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  Table of Contents  
ORIGINAL ARTICLE
Year : 2014  |  Volume : 51  |  Issue : 2  |  Page : 117-123
 

Comparative evaluation of human papilloma virus-DNA test verses colposcopy as secondary cervical cancer screening test to triage screen positive women on primary screening by visual inspection with 5% Acetic acid


Department of Preventive Oncology, Tata Memorial Hospital, Parel, Mumbai, Maharashtra, India

Date of Web Publication7-Aug-2014

Correspondence Address:
S Pimple
Department of Preventive Oncology, Tata Memorial Hospital, Parel, Mumbai, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0019-509X.138165

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 » Abstract 

Introduction: Visual inspection with 5% Acetic acid (VIA) as a low cost screening method has good sensitivity with the limitation of low specificity and low positive predictive values. The present study therefore evaluates the performance of secondary testing by human papillomavirus (HPV) test and Colposcopy in a single-visit screening approach to increase program effectiveness in limited health-care resources settings. Materials and Methods: In a cross-sectional cervical cancer screening trial, 3629 women (30-65 years) were screened by primary screening test VIA. VIA test positive women were subsequently tested for the presence of oncogenic HPV types by hybrid capture II and with colposcopy. The reference investigation histopathology was performed for all primary screen positive women. Results: Data for 3613 evaluable women showed 352 (9.7%) women positive on primary screening by VIA. VIA had a sensitivity of 93% (95% confidence interval (CI): 0.76-0.99) and specificity of 91% (95% CI: 0.90-0.92) respectively to detect the cervical intraepithelial neoplasia grade 2+ . HPV DNA and colposcopy as secondary tests to triage VIA positive women had a sensitivity of 61% (95% CI: 0.41-0.78), 43% (95% CI: 0.24-0.63) and specificity of 99% (95% CI: 0.99-1.00), 99% (95% CI: 0.99-0.99) respectively for detecting CIN2+ lesions. Conclusion: Two step screening model combining highly sensitive low cost test like VIA for primary screening followed by more specific HPV DNA test as triage test for primary screen positive can be a cost-effective cervical screening strategy in resource constrained settings.


Keywords: Cervical intraepithelial neoplasia, cervix cancer screening, colposcopy, hybrid captures II, human papillomavirus testing, sensitivity, specificity


How to cite this article:
Pimple S, Shastri S S. Comparative evaluation of human papilloma virus-DNA test verses colposcopy as secondary cervical cancer screening test to triage screen positive women on primary screening by visual inspection with 5% Acetic acid. Indian J Cancer 2014;51:117-23

How to cite this URL:
Pimple S, Shastri S S. Comparative evaluation of human papilloma virus-DNA test verses colposcopy as secondary cervical cancer screening test to triage screen positive women on primary screening by visual inspection with 5% Acetic acid. Indian J Cancer [serial online] 2014 [cited 2019 Aug 18];51:117-23. Available from: http://www.indianjcancer.com/text.asp?2014/51/2/117/138165



 » Introduction Top


Cervical cancer is the third most common cancer in women world-wide with an estimated 530,000 new cases in 2008. More than 85% of the global burden occurs in developing countries, where it accounts for 13% of all female cancers. India recorded an estimated 141768 new cases and 77096 deaths due to Cervical Cancer in 2010, contributing to over 25% of the disease burden and more than 26% of deaths due to cervical cancer world-wide. Cervical cancer ranks as the first most frequent cancer among women in India and the first most frequent cancer among women between 15 years and 44 years of age. About 7.9% of women in the general population are estimated to harbor cervical human papillomavirus (HPV) infection at a given time and 82.5% of invasive cervical cancers are attributed to HPVs 16 or 18. [1]

India has a population of 366.58 million women with ages 15 years and older who are at risk of developing cervical cancer. One out of every five women in the world suffering from this disease belongs to India. More than three-fourths of these patients are diagnosed at advanced stages leading to poor prospects of long-term survival and cure. [1]

