Dipanwita Banerjee

Study of accuracy of colposcopy in VIA and HPV detection-based cervical cancer screening program.

This population‐based study was conducted to evaluate the performance of colposcopy to assess women with positive visual inspection with acetic acid (VIA) and/or human papillomavirus (HPV) tests.

Diagnostic accuracy of VIA and HPV detection as primary and sequential screening tests in a cervical cancer screening demonstration project in India

Visual inspection after acetic acid application (VIA) and human papillomavirus (HPV) detection tests have been recommended to screen women for cervical cancer in low and middle income countries. A demonstration project in rural India screened 39,740 women with both the tests to compare their accuracies in real population setting. The project also evaluated the model of screening women in the existing primary health care facilities, evaluating the screen positive women with colposcopy (and biopsy) in the same setup and recalling the women diagnosed to have disease for treatment at tertiary center. Accuracy of VIA and HPV test used sequentially was also studied. VIA was performed by trained health workers and Hybrid Capture II (HC II) assay was used for oncogenic HPV detection. Test positivity was 7.1% for VIA and 4.7% for HC II. Detection rate of CIN 3+ disease was significantly higher with HC II than VIA. Sensitivities of VIA and HC II to detect 162 histology proved CIN 3+ lesions were 67.9 and 91.2%, respectively after adjusting for verification bias. Specificity for the same disease outcome and verification bias correction was 93.2% for VIA and 96.9% for HC II. Triaging of VIA positive women with HPV test would have considerably improved the positive predictive value (4.0 to 37.5% to detect CIN 3+) without significant drop in sensitivity. All VIA positive women and 74.0% of HC II positive women had colposcopy. There was high compliance to treatment and significant stage‐shift of the screen‐detected cancers towards more early stage.

Efficacy and safety of human papillomavirus vaccine for primary prevention of cervical cancer: A review of evidence from phase III trials and national programs

The Human Papillomavirus (HPV) vaccines have been widely introduced in the national immunization programs in most of the medium and high income countries following endorsement from national and international advisory bodies. HPV vaccine is unique and its introduction is challenging in many ways – it is the first vaccine developed to prevent any cancer, the vaccine is gender specific, it targets adolescent females who are difficult to reach by any health intervention programs. It is not unusual for such a vaccine to face scepticism and reservations not only from lay public but also from professionals in spite of the clinical trial results convincingly and consistently proving their efficacy and safety. Over the last few years millions of doses of the HPV vaccine have been administered round the world and the efficacy and safety data have started coming from the real life programs. A comprehensive cervical cancer control program involving HPV vaccination of the adolescent girls and screening of the adult women has been proved to be the most cost-effective approach to reduce the burden of cervical cancer. The present article discusses the justification of HPV vaccination in the backdrop of natural history of cervical cancer, the mechanism of action of the vaccines, efficacy and safety data from phase III randomized controlled trials as well as from the national immunization programs of various countries.

Reproducibility of cervical intraepithelial neoplasia diagnosis on histological review of cervical punch biopsies from a visual inspection with acetic acid and HPV detection-based screening program

To assess the reproducibility of cervical intraepithelial neoplasia (CIN) diagnosis in a visual inspection with acetic acid (VIA) and HPV detection‐based screening program, and to correlate CIN diagnosis with oncogenic HPV status.

Phase 2 Randomized Controlled Trial of Radiation Therapy Plus Concurrent Interferon-Alpha and Retinoic Acid Versus Cisplatin for Stage III Cervical Carcinoma

PURPOSE Because a combination of retinoic acid, interferon-alpha, and radiation therapy demonstrated synergistic action and effectiveness to treat advanced cervical cancers in earlier studies, we designed this randomized phase 2 open-label trial to assess efficacy and safety of interferon alpha-2b (IFN) and 13-cis-retinoic acid (RA) administered concomitantly with radiation therapy (IFN-RA-radiation) to treat stage III cervical cancer. METHODS AND MATERIALS Stage III cervical cancer patients were randomized to study and control groups in a 1:1 ratio. All patients were treated with radiation therapy; study arm patients received IFN (3 × 10(6) IU subcutaneously) 3 times a week for 4 weeks and daily RA (40 mg orally) for 30 days starting on day 1 of radiation, whereas control arm patients received weekly cisplatinum (40 mg/m(2)) for 5 weeks during radiation. Patients were followed for 3 years. The primary endpoint was overall survival at 3 years. RESULTS Patients in the study (n=104) and control (n=105) groups were comparable for clinicopathological characteristics, radiation therapy-related variables and treatment response. Proportions of disease-free patients in the study and control groups were 38.5% and 44.8%, respectively, after median follow-up of 29.2 months. Hazard ratios were 0.67 (95% confidence interval [CI]: 0.44-1.01) and 0.69 (95% CI: 0.44-1.06) for overall and disease-fee survival, respectively, comparing the study group to control, and demonstrated an inferior outcome with RA-IFN-radiation, although differences were statistically nonsignificant. Kaplan-Meier curves of disease-free and overall survival probabilities also showed inferior survival in the study group compared to those in the control. Acute toxicities of chemoradiation were significantly higher with 2 acute toxicity-related deaths. CONCLUSIONS Treatment with RA-IFN-radiation did not demonstrate survival advantage over chemoradiation despite being less toxic. The trends predicted an inferior outcome with the RA-IFN combination.

