening approach inrural areas of Shandong Province. Materials and Methods: A total of 3,763 eligible women from Yiyuan Countyin Yimeng mountainous areas of rural Shandong, China, were enrolled and underwent Pap smear, HR-HPVDNA testing by Hybrid Capture 2 (HC2), and VIA /VILI tests. Women positive in any test were referred tocolposcopy and biopsy as indicated. Results: The prevalence of HR-HPV infection among all enrolled womenwas 11.1% and that in healthy women was 9.9%. In total 33 cases of CIN1, 16 cases of CIN2, 6 cases of CIN3 butnone of cervical cancer were detected and the crude prevalence of CIN2+ was 0.58%. For detecting CIN2+, thesensitivity of HR-HPV DNA testing, VIA/VILI, Pap smear was 90.9%, 77.3%, 81.8%, respectively. Pap smearhad the best specificity of 98.2%, followed by HR-HPV DNA testing with specificity of 89.4%, VIA/VILI hadthe lowest specificity of 81.2%. Colposcopy referral rate of HR-HPV DNA testing, VIA/VILI, Pap smear was11.1%, 18.5%, 2.3%, respectively. Conclusions: Our results suggest that HR-HPV DNA testing alone might beappropriate for primary cervical cancer screening in rural low-resource areas of Shandong Province, China.     

Accuracy of concurrent visual and cytology screening in detecting cervical cancer precursors in rural India

The high burden of cervical cancer and inadequate/suboptimal cytology screening in developing countries led to the evaluation of visual screening tests, like visual inspection with acetic acid (VIA) and Lugol's iodine (VILI). We describe the performance of VIA, VILI and cytology, carried out in a multinational project called "Screening Technologies to Advance Rapid Testing" in 5,519 women aged 30-49 years, in detecting cervical intraepithelial neoplasia (CIN). VIA, VILI and cytology were positive in 16.9%, 15.6% and 6.1% women, respectively. We found 57 cases of CIN2, 55 of CIN3 and 12 of cervical cancer; 90% of CIN3 and 43% CIN2 cases were positive for p16 overexpression and high-risk HPV infection, indicating a high validity of histological diagnosis. The sensitivity of VIA, VILI and cytology to detect high-grade CIN were 64.5%, 64.5% and 67.7%, respectively; specificities were 84.2%, 85.5% and 95.4%. A high proportion of p16 positive CIN 3 (93.8%) and 2 (76.9%) were positive on cytology compared with visual tests (68.8% and 53.8%, respectively) indicating a higher sensitivity of cytology to detect p16 positive high-grade CIN. However, the immediate availability of the results from the visual tests permits diagnosis and/or treatment to be performed in the same sitting, which can potentially reduce loss to follow-up when women must be recalled following positive cytology. Organizing visual screening services in low-resource countries may facilitate the gradual building of an infrastructure committed to screening allowing the eventual introduction of more sensitive, highly objective, reproducible and affordable human papillomavirus screening tests in future.     

Accuracy of visual screening for cervical neoplasia: Results from an IARC multicentre study in India and Africa

Visual inspection-based screening tests, such as visual inspection with 4% acetic acid (VIA) and with Lugol's iodine (VILI), have been proposed as alternatives to cytology in mass screening programs. To date, there is only limited information on the accuracy of these tests in detecting High-grade Squamous Intraepithelial Lesions (HSIL). Eleven cross-sectional studies involving 56,939 women aged 25-65 years were conducted in Burkina Faso, Congo, Guinea, India, Mali and Niger to evaluate the accuracy of VIA and VILI performed by health workers. A common protocol and questionnaire was used. For final diagnosis, all women were investigated with colposcopy and biopsies were taken when necessary. Data from the studies were pooled to calculate sensitivity, specificity and predictive values of the tests for the detection of HSIL. Of the screened women, 16.1% and 16.4% were positive on examination using, respectively, VIA and VILI; 1,063 were diagnosed with HSIL. The pooled sensitivity, specificity, positive and negative predictive values for VIA were 76.8% (95% CI: 74.2-79.4%), 85.5% (95% CI: 85.2-85.8%), 9.4% (95% CI:8.8-10.8%) and 99.5% (95% CI:99.4-99.6%), respectively. The values were 91.7% (95% CI: 89.7-93.4%), 85.4% (95% CI: 85.1-85.7%), 10.9% (95% CI: 10.2-11.6%) and 99.8% (95% CI:99.7-99.9%), respectively for VILI. The range of sensitivity and specificity for VIA was 56.1-93.9% and 74.2-93.8%, respectively, between studies and were 76.0-97.0 % and 73.0-91.3% for VILI. VILI had a significantly higher sensitivity than VIA in detecting HSIL, but specificity was similar. VILI appears to be a more accurate visual test for use in screening and treatment programs in low-resource settings.     

