High load for most high risk human papillomavirus genotypes is associated with prevalent cervical cancer precursors but only HPV16 load predicts the development of incident disease

Cervicovaginal human papillomavirus (HPV) viral load has been purported as a potential marker for the detection of high-grade cervical intraepithelial neoplasia or cancer (>/=CIN2). To examine disease association with type-specific viral load for the full-range of anogenital HPV infections, we conducted cross-sectional and prospective analyses of approximately 2,000 HPV-infected women from a 10,000-woman population-based study in Guanacaste, Costa Rica with 7 years of follow-up. Cervical specimens were tested for >40 HPV types using a MY09/MY11 L1 consensus primer PCR method with type-specific dot blot hybridization and PCR signal intensity as a measure of viral load. A positive association was observed between prevalent >/=CIN2 and high viral load compared to low viral load for women with baseline single HPV16 infections (OR = 19.2, 95% CI = 4.4-83.2) and single non-16 carcinogenic infections (OR = 9.2, 95% CI = 2.1-39.9). Inclusion of women with multiple HPV types did not substantially change these associations. In prospective follow-up, only women infected with HPV16 alone (OR = 27.2, 95% = 3.5-213.5) had a strong association between high viral load and incident >/=CIN2; non-16 carcinogenic high viral load was not associated with incident >/=CIN2 (OR = 0.7, 95% CI = 0.2-1.9). Single noncarcinogenic type viral load was not associated with increased risk of prevalent or incident >/=CIN2 (OR = 1.2 and 1.1, respectively). In conclusion, carcinogenic high viral load was associated with prevalent >/=CIN2; however HPV16 was uniquely associated with incident >/=CIN2. The extent to which these observations can be translated into clinical practice must be rigorously examined in the context of the method of viral load measurement and the type-specific differences observed for incident >/=CIN2.     

Cervical screening, high-grade squamous lesions, and cervical cancer in illicit drug users

Background and purpose

Women who use illicit drugs (“drug users”) are exposed to human papillomaviruses (HPVs) from lifestyle risks that include sex risk behaviors, human immunodeficiency virus infection, and high levels of tobacco smoking. Both HPVs and tobacco smoking are recognized causes of cervical cancer, but little is known about risk in drug users. We sought to examine risk of cervical neoplasia and to estimate cervical screening prevalence in drug users compared to non-drug-users in Australia.

Methods

Our study linked hospital admission records of women aged 20–54 in 2000–2007 to Pap Test Register and Cancer Registry records for 19,699 with an illicit drug–related admission and 194,089 without. We designed a nested case–control study of risk of cervical intraepithelial neoplasia (CIN) 2/3 and cervical cancer and a cross-sectional study of screening prevalence in this cohort of women.

Results

Drug users were less likely than non-users to be screened in the past 3 years (crude prevalence 47 vs 58 %; prevalence ratio 0.80; 95 % CI 0.78–0.81). Odds ratios (ORs) in drug users, adjusted for cervical screening history and smoking, were 1.13 (95 % CI 1.04–1.23) for CIN 2/3 and 1.43 (95 % CI 0.96–2.15) for cervical cancer. The adjusted ORs in each case were similar in cannabinoid users and users of other drugs.

Conclusions

The increased risks of CIN 2/3 and cervical cancer we observed are probably due to sex risk behaviors and their associated high risk of HPV. Interventions in drug users, such as HPV vaccination and barrier contraception and more cervical screening, might reduce the risk of cervical neoplasia.     

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.     

Reflex Human Papillomavirus Test Results as an Option for the Management of Korean Women With Atypical Squamous Cells Cannot Exclude High‐Grade Squamous Intraepithelial Lesion

Background.

Current guidelines recommend initial colposcopy with biopsy regardless of human papillomavirus (HPV) test results in women with atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesion (ASC-H). The purpose of this study was to evaluate the value of HPV testing in women with ASC-H based on colposcopic pathology results.

Materials and Methods.

A multicenter cross-sectional study was carried out at three academic hospitals and involved 40,847 Korean women who underwent cervical cancer screening with cytology and HPV tests with or without subsequent colposcopic biopsies between January 2007 and December 2013.

Results.