Association between high risk human papillomavirus infection and co-infection with Candida spp. and Trichomonas vaginalis in women with cervical premalignant and malignant lesions

BACKGROUND Human papillomavirus (HPV) is the necessary cause of cervical cancer. Cervico-vaginal infection with pathogens like Chlamydia is a likely cofactor. The interactions between HPV, Trichomonas vaginalis (TV) and Candida spp. are less understood, though inflammation induced by these pathogens has been demonstrated to facilitate oncogenesis. OBJECTIVE Our study aimed to evaluate the association between Candida spp. and TV co-infection with HPV in cervical oncogenesis. STUDY DESIGN Women with normal cervix who were high-risk HPV-negative (N=104) and HPV-positive (N=105); women with CIN 1 (N=106) and CIN 2/CIN 3 (N=62) were recruited from a community based cervical cancer screening program. Cervical cancer patients (N=106) were recruited from a tertiary care oncology clinic. High-risk HPV was detected by Hybrid Capture II technique; Candida spp. and TV were detected by culturing the high vaginal swabs followed by microscopic examination in all. The disease status was established by histopathology in all the women. RESULT HPV-positive women had significantly higher risk of having precursor lesions (of any grade) and cancer compared to HPV-negative women. Candida spp. or TV infection did not alter the risk of low grade or high grade lesions among HPV- positive women. HPV positive women co-infected with TV had higher risk of cervical cancer but not those co-infected with Candida spp. CONCLUSION The higher risk of cancer observed in the women co-infected with HPV and TV without any enhanced risk of CIN 3 suggests secondary infection of the malignant growth by TV rather than any causal role. Co-infection with Candida spp. and/or TV infection did not increase the carcinogenic effect of HPV on cervix.

Risk of high grade precancerous lesions and invasive cancers in high risk HPV positive women with normal cervix or CIN 1 at baseline – a population based cohort study

Infection with high‐risk human papillomavirus (HR‐HPV) is transient and clears on its own in majority of the women. Only a few women who have persistent infection may finally develop cervical intraepithelial neoplasia (CIN) or cervical cancer in later years. The risk of progression in the HR‐HPV‐positive women with normal cervix or low‐grade lesion on colposcopy and histopathology at baseline is less studied. We performed a longitudinal study on 650 HR‐HPV‐positive women with colposcopy and/or histopathology‐proved normal or CIN1 diagnosis at baseline to assess the cumulative risk of development of high‐grade CIN. After a mean follow‐up of 2.1 person years of observation (PYO) (range 0.1–5.1), the cumulative incidence of CIN2+ (6.4%; 3.0/100 PYO) was significantly higher in women who had persistent HR‐HPV infection compared to those who cleared the infection (adjusted HR 6.28; 95% CI 2.87–13.73). The risk of viral persistence in women aged 50–60 years was two times higher compared to women aged 40–49 years and three times higher compared to women aged 30–39 years. The probability of having persistent infection increased progressively with higher viral load at baseline (adjusted HR 3.29, 95% CI 2.21–4.90 for RLU ≥100; adjusted HR 2.69, 95% CI 1.71–4.22 for RLU 10–100). Women with increasing viral load at follow‐up had four times higher risk of developing CIN2 or worse lesions as compared to those with decreasing load (20.9% vs 4.8%; p < 0.001). In the context of developing countries where cytology or genotyping triaging is not feasible, colposcopy referral of HR‐HPV‐positive women with advancing age, viral persistence, and increasing viral load may be considered.

