Cervical cancer is the leading cause of morbidity and mortality among women worldwide. There are over 500,000 cases of cervical cancer found worldwide, and more than 280,000 women die of it every year. 85% live in developing countries. Cervical cancer is the leading cause of years-of-life lost in women in South Central Asia, Latin America and Sub-saharan Africa, resulting in a greater reduction in a women’s life expectancy even when compared with AID’s, TB, or maternal conditions in Latin America and Europe. (Yang, International Journal of Cancer 2004.)
While the incidence and mortality rates of cervical cancer have declined over 80% in developed countries since the advent of successful screening programs, there has been no such trend in developing countries. (Miller, Int Journal of Cancer 2000). Screening programs were implemented in developing countries since the early 1980’s, yet have failed to reduce the mortality rates. The WHO in 2002 estimated that only 5% of women in developing countries are screened appropriately. Likely reasons for failure in screening programs include lack of funding, insufficient access in rural areas where most of the population in developing countries reside, lack of awareness/education as to need for screening, and poor follow-up. About 50% of all cancers occur in developing countries, yet only 5% of resources are spent on the fight against cancer worldwide (Kitchener, The Lancet 1999).
In light of the poor results from PAP-based screening programs, alternative methods for cervical cancer screening have been sought. One method, direct visualization with acetic acid has gained popularity and proven itself in many clinical trials as an adequate alternative to PAP smears in developing countries. In visual inspection with acetic acid (VIA), 5% acetic acid is applied to the cervix with a large cotton swab and left for 30-60 seconds, after which the cervix is visually examined with the naked eye and a lamp. Pre-cancerous lesions, with a higher ratio of intracellular proteins, turn white when combined with acetic acid. Normal cervices without any precancerous lesions, do not change color. This is the same method used when physicians to colposcopy; using the change in color from acetic acid to guide biopsy.
VIA is an attractive alternative to PAP smears for its ease of use, low-cost and fewer physician visits. Currently, to do a PAP smear, the doctor requires a speculum, lamp, slide, cytobrush, microscope, pathologist and a 2-week or more follow-up visit. With VIA, any trained nurse or physician able to use a speculum can do the test. Tools needed include a speculum, lamp, cotton swab, and acetic acid (vinegar); there is no pathologist or physician needed. And, if the test is negative, the patient can be told immediately without having to return to the doctor for results. In rural areas where people travel hours for a doctors’ visit, a screening method requiring fewer visits will have a much higher success rate.
Many studies have been done to compare VIA to PAP smears as a screening method for cervical cancer. Most studies compared VIA with PAP, looking at sensitivities and specificities of both, while comparing them to colposcopy with biopsy as the gold standard.
Gaffkin in 2003, published a mini- meta-analysis reviewing the data of what had been published about direct visualization with acetic acid from 1982 to 2002. After finding numerous cites on PubMed, she chose 15 studies from which to review. The 15 studies encompassed over 34,000 women from across the world and the specialists performing the tests ranged from nurses to physicians. The range of estimated VIA sensitivity values from these studies was 66-96% and specificity rates from 64% to 98%. In this study, Gaffikin published test qualities of PAP smears ranging from 11-99%. Gaffikin concluded that VIA was comparable to PAP smears in terms of detecting HGSIL’s or cancer. She also went on to say that, although a lower specificity was noted in various publications, the authors nonetheless unanimously concluded that VIA was useful as an adjuvant or alternate to cytology.
In 2001, Bellinson went to rural China and examined 1,997 women considered to be high risk. In this study they compared visual inspection with acetic acid to colposcopy with biopsy. All exams were performed by gynecologist oncologists and their fellows; the person performing the visual inspection was not the same person performing colposcopy and both examiners were blinded to results. The biopsies included directed biopsies if abnormalities seen, one undirected biopsy at 2, 4, 8, or 10 o’clock at the squamocolumnar junction in each normal quadrant, and an ECC. For biopsy proven CIN II or greater, the sensitivity of VIA was found to be 71% and specificity 74%. The PPV of visual inspection in this study was found to be 11% and the NPV 98%. Bellinson concluded that the sensitivity of VIA equaled or exceeded reported rates for conventional cervical cytology and encouraged continued research into the possibility of a see and treat method for cervical cancer screening.
