Lack of agreement between cervicography and cytology and the effect of human papillomavirus infection and viral load.

OBJECTIVE: Cohort studies of the natural history of human papillomavirus (HPV) infection and cervical squamous intraepithelial lesions with repeated screening allow the comparison of different macroscopic and microscopic diagnostic methods. MATERIALS AND METHODS: Concurrent visual inspection using cervicography and conventional Pap cytology tests were performed during multiple visits in a cohort of women attending a maternal and child health clinic in São Paulo, Brazil. HPV infection status at the same visits was determined by polymerase chain reaction followed by typing with specific oligonucleotide probing and viral load quantification. Information on reproductive health and hygiene habits was also collected at each visit. RESULTS: Overall agreement between cervicography and cytology was low (kappa = 0.046), which increased only slightly when high oncogenic-risk HPV types (kappa = 0.120) or high viral burden (>100 copies/cell) (kappa = 0.170) was present. Analysis of reproductive health and hygiene habits revealed somewhat different risk factors for cervical lesions detected by these tests. However, presence of oncogenic HPV DNA (odds ratio = 36.0, 95% CI = 16.6-77.8) and high viral burden (odds ratio = 67.34; 95% CI = 27.1-167.0) were strongly associated with lesions detected by cytology but not by cervicography. CONCLUSIONS: Although changes in the cervix (because of age, gravidity, or hormonal effects) may influence the performance of morphology-based screening tests, the lack of agreement and the different degrees of association with HPV infection measures indicate that a visual inspection method such as cervicography may detect different cervical abnormalities relative to cytology.

Distribution of human papillomavirus types 16 and 18 variants in squamous cell carcinomas and adenocarcinomas of the cervix.

The distributions of human papillomavirus (HPV) types detected in cervical adenocarcinomas and squamous cell tumors differ. However, whether the distributions of intratypic HPV variants seen in these two histological forms of cervical disease differ is unknown. Our objective was to compare the distribution of HPV intratypic variants observed in squamous cell carcinomas (SCC) and cervical tumors of glandular origin (e.g., adenocarcinomas; AC) for two HPV types commonly observed in cervical tumors, HPV16 and HPV18. Participants in a multicenter case-control study of AC and SCC conducted in the eastern United States were studied. A total of 85 HPV16 and/or HPV18 positive individuals (31 diagnosed with AC, 43 diagnosed with SCC, and 11 population controls) were included. For HPV16-positive individuals, both the noncoding long control region and the E6 open reading frame were sequenced, and classified into phylogenetic-based lineage groups (European, Asian-American, African1, and African2). For HPV18-positive individuals, the long control region region only was sequenced and classified into known intratypic lineages (European, Asian-Amerindian, and African). The distribution of these different intratypic lineages among AC cases, SCC cases, and population controls was compared using standard methods. Non-European HPV16 and/or HPV18 intratypic variants were observed in 42% of ACs compared with 16% of SCCs and 18% of population controls (P = 0.04). Intratypic variants from the Asian-American lineage of HPV16 accounted for the differences seen between histological groups. The differences observed between AC and SCC cases were strongest for HPV16, and persisted in analysis restricted to Caucasian women, suggesting that the effect cannot be explained by differences in the ethnic make-up of AC versus SCC cases. Cervical AC and SCC differ not only with respect to the distribution of HPV types detected but also with respect to intratypic variants observed. Non-European HPV16 and/or HPV18 variants are commonly seen in AC. A possible hormonal mechanism is suggested to explain the observed findings.

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.

Obesity as a potential risk factor for adenocarcinomas and squamous cell carcinomas of the uterine cervix.

BACKGROUND: Hormonal factors may play a more prominent role in cervical adenocarcinoma than squamous cell carcinoma. The authors evaluated whether obesity, which can influence hormone levels, was associated with adenocarcinoma and squamous cell carcinoma. METHODS: This case-control study included 124 patients with adenocarcinoma, 139 matched patients with squamous cell carcinoma, and 307 matched community control participants. All participants completed interviews and provided cervicovaginal samples for human papillomavirus (HPV) testing. Polytomous logistic regression-generated odds ratios (ORs) and 95% confidence intervals (95% CIs) for self-reported height and weight, body mass index (BMI; kg/m(2)), and measured waist-to-hip ratio (WHR) for both histologic types were adjusted and stratified for HPV and other confounders. RESULTS: Height, weight, BMI, and WHR were positively associated with adenocarcinoma. BMI >or= 30 kg/m(2) (vs. BMI < 25 kg/m(2); OR, 2.1 and 95% CI, 1.1-3.8) and WHR in the highest tertile (vs. the lowest tertile; OR, 1.8 and 95% CI, 0.97-3.3) were associated with adenocarcinoma. Neither height nor weight was found to be associated with squamous cell carcinoma, and associations for BMI >or= 30 kg/m(2) (OR, 1.6) and WHR in the highest tertile (OR, 1.6) were weaker and were not statistically significant. Analyses using only HPV positive controls showed similar associations. The data were adjusted for and stratified by screening, but higher BMI and WHR were associated with higher disease stage at diagnosis, even among recently and frequently screened patients with adenocarcinoma. Thus, residual confounding by screening could not be excluded as an explanation for the associations. CONCLUSIONS: Obesity and body fat distribution were associated more strongly with adenocarcinoma than with squamous cell carcinoma. Although questions about screening remain, obesity may have a particular influence on the risk of glandular cervical carcinoma.

