Evaluation of cytology and visual triage of human papillomavirus-positive women in cervical cancer prevention in India.

Although virtually all cervical cancers and most cervical intraepithelial neoplasia (CIN) are caused by persistent human papillomavirus (HPV) infection, only a small proportion of HPV-positive women have or will develop CIN. Triaging HPV-positive women has been suggested to reduce the false-positive rate and proportion of women referred for CIN confirmation and/or treatment. In two cross-sectional studies and one randomized trial in India, we evaluated the impact of using cytology or visual inspection with acetic acid (VIA) to triage HPV-positive women on the proportion of women who would be referred for CIN confirmation and on the detection rates of high-grade CIN. We present the numbers of HPV test-positive women found and the CIN detected among them. We further assess the proportions that would be referred for CIN confirmation with colposcopy/biopsy and CIN that would be detected if cytology triage or VIA triage were used. Using cytology triage at atypical squamous cells of undetermined significance threshold or VIA triage reduced referrals for colposcopy by about 62% and 59%, respectively (p-value = 0.012), but missed around 16% and 18%, respectively, of the high-grade CIN (p-value = 0.539) indicating similar performance of both triaging approaches. The choice of a triage test in different low- and middle-income countries (LMIC) would depend on the availability and affordability in the particular setting. Cytology triage may be considered in settings where adequate infrastructure exists, whereas VIA triage may be suitable in settings with limited or no cytology infrastructure.

A case-control nutrigenomic study on the synergistic activity of folate and vitamin B12 in cervical cancer progression.

The present study was designed to identify the role of folate, B12, homocysteine, and polymorphisms of methylene tetrahydrofolatereductase (MTHFR) gene in cervical carcinogenesis among 322 women from Kerala, South India. Serum folate, vitamin B12 (chemiluminescence assay), and homocysteine (EIA) along with genetic polymorphisms of MTHFR gene (polymerase chain reaction/restriction fragment length polymorphism) were analyzed for 136 control subjects, 92 low-grade squamous intraepithelial lesions (LSIL) subjects, and 94 invasive cervical cancer cases (ICC). Statistically significant associations between MTHFR polymorphisms, serum homocysteine, and folate levels with cervical carcinogenesis were not evident, but we found that these parameters acted as effect modifiers of serum vitamin B12. The risk estimates observed for B12 became prominent only when there was a deficiency in serum folate levels [LSIL-odds ratio (OR): 14.9 (95% CI: 2.65 to 84.4); ICC-OR = 8.72 (95% CI = 1.55 to 48.8)] or when MTHFR A1298C polymorphic variant was present [LSIL-OR = 9.8 (95% CI = 2.61 to 36.7); ICC-OR = 10.0 (95%CI = 2.5 to 39.3)]. The statistical significance of this effect modification was further studied using an interaction model, where only folate was observed to have an influence on B12 levels as suggested by the odds ratio of 7.11 (95% CI = 0.45 to 111.9) obtained for ICC group, implicating a synergistic role of these 2 vitamins in invasive cervical cancer.

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.

Effectiveness and safety of loop electrosurgical excision procedure in a low-resource setting.

OBJECTIVE: To evaluate the effectiveness and safety of the loop electrosurgical excision procedure (LEEP) to treat cervical intraepithelial neoplasia (CIN) in a low-resource setting. METHODS: Women participating in a cervical screening study in India with histologically confirmed CIN unsuitable for cryotherapy were advised to undergo LEEP. One year after treatment the cervix was visually inspected with acetic acid, followed by colposcopy and biopsy taken from abnormal areas. Cure was defined as no clinical or histologic evidence of CIN. Factors influencing cure rates were evaluated by chi(2) tests. RESULTS: Of the 311 women who underwent LEEP, 283 reported for 1-year follow-up and 248 (87.6%) were disease free. Cure rates were 93.0% for CIN 1, 85.5% for CIN 2, and 72.7% for CIN 3. Minor adverse effects were observed in 34 women and complications were seen in 5 women. CONCLUSION: LEEP was associated with minimal complications and acceptable cure rates in a low-resource setting, although women with larger lesions had lower cure rates.

Assessing the gain in diagnostic performance when two visual inspection methods are combined for cervical cancer prevention.

