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Background: Persistent infection with high-risk human papillomavirus (HR-HPV) is the most important risk factor for the development of cervical cancer, but factors contributing to HR-HPV persistence are incompletely understood. The objective of this study was to test for associations of chronic stress and two aspects of diurnal cortisol secretion (i.e., the cortisol awakening response [CAR] and total cortisol output over the day [AUCgday]) with HR-HPV status at baseline and 12 months later (follow-up)., Methods: We evaluated 188 women (25 ± 3 years) at baseline. Follow-up investigation was restricted to HR-HPV infected women at baseline. Of the initial 48 HR-HPV positive participants, 42 completed the follow-up (16 HR-HPV positive and 26 HR-HPV negative). At baseline and follow-up, we determined HR-HPV status in cervical smears, assessed chronic stress, and repeatedly measured salivary cortisol over the day. At baseline, we analyzed salivary cortisol only in a subgroup of 90 participants (45 HR-HPV negative and 45 HR-HPV positive)., Results: At baseline, higher chronic stress (excessive demands at work: p = .022, chronic worrying: p = .032), and a higher CAR (p = .014) were related to baseline HR-HPV positivity. At follow-up, there was a statistical trend for a positive association between the CAR and HR-HPV positivity (p = .062). Neither the CAR nor the AUCgday mediated the associations between chronic stress and HR-HPV status., Conclusions: Our findings suggest that both chronic stress and diurnal cortisol are related to the presence of HR-HPV infection and may thus play a role in HPV-associated cervical carcinogenesis.

Human papillomavirus (HPV) persistence is the major cause of cervical cancer, but most HPV infections will not persist and risk factors for HPV persistence are not well known. Chlamydia (C.) trachomatis infection seems to also be associated with cervical cancer. We investigated whether C. trachomatis infection is a risk factor for HPV persistence. In a cohort of 12,527 women participating in a population-based HPV screening trial in Sweden, 6,418 women completed testing for HPV DNA by general primer PCR and typing by reverse dot blot hybridization. On average 19 months later, 303 women that had been HPV-positive and had normal cytology at enrollment completed a new HPV test. Environmental exposures were assessed by an 87-item questionnaire. Previous sexually transmitted infections were also investigated by serology. At follow-up, 44% of the women were positive for the same type of HPV DNA as at enrollment. Persistence correlated with length of follow-up (p < 0.01) and condom use seemed to protect against HPV persistence (p < 0.05). The most significant risk factor for persistent presence of HPV DNA was self-reported history of previous C. trachomatis infection (relative risk in multivariate model = 2.09; 95% confidence interval = 1.05-4.18). We conclude that persistence of oncogenic HPV infections is more likely among women with a previous C. trachomatis infection., ((c) 2005 Wiley-Liss, Inc.)

High-risk human papillomaviruses (HPVs) are major etiological agents of cervical cancer. Despite excellent epidemiological evidence for a direct role of HPV-16 in cervical carcinogenesis, molecular pathways underlying carcinogenesis in vivo remain obscure. The E7 gene is required for immortalization and maintenance of the transformed phenotype in vitro; however, little is known about its role for tumorigenesis in vivo. The E7 gene codes for an unstable protein the abundance of which in cervical biopsies is unknown. We show here that E7 protein levels strongly increase during cervical carcinogenesis, underlining its fundamental role in cervical cancer. The E7 protein was found predominantly in the nucleus and to a minor extent in the cytoplasm in the cervical cancer cell line Ca Ski in vitro and in invasive cervical carcinoma in situ, suggesting that nuclear resident E7 plays a major role in cervical carcinogenesis in humans. The retinoblastoma protein (pRb) is a major E7-target in vitro. We show here that pRb expression is initially upregulated in LSIL and disappears in later stages concomitant with increased E7 levels, suggesting that E7-driven degradation of pRb is involved in cervical tumorigenesis in humans.

