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Obstetrics & Gynecology 2001;98:441-444
© 2001 by The American College of Obstetricians and Gynecologists
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ORIGINAL RESEARCH

Cervical Cancer Screening by Simple Visual Inspection After Acetic Acid

J. L. Belinson, MD, R. G. Pretorius, MD, W. H. Zhang, MD, L. Y. Wu, MD, Y. L. Qiao, MD, PhD and P. Elson, PhD

From the Departments of Gynecology and Obstetrics, and Biostatistics, The Cleveland Clinic Foundation, Cleveland, Ohio; Department of Obstetrics and Gynecology, Division of Gynecologic Oncology and Pelvic Surgery, Kaiser Permanente, Fontana, California; and The Cancer Institute/Hospital, Chinese Academy of Medical Sciences, Beijing, China.

Address reprint requests to: Jerome L. Belinson, MD, Cleveland Clinic Foundation, 9500 Euclid Avenue, A-81, Cleveland, OH 44195; E-mail: belinsj{at}ccf.org.


   ABSTRACT
TOP
ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
OBJECTIVE: To estimate the sensitivity and specificity of visual inspection using acetic acid as a primary screen for cervical intraepithelial neoplasia (CIN).

METHODS: Visual inspection was done on 1997 women aged 35–45 years in a screening trial in rural China. Each women had colposcopy and at least five cervical biopsies (directed biopsy of lesions, one biopsy at 2, 4, 8, or 10 o’clock at the squamocolumnar junction in each normal quadrant, and an endocervical curettage).

RESULTS: Forty-three women had biopsy-proven CIN II, 31 had CIN III, and 12 had invasive cancer. In two women only the endocervix was positive (one with CIN II and one with CIN III). Visual inspection yielded normal results in 1445 women (72%), low-grade intraepithelial neoplasia in 525 (26%), high-grade in 21 (1%), and cancer in six (0.3%). With abnormal visual inspection defined as low-grade intraepithelial neoplasia or worse, the sensitivity for detecting biopsy proven CIN II or worse was 71% (61 of 86, 95% confidence interval [CI] 60%, 80%); the specificity was 74% (1420 of 1911, 95% CI 72%, 76%); the sensitivity was 65% for smaller lesions (37 of 57, 95% CI 51%, 77%), and 89% for larger lesions (24 of 27, 95% CI 71%, 98%) (P = .03).

CONCLUSION: The sensitivity of visual inspection equaled or exceeded reported rates for conventional cervical cytology. Visual inspection and colposcopy have similar specificity profiles for CIN II and greater. The benefit of an inexpensive point-of-care diagnosis and treatment algorithm will be a powerful incentive to pursue visual inspection for cervical cancer screening in developing countries.

The prevalence of cervical cancer varies widely between and within regions throughout the world1,2; this variance is attributable in part to the variable access to cytologic screening programs to detect and treat preinvasive disease of the cervix.3,4 The infrastructure and the financial resources required to develop and maintain a cytologic screening program are beyond reach for most developing countries. Cytology screening programs have been proposed to reduce costs that would be directed to specific age groups at less frequent intervals than the annual to triannual screening frequently done in the developed world.5 Alternative noncytologic methods for screening have also received considerable study in the search for a solution to reduce cervical cancer rates worldwide.6–21

The Shanxi Province cervical cancer screening study was designed to determine the best possible estimate of sensitivity and specificity of six screening technologies for preinvasive and invasive cervical cancer.19 Visual inspection using acetic acid was included because of its known potential as a low-cost screening technique.8,9,11–13,15 We evaluated the accuracy of visual inspection to further define its potential role for primary screening.


   MATERIALS AND METHODS
TOP
ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
The human subject review boards of both the Cleveland Clinic Foundation and the Cancer Institute/Hospital of the Chinese Academy of Medical Sciences approved the study. Acetic acid (5%) was applied to the cervix and, after waiting 1 minute, the cervix was inspected using a single 100-watt tungsten bulb in a goose-neck style light. A normal cervix had no white lesions. A diagnosis of low-grade cervical intraepithelial neoplasia (CIN) showed pale white lesions that might or might not abut the squamocolumnar junction. Areas defined as high-grade CIN had dense white lesions with sharp borders; one border of these high-grade lesions always abutted the squamocolumnar junction. Cancer was diagnosed when a friable mass with an irregular surface was seen. Gynecologic oncology fellows and younger gynecologic oncology staff from China did the visual inspection. All had experience with visual inspection during the pilot study. We believed that this was the appropriate model for this study because our goal was to determine the baseline sensitivity and specificity of the screening technologies for cervical cancer in a high-risk population.

