Routine Cervical Cancer Screening Research Articles

Abstracts of The 29th Annual Meeting of the United Kingdom Environmental Mutagen Society, 19-22 March 2006. Held jointly with The British Toxicology Society at the University of Warwick, UK

The aetiology of cervical cancer is strongly associated with viral infection (i.e. human papillomavirus (HPV)); other risk factors include low socio-economic class, multiple sexual partners, smoking and poor diet. Cervical cancer screening employing smears of exfoliative cytology for the visual identification of atypical cells has successfully led to a fall in mortality from this disease. However, false negatives occur when a smear is determined normal although atypical cells (be they pre-malignant or malignant) are present. The use of attenuated total reflection (ATR)-FTIR microspectroscopy to interrogate samples of exfoliative cytology is a novel approach to screening that may allow the rapid profiling of a pathological status. Changes in derived vibrational spectra may be associated with a biochemical biomarker of dyskaryosis. To investigate this possibility, we interrogated eight cervical samples of exfoliative cytology using ATR-FTIR microspectroscopy. Two were normal, two were low-grade cervical intraepithelial neoplasia (CIN)1, two were high-grade (CIN2/3) and two were invasive carcinoma samples. Cellular material was applied to an ATR crystal and vibrational spectra were obtained using a Bruker Vector 22 FTIR spectrometer with Helios ATR attachment. At least 10 spectra per sample of exfoliative cytology were acquired in the ATR mode using Bruker OPUS software; these spectra were then individually baseline corrected. These derived spectra were subsequently analysed using principal component analysis (PCA). Cluster plots allowed the identification of any spatial separation (pointing to increasing dissimilarity) as a function of spectral differences between different samples in a 3-D ‘‘hyperspace’’. Apparently independent of oncogenic HPV genotype, successful discrimination between normal, CIN1, CIN2/3 and invasive carcinoma samples was obtained. Normal and invasive carcinoma samples exhibited 100% segregation in ‘‘hyperspace’’ and the samples classified as low- or high-grade clustered variously between, pointing towards a model of progression. Retrospective histological analysis of smears confirmed the diagnostic potential of this approach. ATR-FTIR microspectroscopy potentially could be used in routine cervical cancer screening in an objective approach less prone to the current limitation of false-negative occurrence. The combined application of ATR-FTIR microspectroscopy and PCA may also allow for the tracking of biochemical markers of progression from normal to invasive carcinoma. We are currently interrogating larger cohorts to determine the applicability of IR microspectroscopy for routine screening.

New and Surprising Insights Into Pathogenesis of Multicentric Squamous Cancers in the Female Lower Genital Tract

Infection with high-risk types of human papillomavirus (HR-HPV) is extremely common in the cervix, vagina, and vulva; and women with persistent HR-HPV infections at these sites have been shown to be at increased risk for the development of invasive squamous cell cancers at these locations ( 1 – 3 ) . Prior to the establishment of routine cervical cancer screening, invasive cervical cancer was among the most common causes of cancer mortality in women. Compared with cervical cancer, vaginal and vulvar cancers develop infrequently (current age-adjusted incidences of cervical, vaginal, and vulvar cancers = 8.9/100 000 women per year, 0.7/100 000 women per year, and 2.3/100 000 women per year, respectively) ( 4 ) . Previous studies (e.g., [5,6] ) have shown that a history of a prior cervical neoplasm (cervical intraepithelial neoplasia grade 3 [CIN 3] or invasive cervical cancer) is an important risk factor for the development of vaginal and vulvar cancers. The most likely explanation for this association is that women who develop cervical neoplasia frequently are infected with HR-HPV both at the cervix and in the vagina and vulva, and they occasionally develop a second independent neoplasm at the last two sites. Other explanations for this association between a history of a prior cervical neoplasm and the later development of a vaginal or vulvar cancer include recurrence of the original cervical cancer at the surgical margin after hysterectomy