Muslim women are known to have lower incidences of cervical cancer and/or human papillomavirus (HPV) infection. Here we aim to determine any association that may be present between the oncogenic HPV16/18 infections and abnormal cytological lesions along with demographic and other attributes among Indian Muslim women (n = 478) and compare with the neighboring Hindus (n = 534) from a prospective cohort study. Agewise distribution of both subject-groups is similar. HPV16/18 infection is present in 9.6% Muslims and 7.5% Hindu women. Jointly atypical cells of undetermined significance (a typical cells of undetermined significance) and HPV16/18 are present in seven Muslim and two Hindu women. No high squamous intraepithelial lesions or cervical cancer is detected at the baseline. HPV16/18 infections show trends that varied with age, a nonlinear trend among Muslim women. In Hindu women the prevalence is highest at age < or =24 years, which linearly drops with increasing age. Abnormal cytology increases significantly in both religion-groups with increasing age. The data show that these Indian Muslim women are equally susceptible to HPV16/18 infection and for the development of abnormal cytology. There is a paucity in epidemiological data, which justifies the need to screen women of all religions for cervical cancer (that includes oncogenic HPV testing).

Objectives: In women with HIV-associated immunosuppression, HPV infections have an increased risk of progression to high-grade cervical intraepithelial neoplasia (CIN). With the HAART-induced prolonged survival and more protracted clinical course of AIDS, progression of CIN to cervical cancer (CC) has become a clinically relevant issue, and the mechanisms responsible for HIV-HPV interactions need further elucidation. The study design and analysis of the baseline data of our new project are presented., Material and Methods: This project is a combination of a prospective cohort study of HIV- and HIV+ women, and a retrospective analysis of CIN lesions and cervical cancer. Up to the present, 244 women have been enrolled (17 HIV+) and subjected to epidemiological interview, colposcopic examination, sampling for HPV testing and typing (PCR, InnoLiPA), and HPV serology. The retrospective series of biopsies were analysed for 13 biomarkers (monitoring key molecular events) using immunohistochemistry and tested for HPV by PCR and TaqMan., Results: HIV- and HIV+ women differ in their exposure status to many of the key epidemiological risk factors of cervical cancer, the most significant ones being number of sexual partners (p = 0.0001), age at onset of sexual activity (p = 0.002), and contraception (yes-no) (p = 0.009). The differences in the baseline clinical observations are less dramatic; HIV-positive women had more frequent HSIL PAP tests (p = 0.040), CIN2 or higher in cervical biopsy (p = 0.049), and external genital warts (p = 0.019). The factors predicting intermediate endpoint markers of cervical cancer, i.e., HSIL PAP smear, ATZ2 in colposcopy, and high-grade CIN in biopsy were analysed in univariate and multivariate regression models. All factors significant in univariate analysis were entered in the multivariate model; HIV-status and Pap smear history maintained their independent predictive power of the HSIL Pap test. The most powerful predictor of ATZ2 colposcopy was HSIL in Pap test. Only the HSIL Pap test and ATZ2 colposcopy remained significant independent predictors of high-grade CIN (p = 0.0001 and p = 0.008, respectively) in the multivariate model., Conclusions: The three intermediate endpoint markers are closely interrelated, but predicted in part by different covariantes in the causal pathway to cervical cancer. To elucidate whether the increased risk of HIV-positive women to high-grade CIN is due a) to their different exposure status to the risk factors, b) to the direct effects of HIV, or c) to molecular interactions between HIV and HPV, we need to complete these analyses separately in HIV+ and HIV- women.

Objective: Human immunodeficiency virus (HIV)-infected women are at risk for cervical intraepithelial neoplasia (CIN) and cancer due to impaired immunosurveillance over human papillomavirus (HPV) infection. Life stress has been implicated in immune decrements in HIV-infected individuals and therefore may contribute to CIN progression over time. The purpose of this study was to determine whether life stress was associated with progression and/or persistence of squamous intraepithelial lesions (SIL), the cytologic diagnosis conferred by Papanicolaou smear, after 1-year follow-up among women co-infected with HIV and HPV., Method: Thirty-two HIV-infected African-American and Caribbean-American women underwent a psychosocial interview, blood draw, colposcopy, and HPV cervical swab at study entry. Using medical chart review, we then abstracted SIL diagnoses at study entry and after 1-year follow-up., Results: Hierarchical logistic regression analysis revealed that higher life stress increased the odds of developing progressive/persistent SIL over 1 year by approximately seven-fold after covarying relevant biological and behavioral control variables., Conclusions: These findings suggest that life stress may constitute an independent risk factor for SIL progression and/or persistence in HIV-infected women. Stress management interventions may decrease risk for SIL progression/persistence in women living with HIV.

