Impact of immunosuppression and region of birth on risk of cervical intraepithelial neoplasia among migrants living with HIV in Sweden

Little is known about the incidence and risk of cervical intraepithelial neoplasia (CIN) grade 3, adenocarcinoma in situ and invasive cervical cancer (CIN3+) among migrants living with HIV in a European setting. We assessed the cumulative incidence (CuI) and hazard ratio (HR) of CIN2+ and CIN3+ in a cohort of women living with HIV (WLWH) (n = 893) identified from the Swedish national HIV register and HIV‐negative women (n = 205,842) identified from the Swedish Population Register, matched on region of birth and age. Data was collected between 1993 and 2011 by linking our cohort with the Swedish National Cervical Screening Registry, collecting all cytological and histological results since 1993. The CuI of CIN3+ was 13.1% [95% confidence interval (CI) 8.9–17.2] for WLWH and 2.1% (95% CI 2.0–2.2) for HIV‐negative after 18 years of follow‐up. WLWH had more than eight times higher, age and region of birth matched, risk of CIN3+ than HIV‐negative (HR 8.8: 95% CI 6.9–11.3). WLWH born in the East region, dominated by Thai women, had a two times higher risk of CIN3+ compared with WLWH born in Sweden (HR 2.47: 95% CI 1.2–5.0), which remained after adjusting for immunosuppression. Our results showed a substantially increased risk of CIN3+ among WLWH, which differed depending on birth region. Early HIV diagnosis and attendance to cervical cancer screening, with focus on migrants, is of crucial importance to minimize the incidence of cervical intraepithelial neoplasia.     

Can we increase the cervical cancer screening interval with an HPV test for women living with HIV? Results of a cohort study from Maharashtra,India

We are reporting (a) updated incidence of cervical intraepithelial neoplasia (CIN) among women who did not have colposcopic or histopathological disease at baseline and (b) disease outcomes among women treated for CIN and their follow-up HPV status; in a cohort of women living with HIV (WHIV). The median overall follow-up was 3.5 years (IQR 2.8-4.3). The incidence of any CIN and that of CIN 2 or worse disease was 16.7 and 7.0 per 1000 person-years of observation (PYO), respectively. Compared with women who were HPV negative at baseline, women who cleared HPV infection had 23.95 times increased risk of incident CIN 2 or worse lesions (95% CI 2.40-661.07). Women with persistent HPV infection had 138.18 times increased risk of CIN 2 or worse lesions (95% CI 20.30-3300.22). Complete disease regression was observed in 65.6% of the HPV positive women with high-grade CIN and were treated with thermal ablation but HPV persistence was seen in 44.8% of those with high-grade disease. Among those who did not have any disease at baseline and were also HPV negative, about 87% (95% CI 83.79-89.48) women remained HPV negative during consecutive HPV test/s with the median interval of 3.5 years. Long-term surveillance of WHIV treated for any CIN is necessary for the prevention of cervical cancer among them. Our study provides an early indication that the currently recommended screening interval of 3 to 5 years among WHIV may be extended to at least 5 years among HPV negative women. Increasing the screening interval can be cost saving and improve scalability among WHIV to support WHO's cervical cancer elimination initiative.     

Prevalence of human papillomavirus and cervical intraepithelial neoplasia in China: A pooled analysis of 17 population-based studies

High-risk (HR) human papillomavirus (HPV) prevalence has been shown to correlate well with cervical cancer incidence rates. Our study aimed to estimate the prevalence of HR-HPV and cervical intraepithelial neoplasia (CIN) in China and indirectly informs on the cervical cancer burden in the country. A total of 30,207 women from 17 population-based studies throughout China were included. All women received HPV DNA testing (HC2, Qiagen, Gaithersburg, MD), visual inspection with acetic acid and liquid-based cytology. Women positive for any test received colposcopy-directed or four-quadrant biopsies. A total of 29,579 women had HR-HPV testing results, of whom 28,761 had biopsy confirmed (9,019, 31.4%) or assumed (19,742, 68.6%) final diagnosis. Overall crude HR-HPV prevalence was 17.7%. HR-HPV prevalence was similar in rural and urban areas but showed dips in different age groups: at age 25–29 (11.3%) in rural and at age 35–39 (11.3%) in urban women. In rural and urban women, age-standardized CIN2 prevalence was 1.5% [95% confidence interval (CI): 1.4–1.6%] and 0.7% (95% CI: 0.7–0.8%) and CIN3+ prevalence was 1.2% (95% CI: 1.2–1.3%) and 0.6% (95% CI: 0.5–0.7%), respectively. Prevalence of CIN3+ as a percentage of either all women or HR-HPV-positive women steadily increased with age, peaking in 45- to 49-year-old women. High prevalence of HR-HPV and CIN3+ was detected in both rural and urban China. The steady rise of CIN3+ up to the age group of 45–49 is attributable to lack of lesion removal through screening. Our findings document the inadequacy of current screening in China while indirectly raising the possibility that the cervical cancer burden in China is underreported.     