The criterion standard for our trial was cervical biopsy. Colposcopic evaluation and biopsy were done on all subjects. Standard colposcopic criteria were used with the exception that when there was a question of metaplasia versus low-grade CIN, lesions were classified as low grade.22,23 If colposcopy showed no abnormalities in a quadrant, a biopsy was taken from that quadrant at 2, 4, 8, or 10 o’clock on the exocervix at the squamocolumnar junction depending on the quadrant. If there were abnormalities, it was acceptable to take more than one biopsy per quadrant. All biopsies were done with a bronchoscopy biopsy instrument that had 2-mm jaws and is virtually painless for most patients. An endocervical curettage (ECC) was also done on every patient.

The physicians who did the colposcopies and biopsies were masked to the visual inspection results. The biopsies were fixed in formalin, stained with hematoxylin and eosin, and interpreted according to established histologic criteria.24,25 The number of quadrants with biopsy-proven CIN II or worse was used as a surrogate for lesion size. Exact 95% confidence intervals (CI) or upper confidence bounds based on the binomial distribution were calculated for all estimates of sensitivity, specificity, and positive and negative predictive values. Sensitivity between groups of subjects was compared using Fisher exact test. McNemar test was used to compare the sensitivity of visual inspection and colposcopy.


   RESULTS
TOP
ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Among 1997 women screened, 43 had biopsy-proven CIN II, 31 had CIN III, and 12 had invasive cancer. Thirty-nine women had biopsies with at least CIN II in one quadrant, 18 had at least CIN II in two quadrants, 10 had at least CIN II in three, and 17 had at least CIN II in four quadrants, and two had no ectocervical lesion (they had only ECC positive for CIN II and CIN III). Visual inspection was done on all 1997 women in the study. The visual inspection results were normal in 1445 women (72%), low-grade in 525 (26%), high-grade in 21 (1%), and cancer in six (0.3%). With abnormal visual inspection defined as low-grade or worse, the sensitivity for at least CIN II was 71% (61of 86, 95% CI 60%, 80%). The specificity was 74% (1420 of 1911, 95% CI 72%, 76%). The positive predictive value was 11% (61 of 552, 95% CI 9%, 14%). The negative predictive value was 98% (1420 of 1445, 95% CI 97.6%, 98.9%). The sensitivity for at least CIN III was 79% (34 of 43, 95% CI 64%, 90%), and it was 67% (8 of 12, 95% CI 35%, 90%) for cancer. For lesions involving one or two quadrants of the ectocervix on biopsy, the sensitivity of visual inspection was 65% (37of 57, 95% CI 51%, 77%); for lesions involving three or four quadrants it was 89% (24 of 27, 95% CI 71%, 98%)(P = .03).

Colposcopy had a sensitivity of 81% (70 of 86, 95% CI 72%, 89%) (P = .04 compared with visual inspection) and a specificity of 77% (1462 of 1911, 95% CI 75%, 78%) for high-grade disease. The sensitivity for at least CIN III was 91% (39 of 43, 95% CI 78%, 98%) (P = .10) compared with visual inspection, and it was 100% (12 of 12, 95% upper confidence bounds 78%) for cancer (P = .13 compared with visual inspection). Positive and negative predictive values for high-grade disease were 14% (70 of 519, 95% CI 11%, 17%) and 99% (1462 of 1478, 95% CI 98.4%, 99.4%), respectively.

Visual inspection and colposcopy each was unreliable when only one quadrant was involved. Despite this, visual inspection correctly identified 67–100% of the subjects with two or more quadrants involved. Colposcopy on the other hand, correctly identified all such subjects (Tables 1Go and 2Go).


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  		Table 1. Visual Inspection Versus Biopsy
 

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  		Table 2. Sensitivity of Visual Inspection and Colposcopy as a Function of Lesion Size*
 

   DISCUSSION
TOP
ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Early efforts at nonmagnified visual diagnosis of cervical cancer did not use acetic acid. The technique was not specific enough to be practical, especially if a see-and-treat algorithm were to be considered. In addition, the focus was on downstaging cancers at detection rather than the detection of preinvasive disease.6,7,15 The practical aspect of dealing with the complexities of treating cancers as opposed to preinvasive disease led to efforts that would be more sensitive to detect precancers.