ASC-H was diagnosed in 276 women (0.7%). Only 6 of 68 (8.8%) women with ASC-H who were HPV negative had cervical intraepithelial neoplasia grade ≥2 (CIN ≥2) lesions, whereas 47.4% of the women with ASC-H who were HPV positive had CIN ≥2 lesions. No cases of invasive cervical cancer were diagnosed among women with ASC-H who were HPV negative. Logistic regression analysis was performed using the group with normal Papanicolaou test results and HPV-negative status as the reference group. Women with ASC-H who were HPV positive had a significantly increased risk of CIN ≥2 lesions, whereas no significant increase was observed in patients with ASC-H and HPV-negative status.

Conclusion.

If the result of the HPV test was negative, the risk of CIN ≥2 lesions in Korean women with ASC-H cytology was low. Reflex HPV testing should be an option for the management of women with cytology showing ASC-H to decrease unnecessary colposcopic biopsies, which are expensive and invasive.

Implications for Practice:

Current American Society for Colposcopy and Cervical Pathology guidelines recommend universal colposcopy for the management of women with atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesion (ASC-H) on cytology, regardless of human papillomavirus (HPV) test results. The present study suggested that HPV cotesting in patients with ASC-H cytology can provide more detailed and useful information regarding the risk of high-grade cervical intraepithelial neoplasia (CIN) lesions and the need for further treatment. When the result of the HPV test was negative, the risk of CIN lesions of grade ≥2 in women with ASC-H cytology was low. Consequently, reflex HPV testing, rather than immediately performance of invasive and expensive colposcopy with biopsy, should be an option for the management of women with ASC-H.     

Switch from cytology-based to human papillomavirus test-based cervical screening: implications for colposcopy

Human papillomavirus (HPV) testing is more sensitive than cytology; some cervical cancer prevention programs will switch from cytology to carcinogenic HPV test-based screening. The objective of our study is to evaluate the clinical implications of a switch to HPV test-based screening on performance and workload of colposcopy. Women in the population-based, 7-year Guanacaste cohort study were screened at enrollment using cytology. We also took another specimen for HPV DNA testing and collected magnified cervical photographic images (cervigrams). A final case diagnosis (≥cervical intraepithelial neoplasia [CIN] grade 3, CIN2, 相似文献   

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.

     

HPV prevalence and cervical intraepithelial neoplasia among HIV-infected women in Yunnan Province, China: a pilot study

Objectives: To determine the prevalence of HPV and cervical neoplasia among HIV-infected women insouthwestern China. Methods: Cervical cytology, HPV detection by Hybrid Capture-2™ assay, and diagnosticcolposcopy were followed by cervical biopsy if indicated. Logistic regression analysis was used to analyzeassociations between HPV co-infection and cervical intraepithelial neoplasia (CIN), and HIV-related clinicaland laboratory parameters. Results: Colposcopic-histopathologically proven CIN2+ lesions were present in7/83 (8.4%) HIV-infected women. Nearly half (41/83, 43%) were co-infected with carcinogenic HPV genotypes.HPV co-infection was higher in women with colposcopic-histopathologically proven CIN2+ lesions than womenwith 相似文献   

A comparison of single and combined visual, cytologic, and virologic tests as screening strategies in a region at high risk of cervical cancer.

Increased understanding of human papillomavirus (HPV) infection as the central cause of cervical cancer has permitted the development of improved screening techniques. To evaluate their usefulness, we evaluated the performance of multiple screening methods concurrently in a large population-based cohort of >8500 nonvirginal women without hysterectomies, whom we followed prospectively in a high-risk region of Latin America. Using Youden's index as a measure of the trade-off between sensitivity and specificity, we estimated the performances of a visual screening method (cervicography), conventional cytology, liquid-based cytology (ThinPrep), and DNA testing for 13 oncogenic HPV types. The reference standard of disease was neoplasia > or = cervical intraepithelial neoplasia grade 3 (CIN 3), defined as histologically confirmed CIN 3 detected within 2 years of enrollment (n=90) or invasive cancer detected within 7 years (n=20). We analyzed each technique alone and in paired combinations (n=112 possible strategies), and evaluated the significance of differences between strategies using a paired Z test that equally weighted sensitivity and specificity. As a single test, either liquid-based cytology or HPV DNA testing was significantly more accurate than conventional cytology or cervicography. Paired tests incorporating either liquid-based cytology or HPV DNA testing were not substantially more accurate than either of those two test strategies alone. However, a possibly useful synergy was observed between the conventional smear and cervicography. Consideration of age or behavioral risk profiles did not alter any of these conclusions. Overall, we conclude that highly accurate screening for cervical cancer and CIN 3 is now technically feasible. The remaining vital issue is to extend improved cervical cancer prevention programs to resource-poor regions.     