A prospective study of high-grade cervical neoplasia risk among human papillomavirus-infected women

BACKGROUND: In case-control studies, smoking, parity, and oral contraceptive use have been associated with an increased risk of cervical intraepithelial neoplasia grade 3 (CIN3) and cervical cancer among women who are infected with oncogenic human papillomavirus (HPV). However, these potential risk factors have not been adequately studied in prospective studies. METHODS: We studied 1812 women who were enrolled in a 10-year prospective study of cervical neoplasia at Kaiser Permanente in Portland, Oregon, and who at enrollment had tested positive for oncogenic HPV DNA and had responded to a questionnaire that included questions on smoking, oral contraceptive use, and parity. Absolute risks and crude relative risks (RRs) with 95% confidence intervals (CIs) for CIN3 or cervical cancer were computed for three time intervals (0-8, 9-68, and 69-122 months after enrollment) using the Kaplan-Meier method. Conditional logistic regression models were used to control for factors that may have influenced our risk estimates, specifically the cytologic interpretation of baseline Pap smear, number of Pap smears during follow-up, age at enrollment, age at prediagnosis visit, and age at diagnosis. All statistical tests were two-sided. RESULTS: Oral contraceptive use and parity were not associated with risk of CIN3 or cervical cancer. Former smokers, women who smoked less than one pack of cigarettes per day, and women who smoked one or more packs per day had crude RRs for CIN3 or cervical cancer for the entire follow-up period of 2.1 (95% CI = 1.1 to 3.9), 2.2 (95% CI = 1.2 to 4.2), and 2.9 (95% CI = 1.5 to 5.6), respectively, compared with never smokers. In the multivariable model, former smokers, women who smoked less than one pack/day, and women who smoked one or more packs/day had RRs of 3.3 (95% CI = 1.6 to 6.7), 2.9 (95% CI = 1.4 to 6.1), and 4.3 (95% CI = 2.0 to 9.3), respectively, for CIN3 or cervical cancer compared with never smokers. CONCLUSIONS: Smoking is associated with an increased risk of invasive cervical cancer in women who are infected with oncogenic HPV. Subsequent studies should examine the role of smoking in the multistage pathogenesis of cervical cancer.     

Incidence of cervical intraepithelial neoplasia in women infected with human immunodeficiency virus (HIV) with no evidence of disease at baseline: Results of a prospective cohort study with up to 6.4 years of follow-up from India

We report the incidence of cervical intraepithelial neoplasia (CIN) among HIV-infected women who did not have any colposcopic or histopathological evidence of CIN at baseline. Of the 1,023 women without any CIN at baseline, 855 (83.6%) have been followed up to a maximum of 6.4 years contributing 2,875 person years of observation (PYO). Among these 855 women, 54 cases of any CIN were observed resulting in incidence rate of any CIN of 1.9 per 100 PYO. The median time for follow-up for women with any CIN was 3.0 (IQR 1.6–3.7) years. The cumulative incidence rate per 100 PYO of CIN 2 or worse lesion in women with HPV-18 infection at baseline was 13.3% (95% CI 5.1–26.8); in women with HPV-16 infection was 10.8% (95% CI 4.4–20.9); in women with HPV-31 infection was 4.2% (95% CI 0.9–11.7); and in women with other high-risk HPV infections was 5.4% (95% CI 2.6–9.7). HPV-18 infection at baseline contributed highest frequency of incident CIN 2 or worse lesions followed by HPV-16 infection; however, other high-risk HPV types were also responsible for substantial number of incident CIN. The elevated risk of CIN2+ disease in the study cohort was non-significant in women with CD4 count <200, possibly because of the small number of cases. Our results emphasize the need for regular cervical cancer screening of HIV-infected women and urgent implementation of cervical cancer screening services in HIV programs in India and other low and middle-income countries.     

