Mitchell D. Greenberg

HPV co-factors related to the development of cervical cancer: results from a population-based study in Costa Rica.

We examined factors associated with high-grade squamous intraepithelial lesions (HSIL) and cervical cancer among human papillomavirus (HPV)-infected women in a prevalent case–control study conducted within a population-based cohort of 10 077 women in Costa Rica. We compared 146 women with HPV-positive HSIL or cancer (HSIL/CA) against 843 HPV-positive women without evidence of HSIL/CA. Subjects completed a risk factor questionnaire. We evaluated the associations between exposures and HSIL/CA among women positive for any HPV and restricted to those positive for high-risk HPV types. Risk of HSIL/CA increased with increasing number of live births (Ptrend= 0.04). Women who smoked 6+ cigarettes/day had a RR for HSIL/CA of 2.7 (95% CI = 1.1–6.7) compared to non-smokers. Current use of barrier contraceptives was associated with a reduction in risk of HSIL/CA (RR = 0.39; 95% CI = 0.16–0.96). Sexual behaviour and a self-reported history of sexually transmitted diseases (STDs) other than HPV were not associated with HSIL/CA. Oral contraceptive use was associated with HSIL/CA among women with <3 pregnancies. Effects were similar in analysis restricted to women positive for high-risk HPV types. Among women positive for high-risk HPV types, 44% of HSIL/CA could be attributed to multiparity (≥3 pregnancies) and/or smoking. Among HPV-positive women, multiparity and smoking are risk factors for HSIL/CA. Oral contraceptive use may be associated with HSIL/CA in subgroups of women.

Utility of liquid-based cytology for cervical carcinoma screening: Results of a population-based study conducted in a region of Costa Rica with a high incidence of cervical carcinoma

In a study using a split‐sample design, liquid‐based cytology (ThinPrep® Processor, Cytyc Corporation, Boxborough, MA) was compared with the conventional Papanicolaou (Pap) smear in Guanacaste, Costa Rica. The study provides the first population‐based comparison of the ThinPrep® screening technology and includes “gold standard” measures of diagnostic accuracy.

Sexually transmitted papillomaviral infections: I. The anatomic distribution and pathologic grade of neoplastic lesions associated with different viral types☆☆☆

Multiple colposcopic biopsy specimens were collected from 160 women, with sampling of principal cervical and vulvar lesions as well as secondary areas of either minor acetowhitening or normal epithelium. Papillomaviral deoxyribonucleic acid was detected by Southern blot hybridization in 197 (90%) of the 218 principal biopsy specimens and 93 (46%) of 198 secondary biopsy specimens. Although different papillomaviruses were found at different sites in 31 women, only six of 416 specimens contained multiple types within the same sample. Specific viral types were associated with specific disease patterns. Only one of 80 type 6 or 11 infections had a diagnosis greater than cervical intraepithelial neoplasia, grade 2. In contrast, 42 of 48 (90%) biopsy specimens of cervical intraepithelial neoplasia, grade 3, or invasive cancer contained type 16, 18, or 31. Nonetheless, 12 of 124 (10%) cases of condyloma and cervical intraepithelial neoplasia, grade 1, were associated with types 16, 18, and 31 infections. Of 58 women with multicentric disease, 46 had positive hybridizations for both cervical and vulvar lesions (32 showing the same type in both samples and 14 showing different viruses). Differing patterns of papillomavirus-induced disease arise partly from the predilection of specific viral types for certain anatomic sites and partly through variations in host response. Detection of viral deoxyribonucleic acid in 46% of the secondary biopsy specimens suggests that disease expression may represent focal breakdown of host surveillance within a field of latent papillomaviral infection.

Design and methods of a population-based natural history study of cervical neoplasia in a rural province of Costa Rica: the Guanacaste Project

This paper reports on the enrollment phase of a population-based natural history study of cervical neoplasia in Guanacaste, a rural province of Costa Rica with consistently high rates of invasive cervical cancer. The main goals of the study are to investigate the role of human papillomavirus (HPV) infection and its co-factors in the etiology of high-grade cervical neoplasia, and to evaluate new cervical cancer screening technologies. To begin, a random sample of censal segments was selected and enumeration of all resident women 18 years of age and over was conducted with the aid of outreach workers of the Costa Rican Ministry of Health. Of the 10738 women who were eligible to participate, 10049 (93.6%) were interviewed after giving written informed consent. After the interview on cervical cancer risk factors was administered, a pelvic examination was performed on those women who reported previous sexual activity. The pelvic examination included a vaginal pH determination and collection of cervical cells for cytologic diagnosis using three different techniques. Additional cervical cells were collected for determination of the presence and amount of DNA from 16 different types of HPV, and two photographic images of the cervix were taken and interpreted offsite by an expert colposcopist. Finally, blood samples were collected for immunologic and micronutrient assays. Women with any abnormal cytologic diagnosis or a positive Cervigram, as well as a sample of the whole group, were referred for colposcopy, and biopsies were taken when lesions were observed. The enrollment screening will serve as the basis for a prevalent case-control study, and the members of the cohort free from serious disease will be followed actively, at intervals of no more than a year, to study the natural history of HPV infection and the origins of high-grade squamous intraepithelial lesions (HSIL). Details of the field operation are outlined, with particular reference to the realization of this kind of study in developing countries. Descriptive data on the prevalence of disease and exposure to various risk factors are also presented.