Insofar as infection with human papillomavirus (HPV) and Chlamydia trachomatis (CT) are associated with cervical intraepithelial neoplasia (CIN), the aim of this study was to assess the correlation of HPV and CT infection in patients with normal or abnormal cytology. Endocervical samples from patients (n=121; mean age 33.7+7.0) were assessed for HPV and CT DNA by PCR. While there was no statistically significant difference between HPV-positive (n=44) and HPV-negative (n=77) patients to age pregnancies, higher proportion of smokers, patients with multiple male sex partners, or with abnormal cytology was seen in HPV-positive vs. HPV-negative women, respectively. An infection rate of CT of 21/44 was seen in HPV-positive as compared to 11/77 in HPV-negative patients. Within HPV-positive patients, there was no significant difference between CT-positive and CT-negative patients with regards to the risk factors studied. Collectively, this suggests that a causal relationship between HPV and CT infection in the development of CIN disease.

Pregnancy may foster the development of infections, in particular HPV infections. The aim of this study was to evaluate the entity of the relationship between HPV infection and pregnancy, with all the possible complications associated with this relationship. The pathology may be latent or manifest. Possible methods of diagnosis are clinical, namely gynecological examinations, PAP-tests, colposcopy or molecular, using viral DNA assay, Southern Blot, PCR, Hybrid Capture, etc. The prevalence of HPV infection in pregnancy varies between 5.4 and 68.8%. The population with the highest risk, also among pregnant women, are those under the age of 26. A number of different opinions emerge from the literature regarding the possibility of maternal-fetal virus transmission. None of the patients examined carried out treatment during pregnancy. The data reported in the literature on the relationship between HPV and pregnancy are highly discordant. This discrepancy depends on the diagnostic techniques used, the clinical history of the pregnant woman and the period of pregnancy when the sample is collected. Pregnancy enhances the development of the pathology which then often recedes in the postpartum. The possible maternal-fetal transmission of the virus is an important aspect: the letter is the main factor responsible for juvenile laryngeal papillomatosis. A number of Authors report an initial presence of HPV in newborns which often disappears within 6 months after birth.

Analogous to the epidemiology of different types of human papillomaviruses (HPVs), variants of a single type such as HPV16 may differ in the natural course of infection. A prospective study was conducted in a cohort of female university students who did not have HPV16 DNA or antibody at enrollment. Subjects were followed every 4 months with Pap smear and colposcopic examinations and tests for HPV DNA and antibody. Of 528 women, 62 acquired HPV16 infection during follow-up. The 5-year cumulative incidence was 12.6% for infection with HPV16 prototype-like variants and 3.1% for infection with non-prototype-like (NPL) variants. Among those with incident HPV16 infection, the adjusted odds ratio of detecting NPL variants was 6.0 [95% confidence interval (CI), 1.3-27.5)] for nonwhite women or white women who had had nonwhite sex partners compared with white women who had not had nonwhite sex partners. As compared with women who had not used hormonal contraceptives in the 8 months prior to the first HPV16-positive detection, the adjusted odds ratio of detecting NPL variants increased from 1.6 (95% CI, 0.3-9.1) for those who had used hormonal contraceptives for 1-4 months to 5.4 (95% CI, 1.0-28.3) for those who had used hormonal contraceptives for 5-8 months (P for trend = 0.04). There was no difference in HPV16 seroconversion rates between women with prototype-like variants and women with NPL variants. The increased risk for biopsy-confirmed cervical intraepithelial neoplasia grades 2 or 3 associated with detection of incident infection by NPL variants was not explained by differences in persistence between the two variant groups, indicating that biological mechanisms other than viral persistence may be responsible for the observed difference in risk for cervical intraepithelial neoplasia grades 2 or 3.