The age-standardized incidence rates varies from 17.2 to 55/100,000 women through different parts of the country. [2],[3] The prevalence and burden of cervical cancer is much higher among women of low socio-economic status as well as among rural women in India. The primary reason given for this is a lack of access to screening and health services and lack of awareness of the risk factors of cervical cancer. [4],[5]

There are no organized screening programs for cervical cancer in the country. Cytology is the current screening standard world-wide and has been the mainstay of cervical cancer screening for many years. However, despite its history of success in most developed countries for cervical cancer screening, pap cytology has significant limitations, the test has only moderate sensitivity and its high false negative rate (FNR), which carries important public health implications. [6]

There is substantial interest in the use of HPV testing in cervical cancer screening. [7],[8],[9] which currently require logistics that makes use of hybrid capture II (HC II) too costly in many low resource setting like India. Visual inspection-based approaches to cervical cancer screening namely visual inspection with 5% Acetic acid (VIA) have been extensively investigated in large cross-sectional, randomized controlled trials in India and are found to have good sensitivity. Because of the low positive predictive value (PPV) of the test, a considerable number of women who test positive do not have the disease. Thus, low specificity has been its limitation which would invariably result in excess referrals, increasing the referral load as well as the cost of unnecessary treatment on the health system. [10],[11],[12],[13],[14],[15]

Given the demonstrated utility of HPV DNA triage in the management of atypical squamous cells of undetermined significance (ASCUS), [16],[17],[18],[19],[20] this study addresses the potential role of HPV DNA testing as a sequential test in the evaluation of women found positive on visual inspection based approaches.

The results of the performance of VIA for detecting precursor lesions of cervical cancer by trained health-care providers followed by HPV DNA testing as a test of triage for visual inspection test positive women are reported and discussed in this study. The present study is an attempt to devise resource-appropriate screening strategies for an important public health problem in low resource setting.


 » Materials and Methods Top


Study design

A total of 3639 women among low socio-economic slum communities aged 30-65 years, were screened for cervical cancer during the years April 2006 to June 2008 in the population based community clinic based settings in Mumbai, India. The study protocol was reviewed and approved by the institutional review and ethics committees of the institute.

All women participating in the study were tested for primary screening by VIA administered by trained primary health-care workers. HPV testing was undertaken for all women found positive on primary screening test VIA and were further administered the reference investigation, namely, colposcopy with biopsy by trained colposcopist. The study algorithm is presented in [Figure 1].
Figure 1: Study design

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{Figure 1}

Participants

The study participants were recruited from low socio-economic communities from Mumbai. Apparently healthy, asymptomatic women aged 30-65 years with an intact uterus and with no past history of cervical neoplasia were eligible to participate. Women were encouraged to participate in the screening program by making them aware about prevention of cervical cancer and screening by group cancer awareness sessions, focus group discussions and individual counseling, by trained social workers and health workers, using flip charts, posters and audio-visual material.

Training of health workers, technicians and doctors

The screening tests in the study were performed by high school graduate trained health workers. Training for the health-care personnel was conducted with the help of lecture sessions, group discussions and atlas comprising of photographs of normal, abnormal cervix, cervical pre-cancers and cancers. The health workers were trained in a 1 month intensive course utilizing training manual prepared by International Agency for Research in Cancer (IARC). [21] Simultaneous practical demonstration and hands-on training was also carried out in hospital and community cancer clinics. Technicians involved in cytology and HPV testing were trained in collection, processing and testing methodology. Periodic refresher training was also conducted at 6 monthly intervals during the course of study. Doctors received intensive training course on colposcopy and pre-cancer management by cryotherapy and loop electrosurgical excision procedure using manual prepared by IARC. [22]

Data collection

A Medical Social Worker or a trained health worker distributed the written subject information material in local languages explaining the nature and the purpose of the study before obtaining her consent on an informed consent form. Subject information material and Informed consent forms were read out to the subject participants where ever necessary before obtaining signature or left thumb impression. A detailed socio-demographic and reproductive history was then obtained by the health workers in a structured questionnaire before subjecting them to screening.

Screening of women

The screening clinics were conducted on a regular basis in the mobile community clinics or volunteered spaces converted into screening clinics in the chosen community areas. All tests were administered by high school graduate trained health workers recruited under the project. The tests were performed independently and health workers were blinded for the result of the previous tests.

