Alejandra Castanon

Effectiveness of cervical screening with age: population based case-control study of prospectively recorded data

Objective To study the effect of cervical screening on incidence of cervical cancer as a function of age with particular focus on women screened under the age of 25. Design Population based case-control study with prospectively recorded data on cervical screening. Setting Selected centres in the United Kingdom. Participants 4012 women aged 20-69 with invasive cancer diagnosed in participating centres and two controls per case individually matched on age and area of residence. Main outcome measures Odds ratios for strength of association between cervical cancer and screening at particular ages. Results There is no evidence that screening women aged 22-24 reduced the incidence of cervical cancer at ages 25-29 (odds ratio 1.11, 95% confidence interval 0.83 to 1.50). Similar results were seen for cancers restricted to squamous carcinoma or FIGO (International Federation of Gynaecology and Obstetrics) stage IB or worse, but the numbers are insufficient to provide narrow confidence intervals. Screening was associated with a 60% reduction of cancers in women aged 40, increasing to 80% at age 64. Screening was particularly effective in preventing advanced stage cancers. Conclusions Cervical screening in women aged 20-24 has little or no impact on rates of invasive cervical cancer up to age 30. Some uncertainly still exists regarding its impact on advanced stage tumours in women under age 30. By contrast, screening older women leads to a substantial reduction in incidence of and mortality from cervical cancer. These data should help policy makers balance the impact of screening on cancer rates against its harms, such as overtreatment of lesions with little invasive potential.

Screening and adenocarcinoma of the cervix

Screening has had a major impact on cervical cancer in many countries. Although there can be no doubt about its effectiveness in preventing squamous‐cell carcinoma, there is little evidence of any benefit on adenocarcinoma and adenosquamous carcinoma of the cervix, and many authors have concluded that it is ineffective. A population‐based case–control design was used in women aged 20–69 in the United Kingdom, with information on screening obtained from routine databases. Among 3,305 cases with known histology, 641 had adenocarcinoma and 133 adenosquamous carcinoma. The risk reduction associated with 3‐yearly screening was greater for squamous carcinoma (75%, 95%CI 71–79%) and adenosquamous carcinoma (83%, 95%CI 68–91%) than for adenocarcinoma (43%, 95%CI 24–58%). Among stage 1B+ cases, 83% (335/406) of women with adenocarcinoma had been screened within 10 years of diagnosis. This is very similar to controls (82%, 3,292/3,965), but much higher than in women with squamous carcinoma (57%, 852/1,493). Incidence of adenocarcinoma was low within 2.5 years of a negative smear (OR 2.3, 95%CI 0.15–0.34), but was no different from the background rates 4.5–5.5 years after a negative smear. We conclude that screening has reduced the incidence of adenocarcinoma of the cervix, but the prognostic value of cytology is less (in both magnitude and duration) for adenocarcinoma than for squamous carcinoma. The impact of screening on adenosquamous carcinoma is similar to its impact on squamous carcinoma.

Risk of preterm birth after treatment for cervical intraepithelial neoplasia among women attending colposcopy in England: retrospective-prospective cohort study