Objective: To compare Hybrid Capture Tube (HCT) and the second-generation Hybrid Capture II (HC II) test for detection of high-risk human papillomavirus (HPV) DNA at the time of colposcopy., Study Design: Colposcopy and HPV testing were performed by HCT and HC II on 1,309 women for evaluation of abnormal Pap smears. Differences in the proportions were tested with chi 2 and 95% CI calculations., Results: When compared to HCT, HC II was more often positive in women with any abnormal Pap smear (44% [95% CI 41-46%] vs. 34% [31-37%], P < .005) and in the subset of women with atypical squamous cells of undetermined significance Pap smears (32% [29-35%] vs. 24% [22-27%], P < .005). HC II was more sensitive in detecting cervical intraepithelial neoplasia (CIN) 2 or worse (93% [88-97%] vs. 78% [70-84%], P < .005) and had a lower rate of undetected > or = CIN 2 in HPV test-negative subjects (1.5% [0.7-2.7%]) vs. 4.3% [3.0-5.9%], P < .005). HC II was also more often positive in women with negative colposcopic evaluations (29% [25.7-32.4%] vs. 20% [17.6-23.5%], P < .005). The specificity of HC II in detection of > or = CIN 2 was lower than that for HCT (63% [60.5-66.2%] vs. 73% [69.5-74.8%], P < .005).

There is suggestive evidence that the use of wood for cooking increases the risk of invasive cervical cancer. We investigated this association in women with cervical neoplasia in Honduras. Women aged 20-64 years with cervical intraepithelial neoplasia (CIN) grade I (n = 44), CIN II (n = 36) or CIN III (n = 45) were recruited from screening programs in Tegucigalpa City and each was matched by age and clinic to 2 controls (241 total) without cervical abnormalities. The clinics selected women of low socioeconomic status. Cervical scrapes were tested for the presence of human papillomavirus (HPV) DNA using a general primer set directed against the L1 open reading frame, and HPV genotyping was performed. Odds ratios (ORs) were computed through conditional logistic regression; p-values were from tests for linear trend of risk with increasing exposure. HPV DNA was detected in 48% of women with CIN I, 67% with CIN II and 89% with CIN III. The ORs were 1.5, 2.5 and 38.3 respectively. At univariate analysis, age at first intercourse was consistently lower among cases than controls. Risk was reduced by 50% or more in all 3 CIN classes when initiation of sexual activity at age 20 years or older was compared with initiation before age 16 years (p = 0.013 for CIN I). No effect was observed for smoking, oral contraceptives or previous cytologic screening. Effects for number of sexual partners, parity, age at first pregnancy and education were in the expected directions but never persisted after adjustment for HPV. Chronic exposure to wood smoke significantly increased the risk of CIN III (p = 0.022). However, women who said "No" when asked if they ever used wood in the kitchen had a higher risk than those with low or intermediate exposure. This was taken as evidence that the initial screening question had either been misunderstood or that answers were biased. Restricting the analysis to women who reported exposure yielded positive associations in all CIN classes with for CIN III ORs of 2.3 for 25-34 and 9.5 for 35+ years compared with women who had 1-14 years of exposure (p = 0.017). A multivariate analysis of the complete dataset (n = 366) allowed for separate ORs for HPV in each CIN class. Inclusion of age at first intercourse significantly improved this model (p = 0.021). Adding exposure to wood smoke further improved the model only if an interaction between woodsmoke and HPV was allowed for. If, as the data suggest, it was assumed that wood smoke had its effect among HPV-positives only, there was a significant linear dose-response relationship between exposure to woodsmoke and risk of CIN (p = 0.026). This association was independent of other risk factors including education, parity and number of sexual partners. ORs in the final model were 0.37 for age at first intercourse 20 years or higher and 5.69 for more than 35 years of exposure to wood burning in the kitchen. The present study suggests that the use of wood for cooking is a risk factor for cervical neoplasia that deserves further study, given its high prevalence in developing countries., (Copyright 2001 Wiley-Liss, Inc.)

