Postgraduate Training Course in Reproductive Health/Chronic Disease

Visual inspection with acetic acid as a
cervical cancer screening tool for developing countries

Review prepared for the 12th Postgraduate Course in Reproductive Medicine and Biology, Geneva, Switzerland

Maria Julieta V. Germar, M.D.
Section of Gynaecologic Oncology
Department of Obstetrics and Gynaecology
University of the Philippines
Philippine General Hospital
Tutor: Mario Merialdi, M.D.
Department of Reproductive Health and Research
World Health Organization
Geneva, Switzerland

See also presentation

A Bibliographic Review Prepared for the 12th Postgraduate Course in Research Methodology and Reproductive Health organized by the Geneva Foundation for Medical Education and Research, the UNDP/UNFPA/WHO/World Bank Special Programme for Research in Human Reproduction, Department of Reproductive Health and Research, Family and Community Health Cluster (WHO/RHR) and the WHO Noncommunicable Diseases and Mental Health Cluster (WHO/NMH)in collaboration with the Department of Health of the Canton of Geneva, the Faculty of Medicine, Geneva University and the Geneva Medical Association.

Abstract

Background:
Worldwide, 23, 000 women die of cervical cancer every year, over 80 % live in developing countries. In the Philippines, cervical cancer is the 2nd most common cancer in women after breast cancer. Cervical cytology is presently considered to be the only test known to reduce cervical cancer incidence in organized screening programs in developed countries. However, an organized screening program is difficult to implement in developing countries like the Philippines where resources are scarce. A number of cervical cancer screening approaches as alternatives to cervical cytology have been evaluated: automated PAP screening, visual inspection with acetic acid (VIA), human papilloma virus testing and recently the polar probe. Among these, VIA is of particular interest to developing countries because it is inexpensive, only requires supplies usually locally obtainable, and can be competently performed by non-physicians with proper training.

Objectives:

  • to review the evidence on VIA as a cervical cancer screening tool in terms of its sensitivity and specificity in detecting pre-invasive lesions compared to cervical cytology, which is the golden standard of screening at present.
  • to evaluate how this evidence can be used to implement a feasible screening program in a low resource setting like the Philippines.

Search Strategy:
All relevant articles from 1980 to March 2003 were retrieved. Studies were identified by performing a MEDLINE search. Manual searches of relevant journals, reference lists of retrieved articles and direct communication with other researchers in the field made it possible to get unpublished data. Unpublished data from the World Health Organization (WHO) and the International Agency for Research on Cancer (IARC) were cited with permission from the authors.

Results:
Critical appraisal of the 9 studies which investigated the accuracy of VIA compared to cytology and colposcopy (with or without biopsy) as the reference standard, revealed some deficiencies in the study methods. The most important of these is the potential for verification bias and the non-independence of assessments.
From the nine cross-sectional studies reviewed comparing the accuracy of VIA with colposcopy (with or without biopsy) in detecting pre-invasive lesions, the range for sensitivity was between 49.4% to 96%, for specificity between 48.5% to 97%. The positive predictive value ranged from 11% to 26 %. The negative predictive value ranged from 95.5% to 99 %.

Conclusions:
VIA has similar sensitivity to that of cervical cytology in detecting pre-invasive lesions but has lower specificity. It is important for VIA to be evaluated further with regard to improving specificity, standardization of criteria as to disease categories, and standardization and training of personnel involved in screening. Furthermore, long term follow up of women and the consequent impact on disease burden deserve further research.
In resource restricted areas, VIA may find a place as a low technology and low cost method of screening, particularly in regions like the Philippines without extensive cytology laboratory facilities.

key words: Visual Inspection with Acetic Acid (VIA), Cervical cytology, Cervical; cancer; screening, developing countries