All participating women were tested for VIA by trained health workers. The result of VIA test was recorded positive when there were sharp, distinct, well-defined, dense acetowhite areas with or without raised margins, closer to the squamocolumanar junction in the transformation Zone and not for away from the cervicalos.

HPV testing by HC II was performed by cervical sampling (Christmas tree) brush (Digene cervical sampler) in the medium provided for collection and transport. HPV DNA status for high-risk HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59 and 68 was determined with the use of the second-generation HC II probe B, microtiter assay (Digene) by following the manufacturer's instructions. Results were classified as positive for high-risk HPV DNA if the relative light units reading obtained from the luminometer was equal to or greater than the mean of the positive control values supplied by the HC II kit. The chosen positive threshold was 1.0 pg/ml. The laboratory personnel were blinded to the results of visual screening and colposcopy.

Colposcopy was carried out by trained doctors and was administered to all the subject participants tested screening positive on primary screening by VIA. Trained colposcopists performed diagnostic colposcopy on all women who were found positive for VIA screening. The colposcopic findings were classified into the following categories as (1) normal, (2) squamous metaplasia, (3) leukoplakia/condyloma, (4) probably low grade lesion/cervical intraepithelial neoplasia (CIN)-1, (5) probably high grade lesion/CIN2-3 and (6) invasive carcinoma. Further, the colposcopy findings were graded by assigning scores for color of lesion, margins, vascularity and iodine staining, using the reid colposcopy index.

Punch biopsies were obtained from all subjects with positive VIA findings. Biopsy specimens were fixed in formalin and were processed and reported using the CIN system by the histopathology laboratory of the Tata Memorial Center. True disease status was defined as CIN-II and worse lesions. The reference standard for final diagnosis was histopathology.

Reference standard and true disease

The final reference diagnosis was based on histopathology findings. Verification bias was averted to extent by subjecting 10% the women to colposcopy with or without biopsy irrespective of the screening test results. High grade squamous intraepithelial lesion was considered as true positive disease to calculate sensitivity, specificity and predictive values of the screening tests.

Quality control

All health workers, technicians and doctors recruited for the project received intensive training at the beginning as well as refresher courses with assessment at 6 monthly intervals during the course of study.

Data management and statistical analysis

Data were entered using the standard computer software. Data entry was carried out in EPIINFO software. Checks for consistency and analysis were carried out using Stata 7.0 (Stata-Corp LP, Texas, USA). Sensitivity, specificity and predictive values and their 95% confidence intervals (CI) for a single and combined test were calculated using 2 × 2 tables and standard formula with the intention to treat analysis. Data of 3613 women was selected for the present analysis excluding 26 women who were non-compliant for diagnostic investigation. The study was analyzed to evaluate the performance of VIA, HPV DNA testing by HC II as a sequential test (secondary diagnostic triage test) for visual inspection test positive women and colposcopy against the gold standard of histopathology.


 » Results Top


A total of 3639 women were screened with the primary screening test VIA. VIA positive women were then administered sequential secondary screening tests HPV DNA by HC II and further colposcopy with directed biopsy. A total of 26 women refused further tests on primary screening by VIA, thus only 3613 women who complied with the study protocol were included in the final analysis. [Table 1] shows the age distribution by demographic and reproductive characteristics of the recruited women. Nearly, 82% of participating women were aged between 30 years and 50 years. Nearly, 12.5% had had no formal education. Nearly, 74% of the women were pre-menopausal. The mean age of attaining menarche and getting married was 13.8 standard deviation (SD 1.4) and 20.2 (SD 4.7) respectively. The mean number of pregnancies were 2.8 (SD 1.4). Nearly, 29% of the women were tobacco users in some form. The other demographic and reproductive characteristics of the participating women are given in [Table 1].
Table 1: Demographic and reproductive characteristics of recruited women (N=3613)