Cervical human papillomavirus infection and cervical intraepithelial neoplasia in women positive for human immunodeficiency virus in the era of highly active antiretroviral therapy

PURPOSE OF REVIEW: Human papillomavirus (HPV) has been strongly implicated in the pathogenesis of cervical intraepithelial neoplasia (CIN) and cervical cancer. Women who are positive for the human immunodeficiency virus (HIV) have been shown to be at increased risk for cervicovaginal HPV infection and CIN, and cervical cancer is an acquired immunodeficiency syndrome-defining illness. The purpose of this review is to summarize recent studies of cervical HPV infection and CIN in HIV-positive women and to describe the effect of highly active antiretroviral therapy (HAART) on the course of CIN. RELEVANT FINDINGS: HIV-positive women have a higher prevalence of cervical HPV infection than HIV-negative women, and HPV infection is more persistent in the HIV-positive population. The incidence of high-grade CIN is increased in HIV-positive women. HAART has not been shown to affect HPV detection, and data on its effect on the natural history of CIN are mixed. Some studies show no effect of HAART on the natural history of CIN, and others show a statistically significant but modest beneficial effect. SUMMARY: Cervical HPV infection and CIN are clearly increased in HIV-positive women when compared with risk-matched HIV-negative women. HAART appears to have limited ability to clear HPV infection and induce regression of CIN in HIV-positive women. Combined with the high prevalence of cervical HPV infection and CIN, current data suggest that CIN should be aggressively sought and treated in HIV-positive women, including those who have responded well to HAART with good HIV viral load suppression and increasing CD4+ levels.     

Semiquantitative human papillomavirus type 16 viral load and the prospective risk of cervical precancer and cancer.

We examined whether higher human papillomavirus type 16 (HPV16) viral load predicted risk of cervical intraepithelial neoplasia 3 (CIN3) or cancer (together termed > or =CIN3) within a cohort of 20,810 women followed for 10 years with cytologic screening. Semiquantitative viral load for HPV16 was measured on baseline cervicovaginal specimens using a type-specific hybridization probe test with signal amplification. An increased risk of > or =CIN3 associated with higher HPV16 viral load was found only among cytologically negative women in early follow-up, suggesting that these cases were related to the detection of prevalent lesions missed at baseline. Women with higher HPV16 viral load were more likely to undergo ablative treatment during follow-up than those with lower viral load (P(trend) = 0.008), possibly diminishing any additional risk for > or =CIN3 attributable to higher HPV16 viral loads.     

Cervical cancer and herpes simplex virus type 2: Case-control studies in Spain and Colombia,with special reference to immunoglobulin-G sub-classes

Two casecontrol studies, including 449 histologically confirmed cases of cervical intraepithelial neoplasia (CIN) III and 425 controls, and 2 studies on invasive cervical cancer, involving 316 histologically confirmed cases and 330 population controls, were conducted in Colombia and Spain to assess the role of herpes simplex virus type 2 (HSV-2) in cervical neoplasia. Antibodies to this virus were also measured in the sera of 931 husbands of cases and controls. A serological assay using typespecific antigens, glycoprotein C for type I (gC-1) and glycoprotein G for type 2 (gG-2) was employed. Immunoglobulin-G (IgG) subclasses, IgG₁ and lgG3_r were measured in women positive for HSV-2 antibodies. No increase in risk of CIN III or invasive cancer was found in women whose sera or whose husbands' sera were positive to HSV-2. However, compared with women negative to HSV-2, the risk of CIN III progressively increased with increasing levels of IgG₁. The trend was statistically significant in Colombia. There was also a statistically significant increasing trend in risk of invasive cancer with levels of IgG₁ in Spain. The levels of lgG₃ and its ratio to lgG₁, which may indicate recurrent infections, were not associated with the risk of either type of cancer. When the association with lgG₁ was analyzed by human papillomavirus (HPV) DNA status, as determined by polymerase chain reaction, the trend was clearer in women whose HPV status was not determined or in those with negative HPV DNA. These results suggest that the role of HSV-2 is merely marginal and do not support the hypothesis that recurrent HSV-2 infections are of importance for cervical neoplasia.     