Comparison of human papillomavirus genotypes, sexual, and reproductive risk factors of cervical adenocarcinoma and squamous cell carcinoma: Northeastern United States.

OBJECTIVE: Although human papillomavirus causes essentially all cervical carcinoma, cofactors may differ by cancer histologic type. We examined human papillomavirus genotypes and sexual and reproductive risk factors for cervical adenocarcinoma and squamous cell carcinoma. STUDY DESIGN: One hundred twenty-four women with adenocarcinoma, 139 women with squamous cell carcinoma, and 307 control subjects participated in this case-control study. Logistic regression analyses were performed to calculate odds ratios and CIs. RESULTS: Human papillomavirus 18 was associated most strongly with adenocarcinoma (odds ratio, 105; 95% CI, 23-487). Human papillomavirus 16 was associated most strongly with squamous cell carcinoma (odds ratio, 30; 95% CI, 12-77). More than three lifetime sexual partners was a risk factor for adenocarcinoma (odds ratio, 2.1; 95% CI, 1.1-4.0) and squamous cell carcinoma (odds ratio, 3.0; 95% CI, 1.6-5.9). Even being pregnant was associated inversely with adenocarcinoma (odds ratio, 0.4; 95% CI, 0.2-0.8). Five or more pregnancies was associated with squamous cell carcinoma (odds ratio, 2.2; 95% CI, 0.9-5.4). CONCLUSION: The relative importance of human papillomavirus genotypes 16 and 18 and the reproductive co-factor differences suggest distinct causes for cervical adenocarcinoma and squamous cell carcinoma.

Comprehensive analysis of human leukocyte antigen class I alleles and cervical neoplasia in 3 epidemiologic studies.

To comprehensively explore the relationship between human leukocyte antigen (HLA) class I alleles and cervical neoplasia, a subset of participants from 3 large US and Costa Rican cervix studies were typed for HLA class I alleles. Study subjects were women with cervical cancer or high-grade squamous epithelial lesions (HSILs; n=365) or low-grade squamous epithelial lesions (LSILs; n=275) or who were cytologically normal (control subjects; n=681). Allele-disease associations were assessed by logistic regression analysis. Consistent associations across all studies were observed for HLA-CW*0202 with a combined odds ratio of 0.53 (95% confidence interval [CI], 0.29-0.89) for cancer or HSILs and 0.58 (95% CI, 0.37-1.04) for LSILs, compared with control subjects and adjusted for study. This finding supports the hypothesis that a single allele may be sufficient to confer protection against cervical neoplasia. Given the relationship between HLA-C and its receptors on natural killer (NK) cells, a role is proposed for NK function in human papillomavirus infection and cervical neoplasia.

Can cervicography be improved? An evaluation with arbitrated cervicography interpretations.

OBJECTIVE: The purpose of this study was to estimate the optimal performance of cervicography. We compared an arbitrated cervigram classification with an arbitrated referent diagnosis of cervical neoplasia. STUDY DESIGN: From an initial group of 8460 women, a stratified sample of cervigrams from 3645 women and histologic information from 414 women underwent arbitration. Interobserver agreement was assessed for cervicography and the referent diagnosis. Sensitivity, specificity, and predictive values were estimated for initial and arbitrated cervicography results, compared with the initial and arbitrated referent diagnoses. RESULTS: For the detection of arbitrated high-grade lesions or cancer, arbitrated cervicography yielded an overall sensitivity of 63.9% and a specificity of 93.7%. Significantly higher sensitivity was associated with younger age and age-related visual characteristics. CONCLUSION: Optimization of the cervigram classification improved performance over a single interpretation in this population but suggested the limits of static visual screening.

Detection and quantitation of human papillomavirus DNA in the plasma of patients with cervical carcinoma.

Human papillomaviruses (HPVs) play a central role in the development of cervical carcinoma. Plasma DNA from 232 patients taken at diagnosis or after treatment for invasive cervical cancer (n = 175) or carcinoma in situ (n = 57) and 60 normal controls were examined for HPV-16 or HPV-18 E7 DNA by conventional and real-time quantitative PCR assays. We found HPV-16 or HPV-18 E7 DNA in 6.9% (11 of 175) of invasive cervical cancer cases (18.1% of cases positive for HPV-16 or HPV-18 at the genital tract), 1.8% (1 of 57) of carcinoma in situ, and 1.7% (1 of 60) of normal controls by conventional PCR. Quantitative PCR identified the highest concentrations of HPV DNA (copy number of HPV/ml of plasma) in patients with invasive cervical cancer (mean, 11,163; median, 183.5), followed by a level of 8 in the single carcinoma in situ case and 0 copies in the normal control initially positive by conventional PCR. HPV DNA can be detected in the plasma of some patients with HPV-positive cervical tumors. It remains to be demonstrated whether quantitative PCR analysis of HPV DNA in plasma may have utility in patients at high risk of recurrent disease.