Physician Recommendation for Papanicolaou Testing Among U.S. Women, 2000

Many women in the U.S. undergo routine cervical cancer screening, but some women have rarely or never had a Papanicolaou (Pap) test. Studies of other cancer screening tests (for example, mammograms) have shown that physician recommendation to get a screening test is one of the strongest predictors of cancer screening. In this study, we examined whether women in the U.S. had received a physician recommendation to get a Pap test using data from the 2000 National Health Interview Survey. Reported reasons for not receiving a Pap test were also explored. Among women aged > or =18 years who had no history of hysterectomy, 83.3% [95% confidence interval (CI), 82.4-84.1%] of the 13,636 women in this sample had had a Pap test in the last 3 years. Among 2,310 women who had not had a recent Pap test, reported reasons for not receiving a Pap test included: "No reason/never thought about it" (48.0%; 95% CI, 45.5-50.7), "Doctor didn't order it" (10.3%; 95% CI, 8.7-12.0), "Didn't need it/didn't know I needed this type of test" (8.1%; 95% CI, 6.7-9.6), "Haven't had any problems" (9.0%; 95% CI, 7.6-10.5), "Put it off" (7.4%; 95% CI, 6.2-8.7), "Too expensive/no insurance" (8.7%; 95% CI, 7.3-10.2), "Too painful, unpleasant, embarrassing" (3.5%; 95% CI, 2.5-4.6), and "Don't have doctor" (1.7%; 95% CI, 1.2-2.4). Among women who had had a doctor visit in the last year but who had not had a recent Pap test, about 86.7% (95% CI, 84.5-88.6) reported that their doctor had not recommended a Pap test in the last year. African-American women were as likely as White women to have received a doctor recommendation to get a Pap test. Hispanic women were as likely as non-Hispanic women to have received a doctor recommendation to get a Pap test. In multivariate analysis, factors positively associated with doctor recommendation to get a Pap test included being aged 30 to 64 years, having been born in the U.S., and having seen a specialist or general doctor in the past year. These findings suggest that lack of a physician recommendation contributes to underuse of Pap screening by many eligible women. Given research that shows the effectiveness of physician recommendations in improving use, increased physician recommendations could contribute significantly to increased Pap screening use in the U.S.

Assessing the Annual Economic Burden of Preventing and Treating Anogenital Human Papillomavirus-Related Disease in the US

The anogenital human papillomavirus (HPV) is estimated to be the most commonly occurring sexually transmitted infection in the US. Comprehensive estimates of the annual economic burden associated with the prevention and treatment of anogenital HPV-related disease in the US population are currently unavailable. The purpose of this paper is to (i) outline an analytic framework from which to estimate the annual economic burden of preventing and treating anogenital HPV-related disease in the US; (ii) review available US literature concerning the annual economic burden of HPV; and (iii) highlight gaps in current knowledge where further study is particularly warranted. Among eight US studies identified that describe the annual economic burden pertaining to one or more aspects of anogenital HPV-related disease, three met the review eligibility criteria (published between 1990 and 2004, examined multiple facets of annual anogenital HPV-related economic burden, and clearly articulated the data and methods used in the estimation process). All costs were adjusted to 2004 US dollars. Estimates of the annual direct medical costs associated with cervical cancer were comparable across studies (range 300-400 million US dollars). In contrast, there was a wide range across studies for estimates of the annual direct medical costs associated with cervical intraepithelial neoplasia (range 700 million US dollars-2.3 billion US dollars). Only one study reported direct medical costs for anogenital warts (200 million US dollars) and routine cervical cancer screening (2.3 billion US dollars). No studies examined direct medical costs attributable to HPV-related anal, penile, vaginal or vulvar cancers, or the work and productivity losses resulting from time spent receiving medical care, morbidity or mortality. Current economic burden estimates would suggest annual direct medical costs associated with the prevention and treatment of anogenital warts and cervical HPV-related disease of at least 4 billion US dollars. This figure would likely rise to at least 5 billion US dollars per year if direct medical costs associated with other disease entities caused by the sexual transmission of HPV were included, with further additions to the economic burden totalling in the billions of dollars if work and productivity losses were incorporated, a research priority for future studies.