Objective To explore the association between preterm delivery and treatment at colposcopy. Design Retrospective-prospective cohort study using record linkage. Setting 12 National Health Service hospitals in England. Participants Women who had a cervical histology sample taken between 1987 and 2009. These women were linked by hospital episode statistics to hospital obstetric records between 1998 and 2009 for the whole of England to identify singleton live births between 20-43 gestational weeks before or after cervical histology. Main outcome measures Proportion of preterm births (<37 weeks); the relative risk for the strength of association between preterm births and treatment for cervical intraepithelial neoplasia. Results 18 441 singleton births occurred: 4176 before histology and 14 265 after histology. Of the singleton births after histology, 9.0% (n=1284) were preterm compared with 6.7% of all births in England over the same period (excess risk 2.3 per 100 births, 95% confidence interval 1.8% to 2.8%). Among first births after histology, the adjusted relative risk associated with previous treatment was 1.19 (95% confidence interval 1.01 to 1.41); among first births before histology the relative risk associated with subsequent treatment was 1.47 (1.05 to 2.05). Combining these, the relative risk associated with treatment adjusted for timing relative to histology was 0.91 (0.66 to 1.26) corresponding to an absolute difference of −0.25 (−2.61 to 2.11) per 100 singleton births. Among 372 women who gave birth both before and after treatment, there were 30 preterm births after treatment and 32 before treatment (relative risk 0.94, 0.62 to 1.43). Conclusion The risk of preterm delivery in women treated by colposcopy in England was substantially less than that in many other studies, predominantly from Nordic countries. The increased risk may be a consequence of confounding and not caused by treatment. Although this study is reassuring for large loop excision of the transformation zone overall, it is possible that deep conisation or repeated treatment leads to an increased risk of preterm delivery.

Predicted impact of vaccination against human papillomavirus 16/18 on cancer incidence and cervical abnormalities in women aged 20-29 in the UK

Background:Human papillomavirus (HPV) vaccination has been approved in more than 90 countries and is being implemented in many of these. In the UK, vaccination for girls aged 12–13 with catch-up for girls up to age 18 was introduced in 2008, using the bivalent GSK vaccine (Cervarix).Methods:We modelled the proportion of abnormal smears, cervical intraepithelial neoplasia grade 3 (CIN3) and invasive cancer, which will be prevented in women aged 20–29 in the UK as a result of HPV vaccination.Results:It will take many years for the full benefit of vaccination to be achieved. The earliest effects will be seen in women aged 20–29. With 80% coverage in women aged 12–13, we project an eventual 63% reduction in invasive cancer, a 51% reduction in CIN3 and a 27% reduction in cytological abnormalities before age 30. The full effect in this age group will not be seen until 2025, although half of the benefit will be seen by 2019 in England, where screening starts at age 25. However in Scotland and Wales, where screening starts at age 20, 50% of the benefit for CIN3 and abnormal smears (but not cancer) will be seen earlier.Conclusion:Substantial reductions in disease can be anticipated by vaccination, but most of the benefit will not be apparent for at least another decade. High vaccine coverage is the key factor for achieving these benefits.

Risk of preterm delivery with increasing depth of excision for cervical intraepithelial neoplasia in England: nested case-control study

Objective To determine the association between depth of excision of cervical intraepithelial neoplasia and risk of preterm birth. Design Case-control study nested in record linkage cohort study. Setting 12 hospitals in England. Participants From a cohort of 11 471 women with at least one histological sample taken at colposcopy and a live singleton birth (before or after colposcopy), 1313 women with a preterm birth (20-36 weeks) were identified and frequency matched on maternal age at delivery, parity, and study site to 1313 women with term births (38-42 weeks). Main outcome measures Risk of preterm birth and very/extreme preterm birth by depth of excisional treatment of the cervical transformation zone. Results After exclusions, 768 preterm births (cases) and 830 term births after colposcopy remained. The risk of preterm birth was no greater in women with a previous small (<10 mm) excision (absolute risk 7.5%, 95% confidence interval 6.0% to 8.9%) than in women with a diagnostic punch biopsy (7.2%, 5.9% to 8.5%). Women with a medium (10-14 mm) (absolute risk 9.6%; relative risk 1.28, 0.98 to 1.68), large (15-19 mm) (15.3%; 2.04, 1.41 to 2.96), or very large (≥20 mm) excision (18.0%; 2.40, 1.53 to 3.75) had a higher risk of preterm delivery than those with small excision. The same pattern was seen in 161 women with very/extremely preterm births (20-31 weeks) and with increasing volume excised. Most births were conceived more than three years after colposcopy, and the risk of preterm delivery did not seem to depend on time from excision to conception. Conclusions The risk of preterm birth is at most minimally affected by a small excision. Larger excisions, particularly over 15 mm or 2.66 cm3, are associated with a doubling of the risk of both preterm and very preterm births. The risk does not decrease with increasing time from excision to conception. Efforts should be made to excise the entire lesion while preserving as much healthy cervical tissue as possible. Close obstetric monitoring is warranted for women who have large excisions of the cervical transformation zone.