Introduction

Worldwide, cervical cancer comprises 12 % of all cancers in women (1). Of the 466,000 cases estimated to occur in the year 2002, developing countries account for 370,000 cases (2). Worldwide, 231,000 women die of cervical cancer every year, over 80 % of whom live in developing countries (3). Southeast Asia contributes about 25 % of the total disease burden (4).
In the Philippines, cancer ranks third in lead cause of morbidity and mortality, with communicable diseases ranking first and cardiovascular diseases ranking second. In recent years, mortality due to communicable diseases has decreased, while it is increasing for cancer and heart disease. Cervical cancer is the 2nd most common cancer in women after breast cancer. It ranks 4th when both sexes are taken together. The cervical cancer incidence remains unchanged from 1980-1995 with 44 % overall survival rate or about 10 per 100,000 women dying from the disease over 5 years. About 2/3 of cervical cancer in the Philippines are diagnosed at an advanced stage, where due to inadequate radiotherapy facilities, mortality is high (5).
Cervical cancer is a preventable disease. Worldwide, successful cervical cancer prevention is based on an organized screening program. Cervical cytology is presently considered to be the only test known to reduce cervical cancer incidence in organized screening programs (1). The goal of screening is to detect the pre-invasive stage of the disease and treat it appropriately before it progresses to cervical cancer. In developed countries, initiation and sustenance of cervical cytology programs, involving screening of sexually active women yearly, or once every 2-5 years have resulted in a large decline in cervical cancer incidence and mortality. (6-9).
However, an organized screening program is difficult to implement in developing countries where resources are scarce. Although cytology is being carried out in developing countries, this is mostly done in the context of opportunistic screening activities, which are often inadequately performed and of poor quality (10). Particularly in the Philippines being composed of 7,100 islands with some remote areas with no physicians, poses geographic limitations and screening programs for cervical cancer have consistently failed to meet the target population due to lack of manpower and funds (4).
In the Philippine ‘Knowledge, Attitude and Practices behaviour modification study’, the following factors were shown to be the causes of failure of these screening methods: 1) lack of knowledge among women about symptoms that may be associated with cervical cancer 2) a fatalistic attitude towards cancer in general and a lack of awareness that cervical cancer can be cured 3) lack of cytological facilities and expertise, lack of treatment facilities in rural areas 4) lack of patient’s compliance to follow up for check-up and treatment (11).
The cervical cancer screening situation in the Philippines, as presented in a descriptive study conducted in 2000 is as follows (4):

  1. only 42 % of 389 hospitals nationwide offer screening and early detection services for cervical cancer, of these hospitals, only 8 % have clinics dedicated to cancer screening;
  2. the cytology is performed by a physician, however a cytology technician is available in only 21 % of hospitals;
  3. a pathologist is available in 45 % of hospitals;
  4. colposcopy is available in only 22 % of 104 tertiary hospitals, 16 % of 167 secondary hospitals and not available in 118 primary hospitals of the total 398 hospitals surveyed.
  5. it takes 47 +/- 11 days for a woman to travel from her residence to the clinic for a pap smear till the time she obtains the result

Community based screening programs require a relatively sophisticated infrastructure, including highly trained personnel, adequately equipped laboratories and good referral systems to communicate the results of the test to the women (12). In view of these requirements, an alternative method of screening is needed for countries like the Philippines with very limited resources and infrastructure.
A number of cervical cancer screening approaches as alternatives to cervical cytology are described: automated pap screening, visual inspection with acetic acid (VIA), human papilloma virus testing and recently the polar probe. Among these, VIA is of particular interest to developing countries because it is inexpensive, only requires supplies usually locally obtainable, and can be competently performed by non-physicians (13).
Prior to the use of Pap smear and cytology based screening programs, healthcare providers relied on looking at the cervix to detect abnormalities. After the 1950s, cytology became the standard for cervical screening and the colposcope was used to further investigate the cervix. A simple visual approach involving direct unmagnified inspection of the cervix without acetic acid application, unaided visual inspection (downstaging) was evaluated by three cross-sectional studies in India (14-16). The accuracy of downstaging in the early detection of cervical carcinoma and precursor lesions was found to be poor.
VIA first described by Ottaviano and La Torre in 1981 (17), involves the inspection of the cervix with the naked eye before and after application of 3-5 % acetic acid solution with the use of a 100-watt lamp as a light source. The molecular basis is that acetic acid causes dehydration of cells and surface coagulation of cellular proteins thereby reducing the transparency of the cervical epithelium (18). These changes are more pronounced in abnormal epithelium due to greater nuclear density and consequent higher concentration of proteins. A positive test is generally based on the detection of well-defined, acetowhitening of the epithelium of the transformation zone close to the squamocolumnar junction a minute after the application of 3-5 % acetic acid. A patient positive for VIA is then referred for colposcopy and, if abnormal tissue is identified, a biopsy is taken.
VIA was initially explored as an adjunct to the PAP smear or cervical cytology to decrease the high false negative rate of the latter. These studies and the need to find an alternative to cervical cytology led to the investigations of the accuracy and efficacy of VIA as a cervical cancer screening tool to detect cervical neoplasia (1).