Visual inspection after applying acetic acid to the cervix appears to be an improvement in the prior techniques. First reported by Ottaviano and La Torre in 1982,10 visual inspection could identify the transformation zone and detect acetowhite changes identified as abnormal. Visual inspection is easy to learn, possibly easier than the proper placement of a vaginal speculum, especially in heavier women. However, there is much to be learned concerning the most effective techniques for training nonphysician heath care providers in visual inspection.

Our sensitivity (71%) and specificity (74%) for high-grade disease (including the two women positive by ECC only) are comparable to those of The University of Zimbabwe and Johns Hopkins study (76.7% and 64.1%, respectively).9 Using similar criteria Megavand et al13 reported a sensitivity of 64%. Le et al14 found 15% more abnormal cases detected by visual inspection compared with conventional cytology. Sankaranarayanan et al8 reported superior results with visual inspection, detecting 90.1% of the cases with high-grade disease with a qualified specificity (limited biopsies) of 92.2%.

Several variables affect the performance of visual inspection. Most importantly, visual inspection, like colposcopy, is more difficult with small lesions that are limited to one quadrant. Fortunately, small lesions tend to be less severe.26–28 In India, where they have extensive experience with visual inspection, Sehgal identified four important variables that affect visual inspection. First, the source of light should be white, coherent, condensed light around 6000K to provide the most definition. The 100-watt tungsten light we used produces yellow light. Unfortunately, when a light source is available it is usually not a halogen-type source to provide the ideal white light. Second, the thoroughness of training will affect performance directly. We intentionally used physicians familiar with colposcopy to maximize the capabilities of visual inspection. That assumption might not be true. Third, performance is influenced by the epidemiology of the population (eg, diet, hygiene, cultural practices). Fourth, the presence of inflammation, infection, and metaplasia affects the results (Sehgal A. Screening of uterine cervical cancer using VI-aided and unaided, and colposcopic screening. Presented at the National conference on early detection of cervical cancer—Alternative strategies. Jan 6–8, 2001, Delhi, India).

The human and financial resources available in a country or region of a country will determine what screening tests are performed and who will perform them. Visual inspection is likely to assume a central role in prevention of cervical cancer in many parts of the world because it does not require technical supplies and it allows diagnosis and treatment at a single visit.

Increased technology in itself does not guarantee significant improvement in detection of disease. In our study, colposcopy and visual inspection had similar specificity profiles. Findings such as this are empowering, because in developing countries, technical supplies are the dominant component of the cost structure, whereas labor costs overwhelm expenses in developed countries. When compared with other screening options (eg, Papanicolaou smears or human papillomavirus tests), visual inspection requires fewer technical supplies. The labor costs associated with visual inspection depend on who performs the screening. In China there might be enough gynecologists to do visual inspection; in other parts of the world nurses would be more appropriate. Visual inspection will likely assume a central position in many developing countries that lack an infrastructure on which to develop a recall system. Although often difficult in developed countries, identifying and recalling patients with abnormal screening tests in developing countries is frequently impossible.

The effectiveness of visual inspection in preventing cervical cancer remains to be determined by properly defined clinical trials. The sensitivity of visual inspection equals or exceeds reported rates for conventional cervical cytology. Visual inspection and colposcopy have similar specificity profiles for CIN II and greater. The benefits of low cost, ease of implementation, and a point-of-care diagnosis and treatment algorithm will be powerful incentives for developing countries to pursue visual inspection as a screening procedure for cervical cancer.


   Footnotes
 
Supported by Taussig Cancer Center Cleveland Clinic Foundation, Cleveland, Ohio; Cancer Institute/Hospital, Chinese Academy of Medical Sciences, Beijing, China; Terry Fox Foundation, Burnaby, British Columbia; Transamerica Corporation, San Francisco, California; Digene Corporation, Gaithersburg, Maryland; Cytyc Corporation, Boxborough, Massachusetts; Optical Biopsy Tech, LLC., Knoxville, Tennessee; and Carl Zeiss Inc., Thornwood, New York.

PII S0029-7844(01)01454-5

Received November 2, 2000. Received in revised form April 27, 2001. Accepted May 4, 2001.


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 DISCUSSION
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1. Parkin DM. Cancer incidence in five continents. Vol. VII. No. 143. Lyon, France: IARC Scientific Publications, 1997.

2. Pisani P, Parkin DM, Bray F, Ferlay J. Estimates of the worldwide mortality from 25 cancers in 1990. Int J Cancer 1999;83:18–29.[Medline]

3. DeMay RM. Common problems in Papanicolaou smear interpretation. Arch Pathol Lab Med 1997;121: 229–38.[Medline]

4. Laara E, Day NE, Hakama M. Trends in mortality from cervical cancer in the nordic countries: Association with organized screening programmes. Lancet 1987;1247–9.