Human papillomavirus type-specific 18-month risk of high-grade cervical intraepithelial neoplasia in women with a normal or borderline/mildly dyskaryotic smear.

INTRODUCTION: High-risk human papillomavirus (hrHPV) DNA testing is an increasingly used instrument in cervical cancer prevention along cervical cytology. The inclusion of hrHPV testing in cervical screening requires efficient management as many hrHPV infections are transient. We investigated the potential value of hrHPV genotyping in normal and borderline/mildly dyskaryotic (BMD) smears. MATERIALS AND METHODS: From a screening population of 44,102 women in the Netherlands, we included hrHPV-positive women with a normal or BMD smear. We assessed the type-specific 18-month risk of high-grade cervical intraepithelial neoplasia (CIN). RESULTS: In hrHPV-positive women, 18-month risk of CIN grade 3 or invasive cancer (> or =CIN3) was 6% [95% confidence interval (95% CI), 4-9] after normal cytology and 20% (95% CI, 16-25) after BMD. If positive for HPV16, > or =CIN3 risks were 14% (95% CI, 9-21) and 37% (95% CI, 28-48), respectively. In the subset of hrHPV-positive women without HPV16, HPV18 was associated with an increased risk of high-grade CIN after normal cytology and HPV31 and HPV33 were associated with an increased risk, particularly after BMD. HPV16 and HPV18 were also associated with an increased risk of high-grade CIN in women with an hrHPV-positive normal baseline smear and a repeat normal smear at 6 months. DISCUSSION: HrHPV-positive women without type 16, 18, 31, or 33 had a relatively low risk of high-grade CIN. Among women with baseline normal cytology and among women with a baseline and repeat normal smear, HPV16/18-positive women showed an increased risk of high-grade CIN. This warrants more aggressive management of HPV16/18-positive women compared with other hrHPV-positive women.     

Baseline cytology,human papillomavirus testing,and risk for cervical neoplasia: a 10-year cohort analysis

BACKGROUND: Annual Pap smear screening has been favored over less frequent screening in the United States to minimize the risk of cervical cancer. We evaluated whether simultaneous screening with a Pap test and human papillomavirus (HPV) testing is useful for assessing the risk for cervical intraepithelial neoplasia (CIN) 3 or cervical cancer. METHODS: We enrolled 23 702 subjects in a study of HPV infection at Kaiser Permanente, Northwest Division, Portland, OR. Data were analyzed for 20 810 volunteers who were at least 16 years old (mean = 35.9 years) with satisfactory baseline Pap tests and suitable samples for HPV testing. Women were followed for up to 122 months (from April 1, 1989, to June 30, 1999) to determine the risk for histopathologically confirmed CIN3 or cancer. RESULTS: Among 171 women with CIN3 or cancer diagnosed over 122 months, 123 (71.9%, 95% confidence interval [CI] = 65.2% to 78.7%) had baseline Pap results of atypical squamous cells or worse and/or a positive HPV test, including 102 (86.4%, 95% CI = 80.3% to 92.6%) of the 118 cases diagnosed within the first 45 months of follow-up. During this 45-month period, the cumulative incidence of CIN3 or cancer was 4.54% (95% CI = 3.61% to 5.46%) among women with a Pap test result of atypical squamous cells or worse, positive HPV tests, or both compared with 0.16% (95% CI = 0.08% to 0.24%) among women with negative Pap and HPV tests. Age, screening behavior, a history of cervical cancer precursors, and a history of treatment for CIN minimally affected results. CONCLUSIONS: Negative baseline Pap and HPV tests were associated with a low risk for CIN3 or cancer in the subsequent 45 months, largely because a negative HPV test was associated with a decreased risk of cervical neoplasia. Negative combined test results should provide added reassurance for lengthening the screening interval among low-risk women, whereas positive results identify a relatively small subgroup that requires more frequent surveillance.     