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The distribution of primary and secondary triage screening test result with that of the reference diagnosis histopathology are given in [Table 2]. 352 (9.7%) women were reported screen positive on VIA. A total of 352 primary screen positive women received HPV HCII and colposcopy and directed cervical biopsies. 39 (11%, n = 352) women were positive by HC II. Colposcopy detected 208 (59%, n = 352) women with CIN1 and above lesions (includes CIN1, 2, 3 and invasive cancers) and 43 (12.2%, n = 352) women with CIN2 and above lesions (includes CIN2, 3 and invasive cancers).The reference test histopathology detected 32 (0.8%) cases of CIN1 and 28 (0.7%) cases of cervical intraepithelial neoplasia grade 2+ (CIN2+).
Table 2: Distribution of screening test results by final disease status established by the histopathology reference standard

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The test characteristics of primary screening test VIA and triage tests HPV DNA and Colposcopy in terms of sensitivity, specificity and positive and negative predictive values (NPV) for detecting CIN lesions are shown in [Table 3]. The sensitivities of primary screening test VIA for thresholds of CIN1+ and CIN2+ were 92% and 93% respectively. The specificities of VIA for thresholds of CIN1 and CIN2 and above lesions were 92% and 91% respectively. The PPV though were lower i.e. 16% and 7% respectively for thresholds of CIN1 and CIN2 and above lesions.
Table 3: Test characteristics of screening tests (primary and triage tests) to detect CIN1+ and CIN2+ lesions

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Triage of visual inspection test positive (VIA), by HPV HC II, outcome CIN1+ and CIN2+

When HPV DNA test is applied as a secondary test to triage those found positive on VIA, the sensitivity, specificity, positive and NPV for detecting CIN1+ lesion was 40%, 100%, 62% and 99% respectively. The same test characteristics for detecting CIN2+ lesions were 61%, 99%, 44% and 100% respectively. The PPV was higher (62%) for detecting CIN1+ lesions than CIN2+ lesions (44%).

Triage of visual inspection test positive (VIA), by colposcopy, outcome CIN1+ and CIN2+

Similarly if colposcopy is applied as a secondary test to triage all the women who were tested positive on VIA, then the test sensitivity was 75% and 43% respectively for thresholds of detecting CIN1+ and CIN2+ lesions and specificity was 95% and 99% for similar thresholds. The PPV did not show much variation with 22% for detecting CIN1+ lesions and 28% for CIN2+ lesions.


 » Discussion Top


World-wide, interest is growing in the potential uses for HPV DNA testing in cervical cancer screening programs, but currently is too costly to be undertaken at the population level screening programs in developing country settings.

With the emergence of VIA as promising alternatives to cytology, as a primary screening modality, where resources are limited this study evaluates the performance of VIA for primary screening provided by trained health-care workers and also to test the feasibility of the potential role of HPV DNA testing verses that of stand-alone colposcopy as a secondary triage test in women tested positive on VIA.

In our study, VIA has emerged as a promising primary screening method for early detection cervical pre-cancers with sensitivity of 93% (95% CI: 0.76-0.99) and specificity of 91% (95% CI: 0.90-0.92) for detecting high grade intraepithelial cervical neoplasia. Furthermore, there is sufficient evidence through various cross-sectional and randomized trials for visual inspection with 5% Acetic acid in India and Africa to indicate that VIA based screening is a suitable and safe alternative to conventional cytology based screening programs in low resource settings. [10],[11],[12],[13],[14],[15] A major advantage with visual inspection based tests is that it is a real-time screening test as the outcome is known immediately after the administration of the test, so that further diagnostic confirmation or "See and Treat" treatment approach can be planned and carried out during the same visit. However, low Specificity had remained the major limitation of VIA studies published as of now. However, our study results for the specificity of VIA at both the thresholds of CIN1+ AND CIN2+ showed improved specificity of 92% and 91% respectively, which could be because of the utilization of trained staff who had been performing VIA for the last 5-6 years with good quality control and standards maintained during the study. However, low PPV for VIA test in previous published studies and the current study (7% and 16% for CIN1+ and CIN2+ outcomes) means that out of the total who test positive less women actually have the disease.

The literature is replete with studies on clinical application of HPV DNA test in triage of ASCUS and low-grade squamous intraepithelial lesions on cytology. [16],[17],[18],[19],[20] However, there are no studies, which have demonstrated the utility of HPV DNA test to triage VIA test positive women.