Smoking, diet, pregnancy and oral contraceptive use as risk factors for cervical intra-epithelial neoplasia in relation to human papillomavirus infection

Smoking, nutrition, parity and oral contraceptive use have been reported as major environmental risk factors for cervical cancer. After the discovery of the very strong link between human papillomavirus (HPV) infection and cervical cancer, it is unclear whether the association of these environmental factors with cervical cancer reflect secondary associations attributable to confounding by HPV, if they are independent risk factors or whether they may act as cofactors to HPV infection in cervical carcinogenesis. To investigate this issue, we performed a population-based case-control study in the Vasterbotten county of Northern Sweden of 137 women with high-grade cervical intra-epithelial neoplasia (CIN 2-3) and 253 healthy age-matched women. The women answered a 94-item questionnaire on diet, smoking, oral contraceptive use and sexual history and donated specimens for diagnosis of present HPV infection (nested polymerase chain reaction on cervical brush samples) and for past or present HPV infections (HPV seropositivity). The previously described protective effects of dietary micronutrients were not detected. Pregnancy appeared to be a risk factor in the multivariate analysis (P < 0.0001). Prolonged oral contraceptive use and sexual history were associated with CIN 2-3 in univariate analysis, but these associations lost significance after taking HPV into account. Smoking was associated with CIN 2-3 (odds ratio (OR) 2.6, 95% confidence interval (CI) 1.7-4.0), the effect was dose-dependent (P = 0.002) and the smoking-associated risk was not affected by adjusting for HPV, neither when adjusting for HPV DNA (OR 2.5, CI 1.3-4.9) nor when adjusting for HPV seropositivity (OR 3.0, CI 1.9-4.7). In conclusion, after taking HPV into account, smoking appeared to be the most significant environmental risk factor for cervical neoplasia.     

Validation of p16INK4a as a marker of oncogenic human papillomavirus infection in cervical biopsies from a population-based cohort in Costa Rica.

Due to the high prevalence of cancer-associated types of human papillomavirus (HPV) and the poorly reproducible histologic classification of low-grade lesions, identifying infected women at highest risk for cancer prior to neoplastic progression remains a challenge. We therefore explored the utility of p16INK4a immunostaining as a potential diagnostic and prognostic biomarker for cervical neoplasia using paraffin-embedded tissue blocks (punch biopsies and loop electrosurgical excision procedures) obtained from women referred to colposcopy during the enrollment phase of the Guanacaste Project (1993 to 1994). All blocks from 292 women selected by HPV status (HPV negative, nononcogenic HPV positive, or oncogenic HPV positive) and representing the diagnostic spectrum of the population [normal to precancer: cervical intraepithelial neoplasia (CIN) 3] were immunostained for p16INK4a using the p16INK4a research kit based on the monoclonal antibody clone E6H4 (MTM Laboratories, Heidelberg, Germany). For CIN3, the sensitivity of diffuse p16INK4a immunostaining was 100% and the specificity was 95%. For CIN2, the sensitivity and specificity for diffuse staining were 81.1% and 95.4%, respectively. Generalized to the 10,000-woman cohort, this translated to positive predictive value and negative predictive value of 13.9% and 100% for CIN3, respectively, and 20.4% and 99.7% for CIN2 or CIN3, respectively. Of women with an initial diagnosis of less than CIN2 for whom follow-up data for up to 5 to 7 years were available, 44% with diffuse staining developed persistent infection (CIN2 or CIN3). Whereas our data support the diagnostic potential for p16INK4a, further prospective studies with detailed follow-up determining the prognostic capacity of this marker are needed.     

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.     