Impact of cervical screening on cervical cancer mortality: estimation using stage-specific results from a nested case-control study

Background:It is well established that screening can prevent cervical cancer, but the magnitude of the impact of regular screening on cervical cancer mortality is unknown.Methods:Population-based case–control study using prospectively recorded cervical screening data, England 1988–2013. Case women had cervical cancer diagnosed during April 2007–March 2013 aged 25–79 years (N=11 619). Two cancer-free controls were individually age matched to each case. We used conditional logistic regression to estimate the odds ratio (OR) of developing stage-specific cancer for women regularly screened or irregularly screened compared with women not screened in the preceding 15 years. Mortality was estimated from excess deaths within 5 years of diagnosis using stage-specific 5-year relative survival from England with adjustment for age within stage based on SEER (Surveillance, Epidemiology and End Results, USA) data.Results:In women aged 35–64 years, regular screening is associated with a 67% (95% confidence interval (CI): 62–73%) reduction in stage 1A cancer and a 95% (95% CI: 94–97%) reduction in stage 3 or worse cervical cancer: the estimated OR comparing regular (⩽5.5yearly) screening to no (or minimal) screening are 0.18 (95% CI: 0.16–0.19) for cancer incidence and 0.08 (95% CI: 0.07–0.09) for mortality. It is estimated that in England screening currently prevents 70% (95% CI: 66–73%) of cervical cancer deaths (all ages); however, if everyone attended screening regularly, 83% (95% CI: 82–84%) could be prevented.Conclusions:The association between cervical cancer screening and incidence is stronger in more advanced stage cancers, and screening is more effective at preventing death from cancer than preventing cancer itself.

HPV16 L1 and L2 DNA methylation predicts high-grade cervical intraepithelial neoplasia in women with mildly abnormal cervical cytology.

DNA methylation changes in human papillomavirus type 16 (HPV16) DNA are common and might be important for identifying women at increased risk of cervical cancer. Using recently published data from Costa Rica we developed a classification score to differentiate women with cervical intraepithelial neoplasia grade 2 or 3 (CIN2/3) from those with no evident high‐grade lesions. Here, we aim to investigate the performance of the score using data from the UK. Exfoliated cervical cells at baseline and 6‐months follow‐up were analyzed in 84 women selected from a randomized clinical trial of women undergoing surveillance for low‐grade cytology. Selection of women for the methylation study was based on detectable HPV16 in the baseline sample. Purified DNA was bisulfite converted, amplified and pyrosequenced at selected CpG sites in the viral genome (URR, E6, L1 and L2), with blinding of laboratory personnel to the clinical data. The primary measure was a predefined score combining the mean methylation in L1 and any methylation in L2. At the second follow‐up visit, 73/84 (87%) women were HPV16 positive and of these 25 had a histopathological diagnosis of CIN2/3. The score was significantly associated with CIN2/3 (area under curve = 0.74, p = 0.002). For a cutoff with 92% sensitivity, colposcopy could have been avoided in 40% (95% CI 27–54%) of HPV16 positive women without CIN2/3; positive predictive value was 44% (32–58%) and negative predictive value was 90% (71–97%). We conclude that quantitative DNA methylation assays could help to improve triage among HPV16 positive women.

How many cervical cancers are prevented by treatment of screen-detected disease in young women?