Objectives

This paper has the following objectives:

  1. To review the evidence on VIA as a cervical cancer screening tool in terms of its sensitivity and specificity in detecting pre-invasive lesions compared to cervical cytology which is the golden standard of screening at present.
  2. To evaluate how this evidence can be used to implement a feasible screening program in a low resource setting like the Philippines.

Methods

Study Sources

All relevant articles were retrieved from 1980 to March 2003.  Studies were identified by a MEDLINE search.  Manual searches of relevant journals, searching the reference lists of retrieved articles, and direct communication with other researchers in the field made it possible to get unpublished data.  Unpublished data from the World Health Organization (WHO) and the International Agency for Research on Cancer (IARC) were cited with permission from the authors.
The MEDLINE database was searched by linking three broad content areas: cervical cancer screening, tests for cervical dysplasia and cervical cancer. Several subject headings were used within each content area, linked together by the Boolean OR operators. The content areas were linked by an AND operator.  The specific search words used within the content areas were as follows: Direct Visual Inspection/ DVI, Visual Inspection with Acetic Acid /VIA, Acetic Acid, cervicography, Naked Eye Inspection of cervix /NIC.

Study Selection

Articles excluded were technical papers without original data, letters and those that did not address cervical cancer or its precursors.  All but 2 potentially eligible articles that could not be retrieved (one from Italy, the other from India) were reviewed in detail along with those obtained from other sources.
Articles excluded were those that did not use cervical cytology and VIA, did not use colposcopy with or without histology as the reference standard, or did not report sufficient data for the estimation of sensitivity and specificity. The final sample for critical appraisal consisted of 9 studies (Table 1).  All articles were obtained from Medline except for one from the Philippines, which was obtained by direct communication with the authors.

Critical Appraisal

Studies were classified on characteristics important for diagnostic or screening test assessment (19). The characteristics are defined as follows: Setting is described as hospital based, community based, unknown and, when available the region or city where it was conducted. Technique described the instrument used to collect cervical cells, and the procedure for VIA; Independence of assessments refer to studies which assessed cervical cytology  and VIA without knowledge of the histology or the VIA result; Intervention performed by either specialists, general physicians, nurses or midwives was also noted; Criteria for a positive or negative test were also noted, specifically for pre-invasive disease; Point estimates of sensitivity and specificity were reported for cytology and VIA as independent factors.