Test characteristics of visual inspection with 4% acetic acid (VIA) and Lugol's iodine (VILI) in cervical cancer screening in Kerala,India

Simple and inexpensive methods based on visual examination of the cervix are currently being investigated as alternative methods of cervical screening. The test characteristics of visual inspection with 4% acetic acid (VIA), and Lugol's iodine (VILI) and conventional cytology were investigated in a cross-sectional study involving 4,444 women aged 25 to 65 years in Kerala, India. While detection of any acetowhite area constituted a low-threshold positive VIA, detection of well-defined, opaque acetowhite lesions close to or touching the squamocolumnar junction constituted a high-threshold positive VIA test. Detection of definite yellow iodine nonuptake areas in the transformation zone close to or touching the squamocolumnar junction constituted a positive VILI test. Cytology was considered positive if reported as atypia or worse lesions. All screened women were evaluated by colposcopy and biopsies were directed in 1,644 women (37.0%), which allowed the direct estimation of sensitivity, specificity and predictive values. The reference diagnosis was based on a combination of histology and/or colposcopy. True disease status was defined as CIN 2 and worse lesions. A total of 149 (3.4%) women had CIN 2 or worse lesions. The sensitivities of low-threshold VIA, high-threshold VIA, VILI and cytology to detect CIN 2 or worse disease were 88.6%, 82.6%, 87.2% and 81.9%, respectively; the corresponding specificities were 78.0%, 86.5%, 84.7% and 87.8%. Our results indicate that VIA and VILI are suitable alternate screening tests to cytology for detecting cervical neoplasia in low-resource settings.     

Evaluation of multiple primary and combination screening strategies in postmenopausal women for detection of cervical cancer in China

As China's population ages, the importance of determining prevalence of cervical disease and accurate cervical cancer screening strategies for postmenopausal women is increasing. Seventeen population‐based studies were analyzed to determine prevalence of cervical neoplasia in postmenopausal women. All women underwent HPV DNA testing, visual inspection with acetic acid (VIA) and cytology testing. Diagnostic values for primary and combinations screening methods included sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), referral rate and area under curve (AUC) were calculated using directed biopsy or four quadrants biopsy as reference standard. Premenopausal and postmenopausal women had equal HPV infection and cervical neoplasia rates (p > 0.05). HPV DNA testing CIN3+ sensitivity, specificity, PPV, NPV, referral rate and AUC were 97.9% (95% CI: 90.2–99.9%), 84.2% (95% CI: 82.8–85.5%), 9.9% (95% CI: 7.4–12.8%), 100% (95% CI: 99.8–100%), 17.2% (95% CI: 15.9–18.7%), 0.911, respectively. VIA values were 41.7% (95% CI: 28.4–55.9%), 94.5% (95% CI: 93.6–95.3%), 11.8% (95% CI: 7.5–17.3%), 98.9% (95% CI: 98.5–99.3%), 6.2% (95% CI: 5.3–7.1%) and 0.681, respectively. Values for VIA with HPV triage were 39.6% (95% CI: 26.6–53.8%), 99.2% (95% CI: 98.8–99.5%), 45.2% (95% CI: 30.8–60.4%), 98.9% (95% CI: 98.5–99.3%), 1.5% (95% CI: 1.1–2.0%) and 0.694, respectively. VIA and HPV DNA co‐test values were 100% (95% CI: 94.0–100%), 79.5% (95% CI: 78.0–81.0%), 8.0% (95% CI: 6.0–10.3%), 100% (95% CI: 99.9–100%), 21.9% (95% CI: 20.4–23.4%) and 0.898, respectively. VIA sensitivity decreases significantly in postmenopausal women compared to premenopausal performance. HPV DNA testing maintains performance between pre‐ and postmenopausal women and is the most accurate primary modality for screening postmenopausal populations in low resource areas of China.     