Diagnoses and outcomes in cervical cancer screening: A population-based study

Objective This study was undertaken to examine routine cervical cancer screening diagnoses and outcomes on an age-specific basis in a US population. Study design We conducted an observational cohort study using 1997-2002 health plan administrative and laboratory data for women enrolled at Kaiser Permanente Northwest (Portland, Ore) in 1998. Results Across all female enrollees (n = 150,052), the annual rate of routine cervical cancer screening was 294.7 per 1,000, with cytologic abnormalities detected at a rate of 14.9 per 1,000. The annual incidence of cervical intraepithelial neoplasia (CIN) 1 was 1.2 per 1,000 with a rate of 1.5 per 1,000 for CIN 2/3. CIN 1 incidence peaked among women aged 20 to 24 years (5.1 per 1,000), with CIN 2/3 rates highest among those 25 to 29 years (8.1 per 1,000). From among 44,493 routine cervical smears, results were normal for 94.5%, with abnormal diagnoses of atypical squamous cells (3.3%), atypical glandular cells (0.2%), low-grade squamous intraepithelial lesion (1.2%), high-grade squamous intraepithelial lesion (0.3%), and inconclusive/inadequate (0.5%). Of women with abnormal routine smears, CIN or cancer was detected on follow-up in 19.4% of cases, 51.5% were found to have had a false-positive smear, and 29.0% incomplete follow-up as defined by published management guidelines. Conclusion These are the first comprehensive age-specific estimates of routine cervical cancer screening diagnoses and outcomes to be reported within a US general healthcare setting. Overall, 5% of routinely screened women were found to have an abnormal cervical smear with an annual incidence of CIN across all female enrollees of 2.7 per 1000.

The health care costs of cervical human papillomavirus–related disease

Objective The purpose of this study was to examine the health care costs of cervical human papillomavirus–related disease in a US health care setting. Study design We conducted an observational cohort study using 1997 through 2002 administrative and laboratory records from 103,476 female enrollees of the Kaiser Permanente Northwest health plan (Portland, Ore). We examined the cost per case and annual cost per 1000 enrollees for cervical human papillomavirus–related events. Results A cervical examination with a normal routine papanicolaou smear incurred costs of $57 (95% CI, 57-57). Costs that were associated with abnormal routine screening diagnoses ranged from $299 for atypical squamous cells (95% CI, 245-352) to $2349 for high-grade squamous intraepithelial lesion (95% CI, 1,047-3,650). The costs of histologically confirmed cervical intraepithelial neoplasia ranged from $1026 for cervical intraepithelial neoplasia 1 (95% CI, 862-1191) to $3235 for cervical intraepithelial neoplasia 3 (95% CI, 2051-4419); a cost of $376 (95% CI, 315-436) was associated with false-positive test results. At the level of the health plan, overall annual cervical cancer prevention and treatment costs were $26,415 per 1000 female enrollees, with routine cervical cancer screening accounting for expenditures of $16,746 per 1000 female enrollees, cervical intraepithelial neoplasia accounting for expenditures of $4535 per 1000 female enrollees, cervical cancer accounting for expenditures of $2629 per 1000 female enrollees, and false-positive test results accounting for expenditures of $2394 per 1000 female enrollees. Conclusion These are the first direct estimates of both individual and population level costs of cervical human papillomavirus–related disease in a general US health care setting. Routine cervical cancer screening comprises nearly two thirds of total annual cervical human papillomavirus–related health care costs, with 10% of expenditures dedicated to the treatment of invasive cervical cancer, 17% to the management of cervical precancers, and 9% to dealing with false-positive Papanicolaou test results.