OBJECTIVES: The objectives of this study was to establish whether combined screening with visual inspection with acetic acid (VIA) and Lugol's iodine (VILI) improves detection of cervical intraepithelial neoplasia 2-3 (CIN 2-3) lesions and cancer beyond chance, compared with screening with VIA alone or VILI alone; and to estimate the extra number of false-positive (FP) results per additional disease case found with the combined test, and to estimate the additional costs involved. SETTING: Ten cross-sectional studies in Burkina Faso, Congo, Guinea, India, Mali and Niger, between 1999 and 2003. METHODS: Using a common protocol, health workers screened 56,147 women aged 25-65 years with VIA and VILI. All women underwent a colposcopy examination and biopsies were taken when necessary. The disease reference standard was histology or negative colposcopy. A positive result on the combined test was defined if either VIA or VILI were positive. The accuracy of the combined test compared with VIA alone or VILI alone was evaluated using likelihood ratios. RESULTS: The estimated sensitivity and specificity were 81.3% and 87.3%, respectively, for VIA; 91.5% and 86.9% for VILI; and 92.9% and 83.5% for the combined test. The ratio of the positive likelihood ratios of the combined test and VIA alone for CIN 2-3 lesions and cancer was 0.88 (95% confidense interval [CI]: 0.86-0.90), favouring use of VIA alone. The ratio of the negative likelihood ratios was 0.40 (95% CI: 0.37-0.47), favouring use of the combined test. Similar results were obtained when the combined test was compared with VILI alone. Assuming equivalent performance of VIA alone and the combined test with a disease prevalence of 2%, there will be about 16.0 (95% CI: 13.6-18.8) additional FPs for each additional true positive (TP) detected if the combined test is used. This number will be 121.1 (95% CI: 75.4-194.6) if VILI is considered as the single test. CONCLUSIONS: At the trade-off point between the combined test and VIA alone or VILI alone, given the numbers of additional FP results involved for each additional TP case of disease that were found, it would be more likely that settings already using VIA would advocate combined testing, and for settings using VILI to opt for the single test. The additional costs (per 1000 women) incurred with the combined test would be International 4117.68 dollars versus either of the tests above.

Effectiveness of cryotherapy for histologically confirmed cervical intraepithelial neoplasia grades 1 and 2 in an Indian setting.

OBJECTIVE: To describe the effectiveness of cryotherapy for treating women who were histologically confirmed to have cervical intraepithelial neoplasia (CIN) in India. METHODS: Data were analyzed retrospectively from screening projects that collected data from January 2001 to May 2008 in Trivandrum, India. Women with CIN were appropriately treated with cryotherapy by a trained nurse or physician and followed up for cure, adverse events, and complications. Cure was defined as absence of CIN during any follow-up visit at least 1 year after treatment. RESULTS: Among 236 women identified with CIN and appropriately treated with cryotherapy, 173 (81.6%) were followed up (158 CIN 1 and 15 CIN 2 cases). The percentage cure for CIN 1 and 2 lesions was 93.0% and 86.7% respectively. An odds ratio of 0.2 (95% confidence interval, 0.0-0.9) was observed for treatment received more than 2 months after screening as compared with treatment received within 2 months. Complications were observed in 1.2% of treated women and adverse events (discharge and mild pain) in 26.6%. CONCLUSION: The study affirms that trained mid-level providers can appropriately perform cryotherapy in primary healthcare services and that expanding such services in low-resource settings would increase the availability and accessibility of precancer treatment.

Accuracy of visual inspection with acetic acid for cervical cancer screening.

OBJECTIVE: To provide an updated estimation of the accuracy of visual inspection with acetic acid (VIA) in detecting true disease. METHODS: A PubMed search provided original studies on VIA accuracy in which the gold standard for confirmatory testing was histology alone or colposcopy followed by biopsy. The numbers of true-positive, false-positive, false-negative, and true-negative results were extracted from each study. Meta-analyses were then performed with different categories of studies according to confirmatory diagnosis threshold, category of women who received confirmatory testing, and whether a medical condition that could affect VIA accuracy was present at screening. The reference category consisted of 26 studies in which VIA was performed on asymptomatic women who all underwent confirmatory testing and in which the disease threshold was cervical intraepithelial neoplasia grade 2. RESULTS: We report an 80% sensitivity (range, 79%-82%) and a 92% specificity (range, 91%-92%) for VIA. Study region, capacity of screener, or size of the study population did not modify VIA accuracy. The positive predictive value was 10% (range, 9%-10%). CONCLUSION: Screening for precancerous and cancerous cervical lesions using VIA is a simple, low-cost, and efficient alternative to cytologic testing in low-resource areas.

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.

Accuracy of human papillomavirus testing in primary screening of cervical neoplasia: results from a multicenter study in India.

The knowledge that cervical neoplasia are caused by human papillomavirus (HPV) infection has led to the evaluation of its role in screening. We evaluated the accuracy of HPV testing by Hybrid capture II (HC II) method in detecting cervical intraepithelial neoplasia grade 2 and 3 (CIN 2 and 3) lesions in 4 cross-sectional studies with common protocol and questionnaire in 3 different locations (Kolkata, Mumbai and Trivandrum) in India. These studies involved 18,085 women aged 25-65 years. The reference standard for final diagnosis was a combination of colposcopy/biopsy. All women were investigated with colposcopy and 3,116 received directed biopsy. The sensitivity of HPV testing for detecting CIN 2-3 lesions varied from 45.7% to 80.9% across the study sites; the specificity varied from 91.7% to 94.6% and the positive predictive value from 6.7% to 13.7%. Retesting of 298 randomly chosen denatured samples in France revealed an agreement rate of 85.9% and a kappa-value of 0.72. Although HPV testing seems to be a promising approach for cervical cancer prevention, a large range in sensitivity was observed in our study, possibly due to variations in the quality of specimen collection and reference standards. A higher sensitivity was associated with the center performing the test well. Further developments in terms of more reproducible, less expensive and less sophisticated testing are essential to make the test feasible and effective in low-resource settings.

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.