2006-2009年山西省襄垣县VIA/VILI筛查宫颈癌的检出效果评价

目的：通过对2006—2009年山西省襄垣县宫颈癌筛查早诊早治结果分析,评价醋酸或碘染色肉眼观察法（visual inspection with acetic acid/Lugol’s iodine,VIA/VILI）宫颈癌筛查方案在农村高发区推广应用的可行性。方法2006—2009年在山西省襄垣县对30~59岁的妇女进行宫颈癌筛查。用VIA和VILI作为初筛方法,VIA/VILI阳性者进行阴道镜检查,阴道镜异常者在病变处取活检进行病理诊断。对VIA和VILI阴性、VIA/VILI阳性但阴道镜检查正常、VIA/VILI阳性同时阴道镜检查异常且病理活检结果为轻度宫颈上皮内瘤样病变（cervical intraepithelial neoplasia grade 1,CIN1）或正常的妇女一年后用与初筛同样的方法进行复查。结果2006—2010年累计筛查16703人次,其中初筛9618人,复查7085人。4年初筛人群累计阴道镜转诊率、中度CIN及以上（CIN2+）检出率、重度CIN及以上（CIN3+）检出率分别为4.6%（438/9618）、0.9%（82/9618）、0.5%（44/9618）;复查人群上述指标分别为3.1%（221/7085）、0.6%（42/7085）、0.2%（19/7085）;筛查人群累计（包括初筛和复查）上述指标分别为4.0%（659/16703）、1.3%（124/9618）、0.7%（63/9618）。初筛人群阴道镜转诊率、CIN2+检出率和CIN3+检出率均随方案的持续开展呈升高趋势（P<0.001）;复查阴道镜转诊率、CIN2+检出率则呈下降趋势（P<0.001）。结论随着VIA/VILI筛查方案在示范基地的推广,筛查效果越来越显著。VIA/VI-LI是一种经济有效的宫颈癌及其癌前病变筛查方法,适宜在资源有限、经济欠发达的农村地区推广。持续的培训和实践是VIA/VILI筛查方案有效实施的关键措施。     

Comparison of HPV-based assays with Papanicolaou smears for cervical cancer screening in Morelos State,Mexico

Objective: To compare the performance of human papillomavirus (HPV) assays with conventional Pap cytology for cervical cancer (CC) screening in Mexico. Methods: Pap smears, self-collected vaginal specimens (SS) for HPV testing, and clinician-collected cervical specimens (CS) for HPV testing were obtained from 7868 women, aged 15–85 years old, attending CC screening at the Mexican Institute of Social Security (IMSS) between May and October, 1999. SS and CS specimens were screened for oncogenic HPV DNA by Hybrid Capture 2. Women who received cytological interpretations of atypical squamous cells of undetermined significance (ASCUS), and/or a positive HPV test were referred for colposcopy and histologic studies. The relative estimates for sensitivity, specificity and predictive values of each test were calculated using histological diagnoses of cervical intraepithelial neoplasia (CIN) grades 2 or 3, or CC histological diagnosis. Results: Oncogenic HPV detection rate was 11.6% for SS, and 9.3% for CS. Pap smear abnormalities were observed in 2.4% of the women. Of 1147 women who had at least one abnormal test result, 88.5% underwent colposcopy, and 101 biopsy-confirmed CIN2/3 or cancer cases were identified. The relative sensitivity estimates for the Pap test, SS and CS were 59.4% (95% CI: 49.2–68.9), 71.3% (95% CI: 61.3–79.6), and 93.1% (95% CI: 85.8–96.9), respectively, while the specificities were 98.3% (95% CI: 98.0–98.6), 89.2% (95% CI: 88.5–89.9), and 91.8% (95% CI: 91.2–92.4), respectively. The positive predictive values of Pap, SS and CS were 36.1, 9.1 and 14.9, the colposcopy referrals needed to detect a case of CIN2/3 or cancer were 2.8, 11.0 and 6.7, respectively. Discussion: Both HPV assays detected more cases of CIN2/3 or CC than Pap cytology alone. However, the HPV assays increased the number of colposcopy referrals. Our study suggests that HPV testing could be an effective way to improve the performance of CC screening.     