Morphological analysis of squamous cells in routine Pap smears as a predictor of bone mineral density in asymptomatic women

Objective: The present study attempted to find out possible coherence between morphologic characteristics in Pap smears and bone mineral density (BMD) as measured by DEXA. Study Design: DEXA measurement (with the result expressed as T-score) was performed in 79 women in whom Pap smears for routine cervical cancer screening were obtained. The smears were grouped into atrophic and mature cell patterns. Using astereological analysis, the mean areas of squamous cells, their nuclei and cytoplasm were estimated. Results: The mean areas of cells and cytoplasm were significantly lower at lower T-scores ( P<0.01), while the mean areas of nuclei were not ( P>0.5). T-scores were significantly lower in the atrophic cell pattern group ( P<0.001). The study group indicated concurrently high sensitivity of 80.9% and specificity of 78.1%, with positive predictive value of 84.4%. Conclusion: These results suggest that a significant number of women with low BMD could be identified parallel with the routine Pap test for cervical cancer screening without additional costs.

Use of Pap test among Hispanics and non-Hispanic whites in a rural setting

Background. Hispanic women in the United States have a higher incidence of invasive cervical cancer than non-Hispanic whites. A key factor related to the relatively high incidence is the underutilization of cancer-screening services. Several previous investigations have reported that Hispanic women are less likely to comply with screening recommendations for Pap testing; some have identified factors that are associated with non-compliance with screening recommendations. Methods. Using baseline personal interview data from a randomized community trial on cancer prevention in a rural area, we assessed the association between health barriers and non-compliance with cervical screening recommendations. Results. Among Hispanic women ( n = 382), those with a lower level of acculturation were more likely than highly acculturated Hispanic and non-Hispanic white women ( n = 385) to report personal barriers as reasons for not getting an initial or subsequent screening exam. Such barriers include fear of finding cancer, fear of finding diseases other than cancer, and embarrassment about receiving a physical exam. Certain structural barriers, such as cost of care, no time off work, and lack of transportation, were reported to be associated with non-compliance with routine cervical cancer screening, especially among non-Hispanic white women. Conclusions. Future research should examine barriers related to initial and subsequent screening among Hispanics with varying levels of acculturation.

Genital human papillomavirus infection among women recruited for routine cervical cancer screening or for colposcopy determined by Hybrid Capture II and polymerase chain reaction.

The purpose of this study was to evaluate the clinical use of the Hybrid Capture (HC)-II system for the detection of human papillomavirus (HPV) DNA to identify women at risk of progression to high grade squamous intraepithelial lesions (HGSIL) and carcinomas by differentiating low risk (LR) HPV types (6, 11, 42, 43, 44) and high/intermediate risk (HR) HPV types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68). Five hundred and ninety-six women were enrolled in the study. Among them, 466 attended the hospital for routine cytologic screening and 130 were referred for colposcopy because of an abnormal Pap smear. The presence of HPV DNA was tested in cervical samples collected with the Digene Cervical Sampler in Digene Specimen Transport Medium (Digene Corporation, Silver Spring, MD, U.S.A.) using the HC-II assay. Results were compared with those obtained by polymerase chain reaction (PCR) using the MY09-MY11 primers followed by several hybridizations with specific probes. The overall HPV positivity was 32.9% by HC-II and 37.8% by PCR. Among cytologically normal smears, 19.5% were positive by HC-II (14.3% HR) and 25.1% by PCR. Of the atypical squamous cells of undetermined significance samples, 52.9% were positive by HC-II (41.1% HR) and 55.9% by PCR. Of the low grade SIL, 64.5% were positive by HC-II (59.4% HR) and 68.7% by PCR. The HPV positivity rate was found identical by both techniques in high grade smears (81.6%) and squamous cervical carcinomas (100%). By using PCR as the reference method, the sensitivity of HC-II was higher among women with abnormal cytology than with normal cytology (87.3% vs. 70%). Specificity was 80.8% and 97.5%, respectively. In summary, these results indicate that the HC-II method and MY-PCR identified nearly equivalent prevalences of HPV in cervical smear specimens.

Predictors of compliance with recommended cervical cancer screening schedule: a population-based study.