Long‐term risk of cervical intraepithelial neoplasia grade 3 or worse according to high‐risk human papillomavirus genotype and semi‐quantitative viral load among 33,288 women with normal cervical cytology

In this prospective cohort study, we estimated the long‐term risk of cervical intraepithelial neoplasia grade 3 or cancer (CIN3+) by high‐risk human papillomavirus (hrHPV) genotype and semi‐quantitative viral load at baseline among 33,288 women aged 14–90 years with normal baseline cytology. During 2002–2005, residual liquid‐based cervical cytology samples were collected from women screened for cervical cancer in Copenhagen, Denmark. Samples were HPV‐tested with Hybrid Capture 2 (HC2) and genotyped with INNO‐LiPA. Semi‐quantitative viral load was measured by HC2 relative light units in women with single hrHPV infections. The cohort was followed in a nationwide pathology register for up to 11.5 years. In women aged ≥30 years at baseline, the 8‐year absolute risk for CIN3+ following baseline detection of HPV16 was 21.8% (95% confidence interval [CI]: 18.0–25.6%). The corresponding risks for HPV18, HPV31, HPV33, and other hrHPV types, respectively, were 12.8% (95% CI: 7.6–18.0%), 11.3% (95% CI: 7.7–14.9%), 12.9% (95% CI: 7.0–18.8%) and 3.9% (95% CI: 2.7–5.2%). Similar absolute risk estimates were observed in women aged <30 years. Higher HPV16‐viral load was associated with increased risk of CIN3+ (hazard ratio = 1.34, 95% CI: 1.10–1.64, per 10‐fold increase in viral load). A similar trend, although statistically nonsignificant, was found for viral load of HPV18. The 8‐year absolute risk of CIN3+ in women with HPV16‐viral load ≥100.0 pg/ml was 30.2% (95% CI: 21.9–38.6%). Our results support that hrHPV genotyping during cervical cancer screening may help identify women at highest risk of CIN3+.     

A population-based study on the risk of cervical cancer and cervical intraepithelial neoplasia among grand multiparous women in Finland

Previous studies suggest that high parity increases the risk of cervical cancer. We studied the risk of cervical cancer (CC) and cervical intraepithelial neoplasia (CIN3) in a Finnish cohort of grand multiparous (GM) women (at least five children) with low prevalence of sexually transmitted infections (STI). The Finnish Cancer Registry data revealed 220 CC and 178 CIN3 cases among 86 978 GM women. Standardised incidence ratios (SIR) were calculated from the numbers of observed and expected cases. Interval analyses by parity, age at first birth and average birth interval were done using multivariate Poisson regression. Seroprevalence of human papillomavirus (HPV) 16 and Chlamydia trachomatis was tested among 561 GM women and 5703 women with 2-4 pregnancies. The incidence among GM women was slightly above the national average for squamous cell carcinoma of cervix uteri (SIR 1.21, 95% CI 1.05-1.40) and CIN3 (1.37, 95% CI 1.17-1.58), but lower for adenocarcinoma (SIR 0.77, 95% CI 0.52-1.10). The seroprevalence of HPV16 and Chlamydia trachomatis among GM women was lower than in the reference population, except among those women who had their child under age 19. Age under 20 years at first birth increased the risk of CC and CIN3 especially in premenopausal GM women, while increasing parity had no effect. The small relative risks of CC and CIN3 among GM women in our study as compared to studies from other countries can be explained by the exceptionally low prevalence of STIs in Finnish GM women. The observed SIRs between 1.2 and 1.4 should be interpreted to represent increased risk attributable to grand multiparity. The increased incidence of CC and CIN3 among young GM women suggests causal association to HPV 16 and Chlamydia trachomatis infections.     