Accuracy of Visual Inspection with Acetic acid in Detecting High-Grade Cervical Intraepithelial Neoplasia in Pre- and Post-Menopausal Thai Women with Minor Cervical CytologicalAbnormalities

Purpose: To determine the accuracy of visual inspection with acetic acid (VIA) in detecting high-gradecervical intraepithelial neoplasia (CIN) in pre- and post-menopausal women with atypical squamous cells ofundetermined significance (ASC-US) and low grade squamous intraepithelial lesion (LSIL) Papanicolaou (Pap)smears. Materials and Methods: Two hundred women (150 pre-menopausal and 50 post-menopausal) with ASCUSand LSIL cytology who attended the colposcopy clinic, Thammasat University Hospital, between March 2013and August 2014 were included. All women underwent VIA testing and colposcopy by gynecologic oncologists.Diagnostic values of VIA testing including sensitivity, specificity, positive predictive value (PPV) and negativepredictive value (NPV) for detecting high-grade CIN were determined using the histopathology obtained fromcolposcopic-directed biopsy as a gold standard. Results: VIA testing was positive in 54/150 (36%) pre-menopausalwomen and 5/50 (10%) post-menopausal women. Out of 54 pre-menopausal women with positive VIA testing,15 (27.8%) had high-grade CIN and 39 (72.2%) had either CIN 1 or insignificant pathology. Ten (10.4%), 43(44.8%) and 43 (44.8%) out of the remaining 96 pre-menopausal women with negative VIA testing had highgradeCIN, CIN 1 and insignificant pathology, respectively. Out of 5 post-menopausal women with positive VIAtesting, there were 4 (80%) women with high-grade CIN, and 1 (20%) women with insignificant pathology. Outof 45 VIA-negative post-menopausal women, 42 (93.3%) women had CIN 1 and insignificant pathology, and 3(6.7%) had high-grade CIN. Sensitivity, specificity, PPV and NPV of the VIA testing were 59.4%, 76.2%, 32.2%and 90.8%, respectively (60%, 68.8%, 27.8% and 89.6% in pre-menopausal women and 57.1%, 97.7%, 80%and 93.3% in post-menopausal women). Conclusions: VIA testing may be used as a screening tool for detectinghigh-grade CIN in women with minor cervical cytological abnormalities in a low-resource setting in order tolower the rate of colposcopy referral.     

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.     

Cumulative 5-year diagnoses of CIN2, CIN3 or cervical cancer after concurrent high-risk HPV and cytology testing in a primary screening setting

The aim of our study was to assess the cumulative 5-year diagnoses of CIN2, CIN3 or invasive cervical cancer (CIN2+) after concurrent screening by high-risk HPV test and Pap smear in a primary screening setting. Four thousand thirty-four women from Eastern Thuringia/Germany were recruited from 1996 to 1998 for baseline screening that included routine cytology, high-risk HPV testing by consensus primer PCR GP5+/6+ and routine colposcopy. After a median of 59 months 3,153 women participated in final screening using identical methods. Women with abnormal cytology or colposcopy or a positive high-risk HPV test at any time during the study period were recalled for expert colposcopy and histologic verification. CIN2+ was detected in 160 women resulting in a cumulative 5-year proportion of 4.4% (95% CI: 3.7-5.0%). Of 3,702 women who were high-risk HPV negative at baseline, 34 (1.1-95% CI: 0.7-1.4%) had either prevalent CIN2+ or developed CIN2+ within the observation period. HPV/cytology double negatives at baseline were at lowest risk for CIN2+ (1.0-95% CI: 0.7-1.4%) compared to screening positives (16.8-100% depending on combined test results). The 5-year negative predictive value in HPV-/Cyto- women was 99.0% (95% CI: 98.6-99.3%). This suggests that a prolongation of the screening intervals in this group is feasible. However, it should be noted that 1 woman developed a microinvasive carcinoma within the observation period. Moreover, 2 women with prevalent cancer were missed by both tests. The prognostic relevance of concurrent high-risk HPV/cytology screening needs to be verified further by randomized trials.     

Performance of visual inspection of the cervix with acetic acid (VIA) for triage of HPV screen-positive women: results from the ESTAMPA study