This study thus is indicative of the comparative impact of HPV and colposcopy triage of women with test positive result on primary screening by VIA, in terms of referral and detection of CIN2 + outcomes.

It was found that though triage of VIA positive women, based on HPV testing only or on a stand-alone colposcopy (for CIN2+) testing would refer similar proportions (approximately 11-12%) for further diagnostic confirmation by guided biopsy. But HPV DNA testing by HC II showed better sensitivity (61%, 95% CI: 0.41-0.78) than colposcopy (43%, 95% CI: 0.24-0.63) to detect high grade CIN2 + lesions. Both tests though displayed equal specificity. Colposcopy thus shows increased FNR of 57% (95% CI: 0.37-0.76) than the one shown by HPV DNA test (39%, 95% CI: 0.22-0.59). This can result in considerable risk of missing high-grade pre-cursor lesions and occult cancers by secondary screening with colposcopy in low-resource settings where there are no organized repeat screenings and where there is lack of compliance to follow-up. Colposcopy as a triage to VIA a subjective test in itself could also bring in substantial subjectivity in interpretation owing to different levels of experience, training levels and low reproducibility of the test.

The PPV for the HPV DNA test was also twice as high (44%, 95% CI: 0.28-0.60) compared with colposcopy (28%, 95% CI: 0.15-0.44) at CIN2 + threshold for direct referral of all VIA positive cases thereby demonstrating the utility of HPV DNA testing as a superior objective secondary triage test and a more feasible cervical screening strategy.

Consistent evidence in literature is available indicating HPV-triage with the HC II assay being more accurate than repeat cytology to triage women with equivocal Pap smear results for outcomes of CIN2+. [20] Overall, results of meta-analyses of HPV DNA testing for triage of women with findings of abnormal squamous cells of undetermined significance (ASC-US), HC II had a sensitivity of 93.1% (95% CI: 91.1-95.1%) for detecting respectively CIN2 + and the pooled specificity was 62.3% (95% CI: 57.6-67.1%) when the outcome was CIN2+. [23],[24]

Compliance to follow-up for confirmatory diagnosis and treatment remains a challenge in population level programs where multiple visit approaches are not feasible because socio cultural and geographic barriers. In the above context single visit approaches "see-see-treat" approach in cervical cancer screening is being advocated, particularly for low-resource settings offering screening, diagnostic verification and treatment that can improve cervix cancer screening outcomes in the country.

In a recent randomized control trial involving screening with VIA, a 25% significant reduction in the incidence of and a 35% reduction in mortality from cervical cancer were observed, indicating that with good quality training, quality assurance measures, screening with VIA and effective treatment of precancerous lesions can reduce the cancer burden. [25]

Thus with the outcomes of the current study results, combining a sensitive and cost-effective test like VIA for primary screening followed HPV DNA detection, which is more specific test with good PPV for primary screen positive can substantially reduce cost of the program and also lead to immediate treatment of abnormalities for an effective screening program.

The current study test result that assessed test accuracy parameters though would witness some verification bias since the reference investigation was only offered to subjects who were screen positive on primary screening test by VIA, but the 10% VIA negative women who were offered colposcopy with or without biopsy did not detect any CIN cases in the group tested. Thus, our study assessed test accuracy parameters with minimal verification bias.

Such two-step screening test model predicts a substantial decrease in further diagnostic referrals, by prioritizing women with positive primary screening results, to focus on women at highest risk, which can substantially bring down the program costs and can determine the most cost-effective testing intervals, to meet limited resources. Further if the cost of HPV comes down substantially and results become immediately obtainable with fast HPV Kits, this approach offers even more promise to be combined with low cost visual inspection based approaches as a primary screening test. They together can make for a powerful predictive tool in women age 35 and above and single visit "screen- and- treat" strategies may become feasible and therefore a possibly attractive one for local policy makers. Such two-step screening test model probably needs larger community trials to validate its findings and its relevance in population based screening programs.

 
 » References Top

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    Figures

  [Figure 1]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]

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