Validity of combined cytology and human papillomavirus (HPV) genotyping with adjuvant DNA-cytometry in routine cervical screening: results from 31031 women from the Bonn-region in West Germany

Our aim was to improve the accuracy of routine cervical screening by a risk-adapted multimodal protocol with special focus on possible reduction and prognostic assessment of false positive results. A cohort of 31031 women from the Bonn-region in West Germany, median age 36 years, were screened by cytology (conventional or liquid-based), followed by PCR-based HVP detection with genotyping and adjuvant DNA image cytometry, if indicated, in a sequential manner. The true prevalence of high-grade cervical intraepithelial neoplasia and carcinoma (>/=CIN2) was 0.32% in the population as projected from cervical biopsies of 123 women (0.4%), of whom 100 showed >/=CIN2. Sensitivity of the cytology screening program at PapIIID/HSIL threshold for detecting histologically confirmed >/=CIN2 cases was 81%, with specificity, positive predictive value (PPV) and negative predictive value (NPV) of 99, 20.9 and 99.9%, respectively. Of 38 women receiving the complete screening protocol, all the 31 >/=CIN2 cases were correctly detected by cytology alone, 30 by positive high-risk HPV genotype and 30 by aneuploid DNA profile. The combination of the three methods resulted in an up to 6.9% increase in PPV for >/=CIN2 at practically unchanged detection rate with the additional benefit of being able to predict the probable outcome of CIN1 lesions detected as false positives with any single test. Multimodal cervical screening might permit identification of those women with low-grade squamous intraepithelial lesions likely to progress at an earlier and curable stage of disease and lengthen the screening interval in those with transient minor lesions caused by productive HPV infection.     

Socioeconomic status and the risk of cervical intraepithelial neoplasia grade 3 among oncogenic human papillomavirus DNA-positive women with equivocal or mildly abnormal cytology

BACKGROUND: Low socioeconomic status (SES) is a reported risk factor for cervical carcinoma, but few studies have taken into account adequately the possibly confounding effects of oncogenic human papillomavirus (HPV) infection as well as access to screening and subsequent treatment. METHODS: Women (n = 5060 women) with a mean age of 27.5 years and with equivocal or mild cytologic cervical abnormalities were enrolled in the Atypical Squamous Cells of Undetermined Significance/Low-Grade Squamous Intraepithelial Lesion (ASCUS-LSIL) Triage Study (ALTS), a clinical trial that evaluated management strategies. The women were seen every 6 months for 2 years. The enrollment questionnaire assessed three indicators of SES: race/ethnicity, education, and source of payment for medical care. Multivariate logistic regression models were used to identify predictors of oncogenic HPV DNA positivity at enrollment and to assess associations between the SES indicators and risk of cervical intraepithelial neoplasia grade 3 (precancer) and carcinoma (> or = CIN3) identified throughout the study (n = 506 women) among oncogenic HPV-positive women (n = 3133 women). RESULTS: SES indicators were not associated significantly with oncogenic HPV infection after adjustment for age at enrollment, recent and lifetime number of sexual partners, study center, and smoking history. Among women with oncogenic HPV, the risk of > or = CIN3 increased with decreasing education (less than high school education: odds ratio [OR], 2.4; 95% confidence interval [95%CI], 1.5-3.7 vs. completed college). Black women (OR, 0.5; 95%CI, 0.4-0.7) and white/Hispanic women (OR, 0.4; 95%CI, 0.2-0.8) were at decreased risk for > or = CIN3 compared with white/non-Hispanic women. The source of payment for medical care was not associated with risk. CONCLUSIONS: Factors associated with lower SES, such as low education, may serve as a surrogate for unknown factors that influence progression to > or = CIN3 among women with oncogenic HPV infection. In this controlled setting with equalized follow-up and treatment, the decreased risk of > or = CIN3 associated with black and white/Hispanic race/ethnicity could be further examined. Ongoing efforts should emphasize methods for equalizing screening and follow-up among women of varying SES, regardless of race or ethnicity.     

Risk for high-grade cervical intraepithelial neoplasia associated with variants of human papillomavirus types 16 and 18.