Results

Table 1 presents the results of the critical appraisal and the characteristics of the involved studies.
Critical appraisal of the 9 studies which investigated the accuracy of VIA compared to cytology with colposcopy with or without a biopsy, revealed some deficiencies in the study methods. The most important of these is the potential for verification bias and the non-independence of assessments. Verification bias occurs if all study participants are not subjected to the reference standard to determine their true disease status, making direct calculation of sensitivity and specificity impossible (19).
Presented in table 2 are the results of the included studies. The following studies conducted in developing countries reported the following results: In the study by Megevand et al in 1996 (20) conducted in South Africa, in 2426 women, VIA detected 65 % of high grade squamous intraepithelial lesions (HGSIL) confirmed by the reference standard. Specificity is higher for VIA in this study. In a study conducted in India, Sankaranarayanan et al in 1998 (21) found that the performance of cervical cytology and VIA was similar with a sensitivity ratio of 1.05 in detecting low grade squamous intraepithelial lesions (LSIL) and HGSIL in 3000 women . Specificity was similar. In a study conducted by the same authors in 1999 (22), in 1351 women in India, VIA detected more LSIL and HGSIL lesions than cytology but VIA was only 68 % specific compared to the 90 % specificity of cytology. Denny et al (23) compared the performance of cervical cytology, VIA, and HPV DNA in detecting HGSIL in South Africa in 2944 women and found that VIA was similar to cervical cytology in detecting HGSIL but had a very high false positive rate. The same authors in a subsequent study on 2754 women in South Africa (24), compared VIA with and without magnification to cytology and found VIA to be similar to cervical cytology in terms of sensitivity (58.3 vs 57.4 % for cytology) but less specific (83.5 % vs 96.3 % for cervical cytology). Results apply to VIA with or without magnification. In these studies, the reference standard which was colposcopically guided biopsy was done only in those who had a positive finding on cervical cytology and/ or positive findings on VIA. These studies therefore suffered from verification bias (25). Sensitivity and specificity measure the efficacy of a screening test and the positive and negative predictive values measure its accuracy. Sensitivity and specificity could not be measured directly as the reference test, colposcopy with or without a biopsy, was not applied to all. This bias may lead to an overestimation of sensitivity. The authors in the study presented the ratio of sensitivities between cytology and VIA, and the approximated sensitivities and specificities of each parameter.
The first study, which reported direct estimates of sensitivity and specificity, is the study conducted in Zimbabwe by the University of Zimbabwe and JHPIEGO in 1999 (26). The first phase of the study suffered from verification bias with only the 10th woman screened with a negative test result undergoing the reference standard, colposcopy with or without a biopsy. The second phase of the study on 2203 women required that the reference standard be done on all women the day after the screening test. In that study, the sensitivity of VIA was higher than cervical cytology by 1.75 ( 77 % vs 44 % for cervical cytology ) while specificity of VIA was lower (64 % vs 91 % for cervical cytology) .
A subsequent study by Cronje et al in 2000 (27), on 6301 women in South Africa, likewise performed colposcopy with or without a biopsy as the reference standard on all women included in the study and found VIA to be more sensitive than cervical cytology (49.4% vs 19.3 % respectively)but significantly less specific than cervical cytology (48.5 % vs 99.3 % respectively ). Another study conducted by Belinson et al in 2001 (28) in rural China on 1997 women, performed the reference standard on all women and found that VIA had a 71 % sensitivity and 74 % specificity. Compared to cervical cytology, VIA was less sensitive and les specific. The authors attributed this finding to the high number of cases of acute cervicitis. Furthermore, their results may not be easily reproducible in remote areas where there are no available physicians, as VIA was performed by Gynaecologic Oncologists.
The study conducted in the Philippines by Ngelangel et al (29) in 13,710 women from 6 urban and 6 regional hospitals was limited by the fact that the reference standard used was colposcopy and only for suspicious areas biopsy was performed. The estimated sensitivity was 50.3 % for VIA vs 8.5 % for cervical cytology and the estimated specificity was 94.1 % vs 97.3 % for cervical cytology. The very low value of cytology was likely related to the fact that a cotton swab was used to sample the cervix. Their explanation is supported by the observation that sensitivity increased to 18.7% when a cervix brush was used in the same population .
From the nine cross-sectional studies reviewed which addressed the accuracy of VIA in detecting pre-invasive lesions with colposcopy with or without a biopsy as the reference standard, sensitivity ranged from 49.4% to 96%, specificity from 48.5% to 97%. The positive predictive value ranged from 11-26 %. The negative predictive value ranged from 95.5 -99 %.