Others have argued that as many as a third of women treated for high‐grade cervical intraepithelial neoplasia (CIN) would have developed cervical cancer in the absence of screening and treatment. Under various assumptions and using past data on CIN grade 3 (CIN3) registrations in England and Scotland, we estimate what cervical cancer rates would have been in the absence of screening. Data on registrations of cervical carcinoma in situ for England and Scotland were used to project the additional numbers of invasive cervical cancers that would have resulted had the carcinoma in situ not been treated. We compare the resulting cervical cancer rates (under different models) with rates recorded in Cancer Incidence in 5 Continents. In order for the projected rates in England and Scotland at ages 20–24 not to be exceptionally high compared to maximum recorded rates for each registry in Cancer Incidence in 5 Continents, the progression rate from CIN3 to invasive cancer in women aged 20–24 should not exceed 1% per year. Similar progression rates were reasonable for women aged 25–29. Under the previously accepted assumption of 4.33% progression per year, cervical cancer rates in women aged 20–29 in both England and Scotland would have been 2–5 times greater than any observed rate (other than one registry, based on just 4 cases). From this analysis, at most 1.5% of women treated (equivalent to 3% of CIN3 registrations) would have had cancer by age 25, whereas it is reasonable to assume that over half of them would have regressed by age 25.

Head-to-Head Comparison of the RNA-Based Aptima Human Papillomavirus (HPV) Assay and the DNA-Based Hybrid Capture 2 HPV Test in a Routine Screening Population of Women Aged 30 to 60 Years in Germany

ABSTRACT Testing for E6/E7 mRNA in cells infected with high-risk (HR) human papillomavirus (HPV) might improve the specificity of HPV testing for the identification of cervical precancerous lesions. Here we compared the RNA-based Aptima HPV (AHPV) assay (Hologic) and the DNA-based Hybrid Capture 2 (HC2) HPV test (Qiagen) to liquid-based cytology (LBC) for women undergoing routine cervical screening. A total of 10,040 women, 30 to 60 years of age, were invited to participate in the study, 9,451 of whom were included in the analysis. Specimens were tested centrally by LBC, the AHPV test, and the HC2 test, and women who tested positive on any test were referred for colposcopy. Genotyping was performed on all HR-HPV-positive samples. Test characteristics were calculated based on histological review. As a result, we identified 90 women with cervical intraepithelial neoplasia grade 2+ (CIN2+), including 43 women with CIN3+. Sensitivity differences between the AHPV test and the HC2 test in detecting CIN2+ (P = 0.180) or CIN3+ (P = 0.0625) lesions were statistically nonsignificant. Of three CIN3 cases that were missed with the AHPV test, two cases presented lesion-free cones and one had a non-HR HPV67 infection. The specificity (<CIN2) and positive predictive value (CIN2+) of the AHPV test were significantly higher (both P < 0.001) than those of the HC2 test. The overall agreement between the tests was substantial (κ = 0.77). Finally, we present results for several possible triage strategies, based on the primary screening test being either the AHPV test or the HC2 test. In summary, the AHPV assay is both specific and sensitive for the detection of high-grade precancerous lesions and may be used in primary cervical cancer screening for women ≥30 years of age.

Characteristics and screening history of women diagnosed with cervical cancer aged 20-29 years

Background:There was concern that failure to screen women aged 20–24 years would increase the number of cancers or advanced cancers in women aged 20–29 years. We describe the characteristics of women diagnosed with cervical cancer in England aged 20–29 years and examine the association between the period of diagnosis, screening history and FIGO stage.Methods:We used data on 1800 women diagnosed with cervical cancer between April 2007 and March 2012 at age 20–29 from the National Audit of Invasive Cervical Cancers.Results:The majority of cancers (995, or 62% of those with known stage) were stage 1A. Cancer at age 20–24 years was rare (12% of those aged 20–29 years), when compared with age 25 (24%) and age 26–29 years (63%); however, cancers in women aged 20–24 years tended to be more advanced and were more often of a rare histological type. For 59% of women under age 30, the cervical cancer was screen detected, most of them (61%) as a result of their first screening test. A three-fold increase in the number of cancers diagnosed at age 25 years was seen since the start of the study period.Conclusion:Cervical cancer at age 20–24 years is rare. Most cancers in women under age 30 years are screen detected as microinvasive cancer.