5. World Health Organization. Control of cancer of the cervix: A WHO meeting. Bull World Health Organ 1986; 64:607–18.[Medline]

6. Nene BM, Deshpande S, Jayant K, Budukh A, Dale P, Deshpande D, et al. Early detection of cervical cancer by visual inspection: A population-based study in rural India. Int J Cancer 1997;68:770–3.

7. Wesley R, Sankaranarayanan R, Mathew B, Chandralekha B, Beegum A, Amma NS, et al. Evaluation of visual inspection as a screening test for cervical cancer. Br J Cancer 1997;75:436–40.[Medline]

8. Sankaranarayanan R, Wesley R, Somanathan T, Dhakad, N, Shyamalakumary B, Amma N, et al. Visual inspection of the uterine cervix after the application of acetic acid in the detection of cervical carcinoma and its precursors. Cancer 1998;83:2150–6.[Medline]

9. University of Zimbabwe/JHPIEGO Cervical Cancer Project. Visual inspection with acetic acid for cervical-cancer screening: Test qualities in a primary-care setting. Lancet 1999;353:869–73.[Medline]

10. Ottaviano M, La Torre P. Examination of the cervix with the naked eye using acetic acid test. Am J Obstet Gynecol 1982;143:139–42.[Medline]

11. Stjernsward J, Eddy D, Luthra UK, Stanley K. Plotting a new course for cervical cancer screening in developing countries. World Health Forum 1987;8:42–5.

12. Cecchini S, Bonardi R, Mazzotta A, Grazzini G, Iossa A, Ciatto S. Testing cervicography and visual inspection as screening tests for cervical cancer. Tumori 1993;79:22–5.[Medline]

13. Megavand E, Denny L, Dehaeck K, Soeters R, Bloch B. Acetic acid visualization of the cervix: An alternative to cytologic screening. Obstet Gynecol 1996;88:383–5.[Abstract]

14. Le LV, Broekhuizen F, Janzer-Steele R, Behar M, Samter T. Acetic acid visualization of the cervix to detect cervical cancer. Obstet Gynecol 1993;81:293–5.[Abstract/Free Full Text]

15. Singh V, Sehgal A, Luthra U. Screening for cervical cancer by direct inspection. BMJ 1992;304:534–5.

16. Schiffman M, Herrero R, Hildesheim A, Sherman ME, Bratti M, Wacholder S, et al. HPV DNA testing in cervical cancer screening results from women in a high-risk province in Costa Rica. JAMA 2000;283:87–93.[Abstract/Free Full Text]

17. Kuhn L, Denny L, Pollack A, Lorincz A, Richart RM, Wright TC. Human papillomavirus DNA testing for cervical cancer screening in low-resource settings. J Natl Cancer Inst 2000;92:818–25.[Abstract/Free Full Text]

18. Serwadda D, Wawer M, Shah K. Use of a hybrid capture assay of self-collected vaginal swabs in rural Uganda for detection of human papillomavirus. J Infect Dis 1999;180: 1316–9.[Medline]

19. Belinson J, Qiao Y, Pretorius R, Zhange W, Keaton K, Elson P, et al. Prevalence of cervical cancer and the feasibility of screening in rural China: A pilot study for the Shanxi Province cervical cancer screening study. Int J Gynecol Cancer 1999;9:411–7.[Medline]

20. Chirenje ZM, Chipato T, Kasule J, Rusakaniko S, Gaffikin L, Blumenthal P, et al. Visual inspection of the cervix as a primary means of cervical cancer screening: Results of a pilot study. Cent Afr J Med 1999;45:30–3.[Medline]

21. Sellors JW, Lorincz AT, Mahony JB, Mielzynska I, Lytwyn A, Roth P, et al. Comparison of self-collected vaginal, vulvar and urine samples with physician-collected cervical samples for human papillomavirus testing to detect high-grade squamous intraepithelial lesions. Can Med Assoc J 2000;163:513–8.[Abstract/Free Full Text]

22. Coppleson M, Pixley E, Ried B. Colposcopy. 3rd ed. Springfield, Illinois: Charles C Thomas, 1986.

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24. Fu YS, Reagan JW. Pathology of the uterine cervix, vagina, and vulva. Philadelphia: W.B. Saunders, 1989.

25. Fu YS, Reagan JW, Richart RM. Definition of precursors. Gynecol Oncol 1981;12:S220–31.[Medline]

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