Discussion

In the studies reviewed, VIA performed similarly or sometimes better than cervical cytology in terms of detecting pre-invasive lesions but has a lower specificity. This is associated with a high number of false positive rates. The observed high number of false positive results for VIA may lead to high rates of referral, and may increase rates of treatment which may translate to higher costs. On the other hand, the high detection rate of VIA for high grade pre-malignant lesions reported by the studies reviewed may prevent malignancies at a low cost. This deserves further research.
Some authors have addressed this problem and aimed to improve the low specificity of VIA. Denny et al ( 24) used a 2.5 x lens to magnify the cervix after application of acetic acid but this did not improve the specificity of VIA. Others have proposed a sequential screening test like VIA followed by HPV DNA testing (30) to improve the specificity of VIA. In developing countries however, HPV DNA is not routinely available and if available it is very costly. For sequential screening to be effective, the second screening test must be routinely available and affordable.
In the majority of the studies reviewed performance of cytology and VIA were done by nurses and midwives who underwent a 5 day to one week training to adequately recognize acetowhitening. However, the definitions used for a positive VIA test varied considerably, making comparisons difficult. This lack of standardized criteria may explain the varied results among the studies reviewed. VIA is a provider dependent screening test and it is of utmost importance to standardize the definitions. There should be a uniform, reproducible system for categorizing and reporting VIA findings. Once this is in place, standard training should be provided to all health providers involved for quality control.
In the 9 studies reviewed it was also noted that the age range varied from 20-83 years. Among these, only one study (27) did a subgroup analysis with respect to age and found that sensitivity of cytology and VIA increased from 11.0 % to 28.8 % and 48.4 % to 50.6 % respectively in women younger than 35 and women 35 years and older. The importance of this finding for developing countries is with regard to cost effectiveness of screening women at an older age. This may also explain the variations in results observed among the studies reviewed. This deserves further research.

Conclusions

VIA has similar sensitivity as cervical cytology in detecting pre-invasive disease but has lower specificity. It is important for VIA to be evaluated further with regard to improving specificity, without compromising sensitivity. Standardization of criteria as to disease categories, and a comprehensive competency based training of personnel involved in screening must be done. Furthermore, long term follow up of women and the consequent impact on disease burden deserve further study.
The International Agency for Research on Cancer (IARC) is currently conducting 5 cross-sectional studies in India (Table3) evaluating the comparative accuracy of VIA, magnified visual inspection with acetic acid (VIAM), visual inspection with Lugol’s iodine (VILI), cytology and HPV DNA testing by hybrid capture (HC) method in detecting high-grade cervical cancer precursors and invasive cervical cancer (31,32). These studies are located in Calcutta (Chittaranjan National Cancer Institute), Hyderabad (MNJ Cancer Institute), Jaipur (Bhagwan Mahaveer Cancer Hospital and Research Centre), Bombay (Tata Memorial Centre) and Trivandrum (Regional Cancer Centre). These studies involve 35,000 women all together.
The comparative efficacy and cost-effectiveness of once a life-time VIA (provided by nurses), conventional cytology, and HPV testing in detecting cervical neoplasia and in reducing the incidence of and mortality from cervical cancer is being evaluated by the IARC in a cluster randomized, controlled intervention trial in Osmanabad district, Maharashtra, India (31,32). Recruitment of women in this program will be completed and detection rates of CIN 2-3 by the different screening tests will be reported within this year.
Another cluster randomized, controlled intervention trial, initiated in 2000, is investigating the efficacy and cost-effectiveness of VIA (provided by nurses) in reducing incidence of and mortality from cervical cancer in Dindigul district, Tamil Nadu, India, in collaboration with the Christian Fellowship Community Health Centre, Ambillikai (31,32). This program involves 73,000 women aged 30-59 years living in 113 villages. The detection rate of CIN by VIA will be reported by this year.
The currently ongoing studies in several developing countries will further clarify the role of VIA as an alternative cervical cancer screening tool. The information from these studies are likely to provide valuable information on the role of VIA in the prevention of cervical cancer in low resource high risk countries like the Philippines.
In resorce poor settings, VIA may find a place as a low technology and low cost method for screening. The ongoing trials and future research on improving sensitivity of VIA, its efficacy in reducing the incidence and mortality from cervical cancer, its cost effectiveness, acceptability and safety will be useful in the formulation of population based screening programs for developing countries. This must go hand in hand with increasing the awareness of women about cervical cancer and prevention towards an organized system of referral to monitor treatment outcomes in these women.

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