Two years later, a study in the Phillipines was done, a country where there are almost 70,000 cases of cervical cancer, with ~7,000 new cases each year. (Ladines, PGH cancer Institute) Ngelangel compared VIA to two types of PAP smears. 12,992 women between the ages of 25-65 from five different community hospitals throughout the Phillipines underwent four different screening exams: visual inspection with acetic acid, magnified visualization with acetic acid (VIAM), spatula + cotton swab PAP smear and cervical brush PAP smear. He based the quality of these four screening tests on colposcopy with biopsy of suspicious lesions as the gold standard. Both nurses and physicians conducted the studies. Sensitivities for the four tests were found to be 37% for VIA, 34.1% for VIAM, 14.3% for spatula PAP, and 19.1% for cervical brush PAP. The specificity rates were 90.7%, 90.7%, 97.5%, and 97.9% respectively. VIA had the highest sensitivity of the four tests. Ngelangel concluded that the acetic acid visualization and VIAM methods are recommended for initial cervical cancer screening in the Phillipines.
Ghaemmaghami tested the VIA method of cervical cancer screening in Iran where cervical cancer is the number one cause of cancer related death in women. 1,200 women between the ages of 18 and 70 from Tehran, Iran were screened by VIA and PAP smear. The women with positive findings on one or both tests underwent colposcopy. Both sensitivity and specificity for VIA were found to be higher in this study. The sensitivity of VIA was found to be 74.3% compared with 72% for PAP smear. The specificity of VIA was 94% compared to 90.2% for PAP. Ghaemmaghami concluded that sensitivity and specificity of VIA is high comparable with that of cytology making it a feasible method of screening in countries where access to cytopathology is limited.
In 2003-2004, concurrent studies were performed by the Alliance for Cervical Cancer Prevention, funded by the Bill and Melinda Gates Foundation; across the world, looking at VIA as an alternative to PAP smears for cervical cancer screening. Studies reached India, Africa and Central America; where the majority of the cervical cancer burden lies. Doh examined VIA as a screening method in Cameroon, Africa, where cancer of the breast and cervix contribute to over 45% of gynecological malignancies and is the most common cause of cancer deaths in women (Doh, International Journal of OB/Gyn 1994). All patients underwent VIA and PAP. If any of the two tests were positive, patients underwent colposcopy with biopsy and one out of ten “negative” cervices were biopsied for control. Only acetowhite lesions with at least a border close to the squamo-columnar junction was considered as significant and positive. Lesions with faint borders were considered low grade and those with sharp borders were considered high grade. Negative cervices had no white lesions. 4,813 women were screened. Sensitivity of VIA was 70.4 % vs 47.7% for PAP. VIA specificity was 77.6% vs 94.2% PAP. PPV of VIA was 44% and NPV 91.3%. Doh concluded that, although PAP has slightly better testing qualities, VIA has acceptable test qualities and may in low resource settings be implemented as a large scale screening method.
In India, Goel examined 400 women between the ages of 30-34 attending the Gyn outpatient clinic in New Delhi India. The doctors performed PAP cytology, direct visualization with acetic acid, and colposcopy on all 400 women. Goel found VIA to have a sensitivity of 96.7%, much higher than that of a PAP smear, which they found to be a mere 50%. The specificity of VIA, however, was much lower than the PAP smear, 36.4% vs. 97%. Goel found that VIA was a poor test for catching endocervical lesions, missing 2 cases in this study, and the low specificity of VIA would result in high false positive rates. Overall, Goel concluded that VIA with acetic acid is very sensitive for ectocervical lesions; with its low cost and ease of use making it very advantageous for a primary screening method in developing countries. However, it does have a high rate of false positives, which if using the “see and treat method” would lead to over-treatment.