Mortality in a long‐term follow‐up after treatment of CIN

After treatment of the cervical intraepithelial neoplasia (CIN) cervical cancer incidence remains elevated at least for 20 years. Whether the overall or cervical cancer mortality after treatment of CIN is elevated is unknown. The aim of this study was to determine the long‐term survival and cause‐specific mortality among women treated for CIN. The study population consisted of 7,104 women treated for CIN between 1974 and 2001 and 35,437 individually matched controls. The follow‐up of mortality was based on nationwide registries and closed at death, emigration or December 31, 2005. The possible differences in mortality were assessed using Cox proportional hazard model. With follow‐up time of approximately 630,000 woman‐years, overall 2,781 deaths were observed, 530 among women treated for CIN and 2,251 among reference population (HR 1.1, 95% CI 1.0–1.3). Mortality from any cancer (HR 1.4, 95% CI 1.2–1.7), lung cancer (HR 2.7, 95% CI 1.8–4.1) and HPV‐related anogenital cancer (HR 3.1, 95% CI 1.1–8.6) was higher among CIN patients, but mortality from cervical cancer was not (HR 1.0, 95% CI 0.3–4.0). Elevated cervical cancer incidence after treatment of CIN, documented earlier, did not predict elevation in cervical cancer mortality. This suggests high effectiveness of CIN management. Most of the excess mortality observed among CIN patients was due to increased risk of other cancers. These long‐term mortality patterns should be considered when planning and evaluating the management of CIN lesions and related cervical or other cancer prevention activity.     

Persistent human papillomavirus infection and smoking increase risk of failure of treatment of cervical intraepithelial neoplasia (CIN)

Women with abnormal smears have an increased risk of developing cervical cancer. During the 8 years following conservative treatment of cervical intraepithelial neoplasia (CIN), their risk of invasive cervical cancer is about 5 times greater than that of the general population. Human papillomavirus (HPV) has been associated with the natural history of both CIN and cervical cancer. To date, there have been no published reports on the predictive value of HPV testing in the treatment outcome of CIN. A prospective, multi-center, cohort study was conducted on women in the Northwest of England who were attending for treatment of CIN. They were asked to complete a questionnaire, which included a detailed smoking history. Pre- and post-treatment HPV testing was performed on cervical biopsies and cervical swab, being taken with the first follow-up smear at 6 months. A nested case-control analysis was performed, cases being defined as women who developed CIN within the 2 years of treatment and controls being sampled from those who did not experience treatment failure within 2 years. Multiple conditional logistic regression is used to study the factors associated with treatment failure of CIN. The cohort included 958 women of whom 77 (8%) experienced treatment failure (cases). Two controls were matched to each case (154). Smoking status was significantly associated with CIN treatment failure(p= 0.0013). Current smokers had a 3-fold increased risk of treatment failure of CIN as compared to non-smokers (95% CI 1.65 to 5.91). Five hundred twenty-five women underwent HPV sampling following treatment, of whom 47 (8.9%) developed further CIN. Post-treatment positive HPV testing was found to be strongly associated with treatment failure of CIN (OR 23.3; 95% CI 3.15-172.1). In 11/45 cases with negative smear at first follow-up, the HPV test was positive. The combination of both HPV and cytology in the first follow-up visit predicted treatment failure in 72% of the cases. Cigarette smoking is a factor, which, independently of HPV infection, influences the treatment outcome of CIN. Smokers and those who are HPV positive during follow-up appear to require longer, more intensive follow-up. HPV testing requires careful consideration as part of routine follow-up protocol following treatment of CIN.     

Cumulative 5-year diagnoses of CIN2, CIN3 or cervical cancer after concurrent high-risk HPV and cytology testing in a primary screening setting

The aim of our study was to assess the cumulative 5-year diagnoses of CIN2, CIN3 or invasive cervical cancer (CIN2+) after concurrent screening by high-risk HPV test and Pap smear in a primary screening setting. Four thousand thirty-four women from Eastern Thuringia/Germany were recruited from 1996 to 1998 for baseline screening that included routine cytology, high-risk HPV testing by consensus primer PCR GP5+/6+ and routine colposcopy. After a median of 59 months 3,153 women participated in final screening using identical methods. Women with abnormal cytology or colposcopy or a positive high-risk HPV test at any time during the study period were recalled for expert colposcopy and histologic verification. CIN2+ was detected in 160 women resulting in a cumulative 5-year proportion of 4.4% (95% CI: 3.7-5.0%). Of 3,702 women who were high-risk HPV negative at baseline, 34 (1.1-95% CI: 0.7-1.4%) had either prevalent CIN2+ or developed CIN2+ within the observation period. HPV/cytology double negatives at baseline were at lowest risk for CIN2+ (1.0-95% CI: 0.7-1.4%) compared to screening positives (16.8-100% depending on combined test results). The 5-year negative predictive value in HPV-/Cyto- women was 99.0% (95% CI: 98.6-99.3%). This suggests that a prolongation of the screening intervals in this group is feasible. However, it should be noted that 1 woman developed a microinvasive carcinoma within the observation period. Moreover, 2 women with prevalent cancer were missed by both tests. The prognostic relevance of concurrent high-risk HPV/cytology screening needs to be verified further by randomized trials.     