Cervical specimens collected in liquid buffer are suitable for both cytologic screening and ancillary human papillomavirus testing

Several new techniques have been developed to improve the sensitivity of cervical carcinoma screening and reduce equivocal cytologic diagnoses referred to as atypical squamous cells of undetermined significance (ASCUS). This study evaluates the effectiveness of combining two newly introduced diagnostic techniques: preparation of thin‐layer cytologic slides from ThinPrep liquid buffer and selected Hybrid Capture testing for human papillomavirus (HPV) DNA. Because HPV DNA detection has been strongly associated with the presence of a cervical carcinoma precursor (“squamous intraepithelial lesion,” or SIL), HPV testing might be useful for identifying women with ASCUS who have an underlying SIL.

p53 polymorphism and risk of cervical cancer

Storey and co-workers have reported data suggesting that individuals homozygous for arginine at residue 72 of p53 (p53Arg) are about seven times more susceptible to invasive cervical cancer than individuals who carry at least one proline at that position (p53Pro). These preliminary data were supported by in vitro evidence demonstrating that the E6 oncoprotein of human papilloma virus (HPV) degrades p53Arg more efficiently than p53Pro. We have now tested specimens from a total of 1,309 women in three studies for p53 polymorphisms. We find that p53Arg is not associated with an increased risk of preinvasive or invasive cervical neoplasia; indeed, there is a tendency for p53Arg to be associated with a decreased risk of neoplasia.

Should cervical cytologic testing be augmented by cervicography or human papillomavirus deoxyribonucleic acid detection

Criticism of the Papanicolaou smear in the lay press and recent federal legislation regulating cytology laboratories indicate a need to reappraise cervical cancer screening programs. This study directly compares three potential screening tests, used alone or in combination. A total of 1012 women aged 18 to 35 years were screened by cytologic testing, cervicography, and hybridization for human papillomavirus deoxyribonucleic acid, with discrepancies being referred by the last two authors. After findings from the entire lower genital tract were combined, 116 women (11.5%) showed definite clinical abnormalities (either exophytic vulvovaginal condylomas or cervical squamous intraepithelial lesions). Another 72 (7.2%) had positive Southern blot hybridizations without accompanying viral expression, yielding a cumulative frequency for established disease or latent infection of 18.6%. When associated vulvovaginal condylomas are disregarded, final groupings with regard to cervical pathologic classification were: 23 high-grade and 71 low-grade squamous intraepithelial lesions, 164 cases of equivocal atypia (34 of which had detectable human papillomavirus deoxyribonucleic acid), and 754 cases with negative results (38 of which had detectable human papillomavirus deoxyribonucleic acid). Cervical screening tests were compared principally by plotting increasingly liberal recall criteria onto receiver operating characteristic curves (i.e., graphs of true-positive results on the Y axis versus false-positive results on the X axis). Used individually, each screening test was valid, but none was substantially better than the others. No matter how liberal the recall criteria, no single test was able to detect all of the 23 definite precursors in this sample. Applying conventional recall criteria (i.e., high- or low-grade lesion suspected), cytologic testing alone detected 12 high-grade squamous intraepithelial lesions (52.2%), at a cost of having to perform colposcopy in 8.7% of the sample. Combining all three tests and setting the end point as just a high-positive result by at least one test, 19 high-grade squamous intraepithelial lesions (83%) were detected, with a recall of 7%. Optimal test performance (96% sensitivity, 4% recall) would have been attained by recalling all patients with high-grade cytologic results or positive cervicography results, plus any patients with low-grade morphologic atypia in which hybridization detected an oncogenic human papillomavirus type. Our conclusions are as follows: (1) Cytologic detection rates are markedly improved by a second or third test; (2) increased screening costs could be offset by not recalling patients with minor lesions with no apparent potential for progression.

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

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.

Associations between smoking and adenocarcinomas and squamous cell carcinomas of the uterine cervix (United States)

AbstractObjectives: Few studies of smoking and cervical carcinoma have addressed the rare cervical adenocarcinomas or used DNA-based tests to control for human papillomavirus (HPV) infection. Methods: This multicenter case–control study included 124 adenocarcinoma cases, 307 community controls (matched on age, race, and residence to adenocarcinoma cases), and 139 squamous carcinoma cases (matched on age, diagnosis date, clinic, and disease stage to adenocarcinoma cases). Participants completed risk-factor interviews and volunteered cervical samples for PCR-based HPV testing. Polychotomous logistic regression generated adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for both histologic types. Results: Eighteen percent of adenocarcinoma cases, 43% of squamous carcinoma cases, and 22% of controls were current smokers. After control for HPV and other questionnaire data, adenocarcinomas were consistently inversely associated with smoking (e.g. current: OR = 0.6, 95% CI 0.3–1.1; ≥1 pack per day: OR = 0.7, 95% CI 0.4–1.3), while squamous carcinomas were positively associated with smoking (e.g. current: OR = 1.6, 95% CI 0.9–2.9; ≥1 pack per day: OR = 1.8, 95% CI 1.0–3.3). Results in analyses restricted to HPV-positive controls were similar. Conclusion: Smoking has opposite associations with cervical adenocarcinomas and squamous carcinomas. Although both histologic types are caused by HPV and arise in the cervix, etiologic co-factors for these tumors may differ.

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.