The prevalence of routine cervical cancer screening and compliance with screening schedules are low compared to the Year 2000 objectives. Identifying predictors of routine screening and screening schedule compliance will help achieve these objectives. We analyzed data from probability samples of 1,609 Missouri women responding to both the 1994 Behavioral Risk Factor Surveillance System (BRFSS) and the Missouri Enhanced Survey (ES). We generated prevalence odds ratios to identify predictors of non-compliance to cervical cancer screening guidelines. Also, among a sample of women reporting a reason for last Pap test, we estimated the relative odds of a screening v. diagnostic exam. In the combined probability sample, compliance with screening schedule was likely among women younger than 50 years of age and women who had either a recent mammography or a clinical breast exam. Being African-American, not experiencing a cost barrier when seeking medical care, having at least a high-school education and health coverage were each associated with an increased compliance with a screening schedule in the combined probability sample. Among women in the combined probability sample, whites, those who experienced no cost barrier to seeking medical care, the non-obese, and those who had a recent mammography were each more likely to have had a screening as opposed to a diagnostic exam. Cancer control and cardiovascular (CVD) prevention programs should consider jointly targeting those at high risk for cervical cancer and CVD because of aging and associated high-risk behavior such as non-compliance with cervical cancer screening, smoking, and obesity. Also, further research is needed to examine whether the increased compliance with cervical cancer screening guidelines among African American women may be in part due to higher occurrence of diagnostic Pap smears.

Breast and cervical cancer among lesbians.

R esearch to date has not represented the full race, class, age, and cultural diversity of lesbians and other women who partner with women. However, there has been recent suggestion that some populations of lesbians may be at increased risk of developing breast cancer based on a confluence of known or suspected risk factors for the disease. The incidence of cervical cancer among lesbians has not been studied, although risk behaviors have been well documented. Lesbians appear to be less likely to receive routine screening for breast and cervical cancer than recommended by accepted standards of care and may therefore be at risk of increased morbidity and mortality resulting from delayed diagnosis and treatment.

Cervical cancer screening with cervicography and cytology

The results of colposcopy and directed biopsies were compared with the cytological findings and cervicography in 1539 asymptomatic outpatients undergoing routine cervical cancer screening in order to compare the accuracy of cervicography and cytology and to assess the potential benefits of the combination of both screening tests. With the new reporting criteria, cervicography looked less sensitive (53% vs. 56%; P = 0.718) and significantly less specific vs. 98%; P = 0.040) than cytology. In comparison with cytology and at the expense of a recall rate of 9%, the combination of both screening tests led to an increase of the sensitivity (77% vs. 56%; P = 0.013) but also to a decrease of the specificity (95% vs. 98%; P < 0.0001) and of the positive predictive value (44% vs. 60%; P = 0.051). When the original reporting criteria were applied to cervicography, the combination of both screening tests led to optimal sensitivity and negative predictive value (100%, respectively) at the expense of an unrealistic recall rate of 20%. Consequently, cervicography should not be considered as an alternative to cytology for cervical cancer screening since its accuracy is not significantly better and its rate of technically defective tests is significantly higher. The combination of both methods increases the sensitivity of cervical cancer screening at the expense of a high recall rate, of which cost effectiveness has to be assessed.

The effect of age, gravidity, and parity on the location of the cervical squamocolumnar junction as determined by colposcopy

Colposcopy was used to determine the location of the squamocolumnar junction in 1,838 patients during evaluation for abnormal Papanicolaou smears. More than 50 per cent of women over 26 years of age or with gravidity and parity of 2 or greater demonstrated an endocervical squamocolumnar junction. The frequency further increased as age, gravidity, and parity advanced. Age is the most powerful predictor of the location of the squamocolumnar junction. As a result of the increasing proportion of patients with endocervical squamocolumnar junctions associated with advancing age, gravidity, and parity, the physician must assign greater importance to the endocervical cytologic specimen in his routine cervical cancer screening.

Assessing the State of Cancer Research

Assessing the State of Cancer Research