In rural areas of Northeast Brazil, Bomfim did a similar study. 1,154 women underwent PAP smear and VIA concurrently, with colposcopy if one or both screening tests were positive. Exams were conducted by either nurses or physicians. Sensitivity of VIA was found to be 100% vs 18% for PAP smears and specificity was 78% for VIA vs 100% for PAP smears in detecting LGSIL and HGSIL. The positive predicitive value (PPV) of VIA was 15.6% for LGSIL and 2.8% for HGSIL. The negative predictive value (NPV) of VIA was much better and found to be 100% for both. PAP smear NPV was 97% and 99%. Bomfim concluded that VIA could be an excellent screening method for detecting cervical cancer and affirmed that both trained nurses and physicians would be capable of performing VIA assessment.
In urban Africa, Nairobi (Kenya), De Vuyst studied VIA comparing it to three other screening methods, including HPV DNA typing. De Vuyst had 653 women undergo four concurrent screening methods: pap smear, visual inspection with acetic acid (VIA), PCR for high risk HPV and cervicography. The gold standard for affirmative diagnosis was colposcopy and/or biopsy. Sensitivity and specificity were 83.3% and 94.6% for Pap smear, 73.3% and 80.0% for VIA, 94.4% and 73.9% for HR HPV PCR, and 72.3% and 93.2% for cervicography. Although pap smear had the highest sensitivity and HPV PCR the highest specificity, the visual inspections showed an accuracy between the two. De Vuyst concluded that in poor resource countries VIA is effective as a primary screening tool.
In 2005, after many evidence based articles substantiated VIA as an adequate screening method for cervical cancer, Lawrence went to Guatemala and implemented a pilot study in evaluating VIA with the “see and treat” method. Lawrence looked at the acceptability of cervical screening using direct visual inspection after acetic acid application followed by immediate cryotherapy for CIN among women in rural Guatemala. Lawrence and colleagues offered cervical cancer screening to 1,052 Guatemalan women using VIA. 9.3% of patients deferred screening at all and refused examination. Among the 954 women screened, 13% were found to have findings consistent with CIN I or higher. 99% of the women with positive findings agreed to undergo immediate treatment with cryotherapy. This study shows that the “see-and-treat” method with VIA could be accepted by patients in developing countries. The drawback to this study was that it did not try and confirm the results of VIA by cytology or histology and treated assuming the VIA test was accurate. However, they did note that their rate of 13% abnormalities was comparable to the numbers found in other studies in the region.
These studies have shown that VIA is an adequate and acceptable screening method for cervical cancer. Furthermore, in low-resource areas, VIA can be better than PAP smears for its ease of use and low cost. VIA confers a very high NPV, which means that when a test is negative, the women can go home reassured that she is not likely to have a neoplastic cervical lesion; eliminating the need for follow-up visits. However, the low PPV of VIA does present the problem of many false positives, discouraging the see-and-treat method. However, PPV is dependent on incidence and if a see-and-treat method were implemented in a high-risk population with a high incidence of cervical cancer, the qualities of the VIA test may improve.
Bellinson, JL., Pretorius, RG., Zhang, WH. “Cervical Cancer Screening by Simple Visual Inspection After Acetic Acid.” Obstetrics and Gynecology. 2001. 98(3). 441-444.
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De Vuyst, H. “Comparison of pap smear, visual inspection with acetic acid, HPV DNA-PCR testing and cervicography.” International Journal of Gyn and OB. 2005. 89.
Doh, A.S. “Visual Inspection with acetic acid and cytology as screening methods for cervical lesions in Cameroon.” International Journal of Gyn and OB. 2005. 89.
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Lawrence, MJ, Wigton, TR, Leonhardt, JG. “Screening for Cervical Neoplasia in an Unselected Rural Guatemalan Population Using Direct Visual Inspection after Acetic Acid Application: A pilot study.” Journal of Lower Genital Tract Disease. 2005. 9(4). 232-235.
Ngelangel, C.A. “Acetic-acid guided visual inspection vs. cytology-based screening for cervical cancer in the Phillipines.” International Journal of Gyn and OB. 2003. 83.