VIA is recommended for triage of HPV-positive women attending cervical screening. In the multicentric ESTAMPA study, VIA performance for detection of cervical intraepithelial neoplasia grade 3 or worse (CIN3+) among HPV-positive women was evaluated. Women aged 30-64 years were screened with HPV testing and cytology and referred to colposcopy if either test was positive. At colposcopy visit, study-trained midwives/nurses/GPs performed VIA ahead of colposcopy. VIA was considered positive if acetowhite lesions were observed in or close to the transformation zone. Ablative treatment eligibility was assessed for VIA positives. Performance indicators were estimated. Three thousand one hundred and forty-two HPV-positive women were included. Sensitivity for CIN3+ was 85.9% (95% CI 81.2-89.5) among women <50 years and, although not significant, slightly lower in women 50+ (78.0%, 95% CI 65.9-86.6). Overall specificity was 58.6% (95% CI 56.7-60.5) and was significantly higher among women 50+ (70.3%, 95% CI 66.8-73.5) compared to women <50 (54.3%, 95% CI 52.1-56.5). VIA positivity was lower among women 50+ (35.2%, 95% CI 31.9-38.6) compared to women <50 (53.2, 95% CI 51.1-55.2). Overall eligibility for ablative treatment was 74.5% and did not differ by age. VIA sensitivity, specificity, and positivity, and ablative treatment eligibility varied highly by provider (ranges: 25%-95.4%, 44.9%-94.4%, 8.2%-65.3%, 0%-98.7%, respectively). VIA sensitivity for cervical precancer detection among HPV-positive women performed by trained providers was high with an important reduction in referral rates. However, scaling-up HPV screening triaged by VIA will be challenging due to the high variability of VIA performance and providers' need for training and supervision.     

Comparison between Visual Inspection of Cervix and Cytology Based Screening Procedures in Bangladesh

Background: Cervical cancer continues to be a major problem in Bangladesh with approximately 18,000 newcases annually of which over 10,000 women die from it. Visual inspection of the cervix after 3-5% acetic acid(VIA) application is a simple and easy to learn method for cervical cancer screening, although cytology-basedscreening is more often applied in developed countries where it has successfully reduced the prevalence of cervicalcancer. Objective: To compare the efficacy of VIA and cytology-based primary methods for cervical cancerscreening in Bangladesh. Materials and Methods: This hospital based comparative study was conducted at theVIA centre and Colposcopy Clinic of Bangabandhu Sheikh Mujib Medical University (BSMMU) from October2008 to October 2010. Results: Among 650 women, 74 (11.4%) were VIA+ve and 8 (1.2%) had abnormalitiesin their Pap smear reports. During colposcopy, 38 (7.7%) women had different grades of CIN and 4 (0.6%)had cervical cancer. The gold standard histology findings proved 20 women had CIN I, 14 had CIN II/II and 4had cervical cancer. Among the 38 histology diagnosed abnormalities, VIA test could identify 30 abnormalitiesincluding two cervical cancers. However, Pap smear could detect only 8 cases of histological abnormalities (2low grade and 6 had high grade lesion) and it missed all the cervical cancer cases. The sensitivity and specificityof VIA were 88.9% and 52.1%. The positive predictive value (PPV) and negative predictive value (NPV) were41.0%, and 92.6% respectively. Moreover, the sensitivity, specificity, PPV and NPV of Pap smear were 33.3%,95.8%, 75.0% and 79.3%, respectively. Conclusions: VIA test should be used as the primary screening tool evenwith its low sensitivity and specificity in low resource countries like Bangladesh. False positive results may begreater, but overtreatment can be minimized by colposcopy evaluation of the VIA positive women.     

山西省襄垣县2009~2015年农村女性宫颈癌筛查项目结果分析

[目的]通过分析襄垣县2009～2015年农村妇女宫颈癌筛查结果,为国家宫颈癌筛查项目的评价和优化提供理论依据.[方法]对襄垣县35～64岁妇女开展宫颈癌筛查.2009～2013年采用醋酸/碘染色后肉眼观察(VIA/VILI),2014年开始部分引入人乳头状瘤病毒(HPV)检测,2015年又引入新柏氏液基细胞学(TCT)检测,根据卫生资源情况在不同人群中分别使用三种方法.任意筛查结果阳性者转诊阴道镜,镜下有病变时取活检,以病理诊断为金标准.通过评价不同方法对宫颈上皮内瘤变(CIN)2级及以上病变的检出率评价不同方法对宫颈癌的筛查效果.[结果] 2009～2015年共筛查62 618名女性,其中CIN2级及以上(CIN2+)病变的患病率为0.76％,早诊率为90.53％,下生殖道感染率为25.68％,其中滴虫性阴道炎、细菌性阴道炎和宫颈炎与HPV感染相关.根据2014及2015年数据,VIA/VILI的CIN2+病变检出率为0.74％,TCT的病变检出率为0.70％,两者相似,但均低于HPV检测,其病变检出率为1.37％.[结论]HPV检测是首选的宫颈癌初筛方法,在资源匮乏地区,培训合格的基层医生使用VIA/VILI或TCT方法对适龄妇女开展宫颈癌筛查是有效的备选方案.     