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.     

Predictors of Absent High-grade Cervical Intraepithelial Neoplasia (CIN) in Loop Electrosurgical Excision Procedure Specimens of Patients with Colposcopic Directed Biopsy-Confirmed High-Grade CIN

Objective: To determine predictors of having cervical intraepithelial neoplasia (CIN) 1 or less in loopelectrosurgical excision procedure (LEEP) specimens of patients with colposcopic directed biopsy-confirmed CIN 2-3.Methods: Two hundred and eighty patients with colposcopic directed biopsy-confirmed CIN 2-3 who subsequentlyunderwent LEEP were enrolled in the retrospective study. Related clinical data were collected to determine the predictors ofCIN 1 or less in LEEP specimens. Results: CIN 1 or less in LEEP specimens was found in 71 (25.4%) of 280 patients.Multivariate logistic regression analyses demonstrated that nulliparity [OR (95% CI) = 3.375 (1.245-9.150)], lowgrade Papanicolaou (Pap) results [OR (95% CI) = 6.410 (2.877-14.280)] and low grade colposcopic impression[OR (95% CI) = 16.506 (5.844-46.632)] were significant risk factors of having CIN 1 or less in LEEP specimens. Neitherpersistent nor recurrent CIN 2-3 was detected in 71 patients who had CIN 1 or less in LEEP specimens. However,persistent or recurrent CIN 2-3 developed in 3 out of 209 (1.4%) patients with CIN 2-3 found in LEEP specimens.Conclusion: Approximately 25% of patients with CIN 2-3 in colposcopic directed biopsy specimens had CIN 1 or lessfound in LEEP specimens. Predicting factors of having CIN 1 or less in LEEP specimens were nulliparity, low gradePap results and low grade colposcopic impression.     

Disease detection at the 48-month exit round of the HPV FOCAL cervical cancer screening trial in women per-protocol eligible for routine screening

HPV FOCAL is a randomized control trial of cervical cancer screening. The intervention arm received baseline screening for high-risk human papillomavirus (HPV) and the control arm received liquid-based cytology (LBC) at baseline and 24 months. Both arms received 48-month exit HPV and LBC cotesting. Exit results are presented for per-protocol eligible (PPE) screened women. Participants were PPE at exit if they had completed all screening and recommended follow-up and had not been diagnosed with cervical intraepithelial neoplasia Grade 2 or worse (CIN2+) earlier in the trial. Subgroups were identified based upon results at earlier trial screening. There were 9,457 and 9,552 and women aged 25–65 randomized to control and intervention and 7,448 (77.8%) and 8,281 (86.7%), respectively, were PPE and screened. Exit cotest results were similar (p = 0.11) by arm for PPE and the relative rate (RR) of CIN2+ for intervention vs. control was RR = 0.83 (95% CI: 0.56–1.23). The RR for CIN2+ comparing intervention women baseline HPV negative to control women with negative cytology at baseline and at 24 months, was 0.68 (95% CI: 0.43–1.06). PPE women who had a negative or CIN1 colposcopy in earlier rounds had elevated rates (per 1,000) of CIN2+ at exit, control 31 (95% CI: 14–65) and intervention 43 (95% CI: 25–73). Among PPE women HPV negative at exit LBC cotesting identified little CIN2+, Rate = 0.3 (95% CI: 0.1–0.7). This per-protocol analysis found that screening with HPV using a 4-year interval is as safe as LBC with a 2-year screening interval. LBC screening in HPV negative women at exit identified few additional lesions.     