Sensitivity of APTIMA HPV E6/E7 mRNA test in comparison with hybrid capture 2 HPV DNA test for detection of high risk oncogenic human papillomavirus in 396 biopsy confirmed cervical cancers

The sensitivity of E6/E7 mRNA‐based Aptima HPV test (AHPV; Hologic, Inc.) for detection of cervical cancer has been reported based on only a small number of cases. We determined the sensitivity of AHPV in comparison with the DNA‐based Hybrid Capture 2 HPV test (HC2; Qiagen) for the detection of oncogenic HPV in a large number of cervical cancers at the time of diagnosis using cervical samples obtained in ThinPrep (Hologic). Samples yielding discordant results were genotyped using Linear Array assay (LA; Roche). Of 396 cases tested, AHPV detected 377 (sensitivity, 95.2%; 95%CI: 93.1–97.3), and HC2 376 (sensitivity, 94.9%; 95%CI: 92.7–97.1) with an agreement of 97.2% (kappa 0.7; 95%CI: 0.54–0.87). Among six AHPV+/HC2‐ cases, LA identified oncogenic HPV types in four including a type 73 and was negative in two. Among five AHPV‐/HC2+ cases, LA detected oncogenic HPV types in two including a type 73 and was negative in three. Of 14 AHPV‐/HC2‐ cases, 13 were genotyped. LA detected oncogenic HPV types in six, non‐oncogenic types in three, and was negative in four. This is the largest study to demonstrate the sensitivity of AHPV for the detection of invasive cervical cancer and this assay showed equal sensitivity to HC2. J. Med. Virol. 88:1271–1278, 2016.

Study of Correlation of Cervical Epithelial Thickness With the Grade of Colposcopic Abnormality.

Low epithelial thickness has been identified as the cause for nonvisualization of high-grade cervical intraepithelial neoplasia (CIN) on colposcopy in an earlier study. Multiple random biopsies are recommended by some authors to detect these “thin” CIN lesions in absence of colposcopic abnormalities. The present study was conducted to evaluate the correlation between the severity of colposcopic impression and the thickness of the epithelium so that the results of previous study could be validated. The cross-sectional study examined 209 histopathology slides with normal, human papillomavirus, or CIN diagnosis from a population-based study. Average epithelial thickness was measured by obtaining mean of the thicknesses at thinnest and thickest areas. Average thickness of dysplastic layer was also measured. These values were correlated with age, human papillomavirus status, colposcopic appearance and histopathology. Mean epithelial thicknesses were 212.8 &mgr;m for normal (N=28), 297.3 &mgr;m for human papillomavirus changes (N=48), 245.3 &mgr;m for CIN1 (N=46), 191.4 &mgr;m for CIN2 (N=50), and 218.5 &mgr;m for CIN3 (N=37). Within each histologic category, no correlation was observed between epithelial thickness and severity of colposcopic appearance. Mean epithelial thickness of CIN1/CIN2 lesions with normal colposcopy was more than that of CIN1/CIN2 lesions with high-grade appearance on colposcopy. Thickness of CIN3 lesions with high-grade abnormalities was higher than those without visible colposcopic abnormality but the difference was not statistically significant. Thickness of dysplasia increased with higher grades of CIN but did not have any relation to colposcopic appearance. Colposcopic appearance does not depend on the thickness of the epithelium affected by CIN. False-negative colposcopy in presence of high-grade CIN is likely due to failure of detecting small or predominantly endocervical lesions rather than “thin” CIN.

Implications of semi-quantitative HPV viral load estimation by Hybrid capture 2 in colposcopy practice

Objective High viral load of oncogenic human papillomavirus (HPV) significantly increases risk of CIN 2 or worse (CIN 2+) lesions. Semi-quantitative estimation of oncogenic HPV viral load by Hybrid Capture 2 (HC2) correlates well with viral load estimated by real-time polymerase chain reaction. We correlated viral load estimated by HC2 with colposcopy and histology diagnosis, to determine if high viral load could detect the CIN 2+ lesions missed by colposcopy in HPV positive women. Methods Using HPV testing by HC2, 39,728 women were screened. Positive results were categorized into low-positive, intermediate, and high viral load groups, based on relative light unit/cut-off ratios. HPV-positive and some HPV-negative women underwent colposcopy and biopsy. Results A total of 278 CIN 2+ lesions were detected. Detection rate of CIN 2+ was significantly higher in intermediate and high viral load groups. Nearly half (48.3%) of CIN 2+ and 80.4% of CIN 3+ lesions missed or under-diagnosed by colposcopy had viral load in intermediate to high ranges. Risk of CIN 2+ in the high viral load group was 46 times higher than HPV-negative women, even when colposcopy was apparently normal. Discussion Women with intermediate or high viral load should have multiple punch biopsies, even if colposcopy is apparently normal or suggests low grade lesions. Women with high viral load and suspected low grade lesion on colposcopy may be considered for ‘see-and-treat’, as their risk of CIN 2+ is nearly 200 times higher than HPV-negative women.