Effectiveness of a two‐stage strategy with HPV testing followed by visual inspection with acetic acid for cervical cancer screening in a low‐income setting

The World Health Organization recently advocated a two‐stage strategy with human papillomavirus (HPV) testing followed by visual inspection of the cervix with acetic acid (VIA) as a suitable option for cervical cancer screening. However, its accuracy has never been directly assessed in the context of primary screening. To evaluate effectiveness of HPV testing on self‐obtained specimens (self‐HPV) followed by VIA (sequential testing) in a low‐income setting, we recruited 540 women aged between 30 and 65 years in two Cameroonian periurban areas. Eligible women were counseled about cervical cancer and how to perform self‐sampling. HPV positive and a random sample of HPV‐negative women were called back for VIA and biopsy. Disease was defined by interpretation of cervical intraepithelial neoplasia Grade 2 or worse (CIN2+). Performances of VIA, self‐HPV and sequential testing were determined after adjustment for verification bias. HPV prevalence was 27.0%. VIA positivity was 12.9% and disease prevalence was 5%. Sensitivity and specificity of VIA for CIN2+ were 36.4% [95% confidence interval (CI): 15.2–64.6%] and 90.4% (95% CI: 85.4–93.7%), respectively. Sensitivity of self‐HPV [100.0% (95% CI: 79.6–100.0%)] was 66% higher than that of sequential testing [33.3% (95% CI: 15.2–58.3%)]. Meanwhile, specificity of self‐HPV [74.5% (95% CI: 70.6–78.1%)] was 22% lower than that of sequential testing [96.7% (95% CI: 94.8–97.9%)]. A two‐stage screening strategy with self‐HPV followed by VIA improves specificity of cervical cancer screening, but at the cost of an important loss of sensitivity. Ways to improve VIA performance or other tools are needed to increase positive predictive value of HPV testing.     

Risk assessment to guide cervical screening strategies in a large Chinese population

Three different cervical screening methods [cytology, human papillomavirus(HPV) testing and visual inspection with acetic acid(VIA)] are being considered in China for the national cervical screening program. Comparing risks of CIN3 and cervical cancer (CIN3+) for different results can inform test choice and management guidelines. We evaluated the immediate risk of CIN3+ for different screening results generated from individual and combined tests. We compared tests using a novel statistic designed for this purpose called Mean Risk Stratification (MRS), in a pooled analysis of 17 cross sectional population‐based studies of 30,371Chinese women screened with all 3 methods and diagnosed by colposcopically‐directed biopsies. The 3 tests combined powerfully distinguished CIN3+ risk; triple‐negative screening conferred a risk of 0.01%, while HPV‐positive HSIL+ that was VIA‐positive yielded a risk of 57.8%. Among the three screening tests, HPV status most strongly stratified CIN3+ risk. Among HPV‐positive women, cytology was the more useful second test. In HPV‐negative women, the immediate risks of CIN3+ ranged from 0.01% (negative cytology), 0.00% (ASC‐US), 1.1% (LSIL), to 6.6 (HSIL+). In HPV‐positive women, the CIN3+ risks were 0.9% (negative cytology), 3.6% (ASC‐US), 6.3% (LSIL) and 38.5% (HSIL+). VIA results did not meaningful stratify CIN3+ risk among HPV‐negative women with negative or ASC‐US cytology; however, positive VIA substantially elevated CIN3+ risk for all other, more positive combinations of HPV and cytology compared with a negative VIA. Because all 3 screening tests had independent value in defining risk of CIN3+, different combinations can be optimized as pragmatic strategies in different resource settings.     

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.     

Performance of a low cost magnifying device,magnivisualizer, versus colposcope for detection of pre-cancer and cancerous lesions of uterine cervix

Objective

To assess the performance of a low cost magnifying device (Magnivisualizer) compared to a standard optical colposcope for detection of precancerous and cancerous lesions of the uterine cervix.

Methods

A total of 659 consecutive symptomatic women attending a gynecologic outpatient clinic underwent unaided visual inspection followed by cytology, visual inspection of the cervix using 5% acetic acid (VIA), and VIA under magnification (VIAM) with the Magnivisualizer. All women, independently of test results, were referred for colposcopic examination. Colposcopic-directed biopsies were obtained from all positive lesions and compared to positive VIAM cases.