Cervical HPV infection and neoplasia in a large population-based prospective study: the Manchester cohort

Cytology and histology records and cervical samples for HPV assay were obtained from a prospective cohort of 49 655 women attending clinics for routine cervical cytology in or near Manchester between 1988 and 1993. The women were followed up for cytological abnormality and neoplasia through the cytology laboratory's records. HPV at entry was assayed in an age- and period-stratified random sample of 7278 women and in prevalent and incident CIN3 cases. The prevalence of newly diagnosed CIN3 increased with time since last normal smear, indicating that most cases persist for several years. CIN3 prevalence did not increase further for screening intervals exceeding 5 years, however, suggesting that CIN3 eventually regresses cytologically. CIN2 prevalence increased less steeply with screening interval, while the prevalence of lesser abnormality was almost independent of screening interval. The prevalence of oncogenic HPV at entry declined from 19% among women aged under 25 to less than 3% at age 40 or above. Oncogenic HPV infection was strongly predictive of subsequent CIN3 (OR 17.2, 95% CI 10.4-28.4), but only weakly related to CIN2 (OR 2.3, 95% CI 0.5-10.7) and lesser abnormality (OR 1.4, 95% CI 0.8-2.5). At current incidence rates, the lifetime risk of developing CIN3 will be 9% in this population. The cumulative risk of CIN3 diagnosis among cytologically normal women with oncogenic HPV detected at entry was 28% (CI 18-43%) after 14 years. Persistence of oncogenic HPV may be more sensitive and specific than cytology for early detection of CIN3 and invasive cancer.     

Progression of Precancerous Cervical Lesion Predicted by p16 Protein Immunohistochemistry in Rajavithi Hospital

Objective: To assess the association of p16 immunohistochemical (IHC) staining in cervical squamous intraepitheliallesions (SIL) and progression of cervical intraepithelial neoplasia (CIN) 1 to CIN2+ or recurrence of CIN2+. Materialand Methods: A retrospective cohort study of women with newly diagnosed SIL from colposcopy-directed biopsy atRajavithi Hospital, 2013-2017. Pathologic specimens were reviewed and submitted to p16-IHC staining. Adjusted hazardratios (HR) of disease-free interval (DFI) and 95% confidence intervals (CI) were carried out using the Cox proportionalhazard regression model. Results: A total of 187 women was recruited, 91 cases of positive p16-IHC staining and 96cases of negative staining. With the median follow-up time of 22 months, women with positive p16-IHC had significantlylower 1-year DFI than those with negative p16-IHC (86.8% vs. 96.6%, p = 0.006). Women with CIN 1 had 22.6% ofpositive p16-IHC, while those with CIN2-3 had 86.7%. From multivariate analysis, the positive p16-IHC and age >35 years were the significant prognostic factors of progression/recurrent CIN2+ (adjusted HR 5.33, 95%CI 1.77-16.01,p = 0.003; and adjusted HR 5.80, 95%CI 1.34-25.08, p = 0.019, respectively). From subgroup analysis, the positivep16-IHC was the significant prognostic factor in women with initial CIN1 (HR 5.29, 95%CI 1.18-23.76, p = 0.030), butwas not associated with prognosis in women with initial CIN 2-3 (HR 2.13, 95%CI 0.28-16.38, p = 0.468). Conclusion:Overexpression of p16 protein has the prognostic significance of SIL. Using p16-IHC may help stratify patients aslow-risk and high-risk groups to progression/recurrence CIN2+.     

Cervical carcinoma and reproductive factors: collaborative reanalysis of individual data on 16,563 women with cervical carcinoma and 33,542 women without cervical carcinoma from 25 epidemiological studies

The International Collaboration of Epidemiological Studies of Cervical Cancer has combined individual data on 11,161 women with invasive carcinoma, 5,402 women with cervical intraepithelial neoplasia (CIN)3/carcinoma in situ and 33,542 women without cervical carcinoma from 25 epidemiological studies. Relative risks (RRs) and 95% confidence intervals (CIs) of cervical carcinoma in relation to number of full-term pregnancies, and age at first full-term pregnancy, were calculated conditioning by study, age, lifetime number of sexual partners and age at first sexual intercourse. Number of full-term pregnancies was associated with a risk of invasive cervical carcinoma. After controlling for age at first full-term pregnancy, the RR for invasive cervical carcinoma among parous women was 1.76 (95% CI: 1.53-2.02) for > or => or =7 full-term pregnancies compared with 1-2. For CIN3/carcinoma in situ, no significant trend was found with increasing number of births after controlling for age at first full-term pregnancy among parous women. Early age at first full-term pregnancy was also associated with risk of both invasive cervical carcinoma and CIN3/carcinoma in situ. After controlling for number of full-term pregnancies, the RR for first full-term pregnancy at age <17 years compared with > or => or =25 years was 1.77 (95% CI: 1.42-2.23) for invasive cervical carcinoma, and 1.78 (95% CI: 1.26-2.51) for CIN3/carcinoma in situ. Results were similar in analyses restricted to high-risk human papilloma virus (HPV)-positive cases and controls. No relationship was found between cervical HPV positivity and number of full-term pregnancies, or age at first full-term pregnancy among controls. Differences in reproductive habits may have contributed to differences in cervical cancer incidence between developed and developing countries.     