BACKGROUND: Although the variant lineages of human papillomavirus (HPV) types 16 and 18 are well established, their individual associations with high-grade cervical intraepithelial neoplasia (CIN) have not been extensively evaluated. METHODS: Study subjects were women participating in the Atypical Squamous Cells of Undetermined Significance/Low-Grade Squamous Intraepithelial Lesion Triage Study who were positive for HPV16 or HPV18 at enrollment. These women were followed every 6 months for 2 years. Viral isolates from enrollment samples were characterized by DNA sequencing and classified as variant lineages. RESULTS: Over a 2-year study period, CIN3 was histologically diagnosed in 291 of the 779 HPV16-positive women and 47 of the 275 HPV18-positive women. Among women without CIN2-3 at enrollment, the risk of subsequent CIN3 was 2.7-fold greater for those with HPV16 African-2 [95% confidence interval (95% CI), 1.0-7.0] and 3.1-fold greater for those with HPV16 Asian American (95% CI, 1.6-6.0), compared with European variants. Relative to infection with HPV18 African variants, the risk associating subsequent CIN3 was 3.8 (95% CI, 0.9-17.2) for infection with HPV18 European variants and 4.8 (95% CI, 1.0-23.6) for infection with HPV18 Asian American variants. Similar associations were observed when the 2-year prevalence of CIN3 was used as the end point. Further, for those with HPV16 European variants, the 2-year prevalence of CIN3 was higher in White women than in African American women (P = 0.01); this trend was reversed for those with HPV16 African-1 variants (P = 0.22). A similar pattern was present for infections with HPV18 European versus African variants. CONCLUSIONS: The lineages of HPV16 and HPV18 variants are associated with differing risks for high-grade CIN.     

叶酸水平及 HPV16感染对妇女发生宫颈癌变的协同作用研究

目的：探讨叶酸水平、HPV16感染及HPV16 E2和E6 mRNA水平与宫颈癌变的关系,并研究叶酸水平及HPV16感染在宫颈癌变中的协同作用。方法选择新发宫颈炎症（ CI）患者40例、宫颈上皮内瘤样变（ CIN）患者80例（ CINⅠ患者36例,CINⅡ／Ⅲ44例）、宫颈鳞状细胞癌（ SCC）患者48例作为研究对象,采用微生物法测定血清叶酸和红细胞叶酸含量,采用PCR检测宫颈癌组织HPV16的感染情况,采用荧光定量PCR检测宫颈癌组织和叶酸体外干预后Caski宫颈癌细胞中HPV16 E2及E6 mRNA水平,检测不同叶酸浓度对Caski和C33A细胞抑制情况。结果 CINⅠ组、CINⅡ／Ⅲ组和SCC 组HPV16感染率分别与CI 组宫颈组织HPV16感染率比较,差异具有统计学意义（ P＜0．05）。CINⅠ、CINⅡ／Ⅲ、SCC 各组HPV16 E2和E6 mRNA水平与CI组比较差异均具有统计学意义（P＜0．0001）。宫颈癌的严重程度与HPV16 E2和E6 mRNA水平均呈明显正相关性,与血清叶酸和红细胞叶酸含量均呈显著负相关性。叶酸浓度与Caski细胞和C33A细胞的相对抑制率及HPV16 E2和E6 mRNA水平呈明显负相关性。结论叶酸水平低、HPV16感染及HPV16 E2及E6 mRNA低表达均与宫颈癌变有关,补充叶酸明显抑制宫颈癌细胞的增殖,逆转HPV16 E2及E6高表达,提示叶酸水平及HPV16感染在宫颈癌变的过程中具有协同作用。     

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.     

Human papillomavirus and cervical neoplasia: A case-control study in Taiwan

As part of a large-scale, community-based cervical neoplastic screening project in rural Taiwan, a case-control study was undertaken to evaluate the etiologic role of human papillomavirus (HPV) infection in this mainly monogamous (2% reported having multiple sexual partners) female population. A total of 88 biopsy-confirmed cases and 261 cytologically normal controls were selected for the study. The case group included 40 cases of cervical intraepithelial neoplasia (CIN) 1, 9 of CIN 2, 36 of CIN 3 and 3 cases of invasive cancer. Cervical swabs collected at screening from study subjects were tested for HPV DNA by an LI consensus primer polymerase chain reaction (PCR)-based technique. HPV DNA was found in 92% of high-grade cases (CIN 2-3 and invasive cancer); 54% of low-grade cases (CIN I); and 9% of controls. HPV was significantly associated with both high-grade and low-grade cervical neoplasia. As reported in Western countries, HPV 16 was the predominant type among HPV-positive high-grade cases. However, HPVs 52 and/or 58 combined were the most common types among HPV-positive low-grade cases and controls. Among women without any high-risk HPV infection (types 16, 18, 31 or 45), those with multiple-type HPV infection had a higher risk for high-grade cervical neoplasia than those with single-type infection. Overall, 91% of high-grade cases and 50% of low-grade cases could be attributed to HPV infection. Our results show that, even in this monogamous population, HPV is the major risk factor for high-grade cervical neoplasia. © 1995 Wiley-Liss, Inc.