Results

The detection rate for VIA positive lesions was 12% (134/659), while it was 29% for VIAM positive lesions (191/659). The sensitivities of detection of cervical intraepithelial neoplasia (CIN) 2 and higher lesions were 61.7% for VIA, 88.3% for VIAM, and 86.7% for colposcopy, with a specificity of 58.5% for VIA, 55.8% for VIAM, and 90.4% for colposcopy. The performance of colposcopy and VIAM was moderate (κ, 0.48; 95% confidence interval [CI], 0.41 to 0.54) for detection of CIN 1 and higher lesions and excellent (κ, 0.87; 95% CI, 0.82 to 0.94) for detection of CIN 2 and higher lesions.

Conclusion

In low resource settings, where colposcopic facilities are not available at the community level, a simple low-cost, handheld Magnivisualizer can be considered a valid option for detection of cervical precancerous and cancerous lesions. However, it cannot replace traditional colposcopy because it has a low specificity that results in many unnecessary biopsies.     

Comparison of visual inspection with acetic acid and cervical cytology to detect high-grade cervical neoplasia among HIV-infected women in India

Human immunodeficiency virus (HIV)-infected women in India and other developing country settings are living longer on antiretroviral therapy, yet their risk for human papillomavirus (HPV)-induced cervical cancer remains unabated because of lack of cost-effective and accurate secondary prevention methods. Visual inspection after application of dilute acetic acid on the cervix (VIA) has not been adequately studied against the current standard: conventional cervical cytology (Pap smears) among HIV-infected women. We evaluated 303 nonpregnant HIV-infected women in Pune, India, by simultaneous and independent screening with VIA and cervical cytology with disease ascertainment by colposcopy and histopathology. At the cervical intraepithelial neoplasia (CIN2+) disease threshold, the sensitivity, specificity and positive and negative predictive value estimates of VIA were 80, 82.6, 47.6 and 95.4% respectively, compared to 60.5, 59.6, 22.4 and 88.7% for the atypical squamous cells of undetermined significance or severe (ASCUS+) cutoff on cytology, 60.5, 64.6, 24.8 and 89.4% for the low-grade squamous intraepithelial cells or severe (LSIL+) cutoff on cytology and 20.9, 96.0, 50.0 and 86.3% for high-grade squamous intraepithelial lesion or severe (HSIL+) cutoff on cytology. A similar pattern of results was found for women with the presence of carcinogenic HPV-positive CIN2+ disease, as well as for women with CD4+ cell counts <200 and <350 μL(-1) . Overall, VIA performed better than cytology in this study with biologically rigorous endpoints and without verification bias, suggesting that VIA is a practical and useful alternative or adjunctive screening test for HIV-infected women. Implementing VIA-based screening within HIV/acquired immunodeficiency syndrome care programs may provide an easy and practical means of complementing the highly anticipated low-cost HPV-based rapid screening tests in the near future, thereby contributing to improve program effectiveness of screening.     

Screening for cervical cancer in India: How much will it cost? A trial based analysis of the cost per case detected

The cost and cost effectiveness of screening previously unscreened women by VIA, cytology or HPV testing was investigated within a large cluster randomised trial involving 131,178 women in rural India. All resources involved in implementation, training, management, recruitment, screening and diagnosis were identified and costed. We estimated the total costs and detection rates for each cluster and used these data to calculate an average cluster cost and detection rate for each screening approach. These estimates were combined to estimate a cost per case of cervical intraepithelial neoplasia grade 2/3 or invasive cancer (CIN 2/3+) detected. The average total costs per 1,000 women eligible for screening were US dollar 3,917, US dollar 6,609 and US dollar 11,779 with VIA, cytology and HPV respectively. The cost of detecting a case of CIN2/3+ using VIA was dollar 522 (95% CI dollar 429- dollar 652). Our results suggest that more CIN2/3+ cases would be detected in the same population if cytology were used instead of VIA and each additional case would cost US dollar 1065 (95% CI dollar 713- dollar2175). Delivering cervical cancer screening is potentially expensive in a low-income country although costs might be lower outside a trial setting. We found screening with VIA to be the least expensive option, but it also detected fewer cases of CIN2/3+ than other methods; its long-term cost-effectiveness will depend on the long-term benefits of early detection. Cytology was more effective at detecting cases than VIA but was also more expensive. Our findings indicate that HPV may not be a cost effective screening strategy in India at current consumable prices.