International agreement to join forces in synthesizing evidence on new methods for cervical cancer prevention

Recently published baseline results of randomised controlled trials, comparing cytology with HPV-based cervical cancer screening, consistently show increased detection of high-grade cervical intraepithelial neoplasia (CIN) in the HPV-arm. These results are in line with the pooled estimates of the relative sensitivity derived from cross-sectional studies. From two randomised trials, also the longitudinal outcomes observed at the second screening round were reported. HPV-negative women, had a relative risk of developing CIN3 in the next 3 to 5 years, compared to cytology-negative women, of 0.53 (95% CI: 0.29-0.92) and 0.45 (95% CI: 0.28-0.67), respectively in the Swedish and Dutch trial. Consensus was reached at the Cochrane Workshop on Cervical Cancer Prevention, organized at the occasion of the 24th Conference of the International Papillomavirus Society, to join forces to conduct future meta-analyses of the HPV screening trials and to synthesize evidence on new methods for cervical cancer prevention.     

Socio-demographic and reproductive determinants of cervical neoplasia in seven sub-Sahara African countries

Background

Since most human papilloma virus (HPV) infections regress without any intervention, HPV is a necessary but may not be a solely sufficient cause of cervical intraepithelial neoplasia (CIN) and cervical cancer. Hence, the influence of cofactors on progression from cervical HPV infection to high-grade CIN and invasive cervical cancer has been a subject of intensive research.

Objective

We assessed the effect of socio-demographic and sexual reproductive factors on the prevalence of invasive cervical cancer and CIN diagnosed in cross-sectional cervical cancer screening projects carried out in seven sites of different sub-Saharan countries.

Methods

Between January 2000 and August 2007, healthy women aged 25–59 who participated in the screening projects were interviewed for socio-demographic, reproductive, and behavioral characteristics, investigated for disease confirmation with colposcopy, and had biopsies directed from colposcopically abnormal areas by trained local physicians. Odds ratios (ORs) and their 95% confidence intervals (CIs) from logistic regression analyses were used to assess the effect of women characteristics on CIN 1, CIN 2–3, CIN 3, and invasive cancer outcome measures.

Results

Among 47,361 women screened and investigated for disease confirmation, CIN 1 was diagnosed in 1,069 (2.3%), CIN 2 in 517 (1.1%), CIN 3 in 175 (0.5%), and invasive cancer in 485 (1.0%). The site-specific prevalence of CIN 2–3 lesions ranged from 0.3 to 5.1% and from 0.2 to 1.9% for invasive cancers. Risk factors for CIN 2–3 were being widowed or separated versus currently married (OR 1.3, 95% CI 1.0–1.7 a); and having had at least four pregnancies versus zero or one pregnancy (OR at least 1.4-fold, 95% CI 1.1–1.8). Risk factors for invasive cancer were being widowed or separated versus currently married (OR 2.0, 95% CI 1.3–3.1); and having had at least three pregnancies versus zero or one pregnancy (OR at least 3.0-fold, 95% CI 2.1–4.2). Additionally, cervical cancer risk increased with increasing age, age at menarche, and age at marriage, while the risk decreased with increasing level of education and in those with some form of employment compared to housewives.

Conclusion

The exposure of the exocervix and/or the increased levels of estrogen and progesterone for more prolonged periods during pregnancy in multiparous women and the vulnerability of widowed/separated women in society might result in increased risk of cervical neoplasia more so among women exposed to HPV infection. High parity probably explains the persistently high rates of cervical cancer in sub-Saharan Africa.