Objective: The purpose of this study was to describe the prevalence of human papillomavirus infection and the likelihood of human papillomavirus expression and Papanicolaou test abnormalities among women who have and who are at risk of having human immunodeficiency virus infection., Study Design: Cross-sectional analysis of 767 women who had human immunodeficiency virus infection and 390 women who were at risk of having human immunodeficiency virus infection in 4 cities in the United States., Results: Women who were infected with human immunodeficiency virus were more likely than women who were not infected to have human papillomavirus infection (prevalence ratio, 2.3; 95% CI, 2.0-2.8) but had similar human papillomavirus types. Among women who tested positive for human papillomavirus by polymerase chain reaction, human immunodeficiency virus infection was associated with a high level of human papillomavirus expression (prevalence ratio, 1.3-1.6) and multiple human papillomavirus infections (prevalence ratio, 1.9). However, among women with a high level of human papillomavirus expression or infection with multiple types, there was no association between human immunodeficiency virus serostatus and risk of cervical dysplasia., Conclusion: Through its association with a high level of expression and multiple human papillomavirus infections, human immunodeficiency virus infection may increase the risk of cervical dysplasia in women who are infected with human papillomavirus.

Objectives: This case-control study was conducted to investigate the role of viral load of high-risk human papillomaviruses (HPVs) in the development of cervical squamous intraepithelial lesions (SILs) and invasive cancers., Methods: A total of 30 female cases who had histological evidence of low-grade SIL (n=10) or high-grade SIL and above (n=20) were identified as the case group at the Tri-Service General Hospital, Taipei between September 1998 and March 1999. In addition, 80 female controls who had normal cervical cytology were enrolled and individually matched on age (+/-5 years) and date of recruitment to each case. Cervical swabs collected from study subjects were tested for the positivity and viral load of high-risk HPVs by Hybrid Capture II assay. Additionally, subjects completed a risk factor questionnaire., Results: Among sex behavioral factors studied, younger age at first intercourse was associated with a significantly elevated risk of cervical SIL and invasive cancers. With respect to HPV infection, high-risk HPV DNA was present in 70% (21/30) of case and 21% (17/80) of control subjects, resulting in an odds ratio (OR) of 6.6 [95% confidence interval (C.I.)=2.6-17.0]. Moreover, women who had a high viral load were at significantly greater risk for cervical SIL and invasive cancers than those who were infected with a low viral load (OR=18.0, 95% C.I.=3.0-108.5)., Conclusions: Among the variables tested, infection with a high viral load of high-risk HPVs is the strongest determinant for cervical SIL and cervical cancers in Taiwan.

Few studies have evaluated the role of passive smoke exposure and cervical neoplasia risk. We assessed the role of active and passive cigarette smoke exposure and risk of cervical squamous intraepithelial lesion (SIL) in a case-control study based in a South Carolina Health Department; 59 high-grade SIL (HSIL) cases, 313 low-grade SIL (LSIL) cases and 427 controls were recruited and interviewed. Passive cigarette smoke exposure was significantly (P < 0.05) associated with high grade SIL (adjusted odds ratio (aOR) = 2.2) and low-grade SIL (aOR = 1.4). Active smoking was associated with SIL only among White women (aOR = 1.8). High-risk human papillomaviruses (HR-HPVs) appear to interact with active cigarette smoking to increase HSIL risk. HSIL cases compared with LSIL cases were significantly more likely to be HR-HPV positive current smokers (aOR = 3.0; 95% CI: (1.2, 7.7)). These data suggest that active and perhaps passive smoke exposure may be important co-factors in HSIL development among HR-HPV positive women.

Background: The effect of smoking on human papillomavirus (HPV) activity and subsequent dysplasia and neoplasia remains controversial., Objective: To determine any reported effects of smoking on either HPV activity or HPV-related dysplasia/cancer using retrospective analysis of the literature from 1966 through 1998 via Toxline and PubMed to search for "smoking," "papillomavirus," and "cancer.", Conclusion: Several recent large studies demonstrated that smoking was associated with a greater incidence of cervical, vulvar, penile, anal, oral, and head and neck cancer in a dose-dependent fashion, while other studies did not show any correlation between smoking and cervical dysplasia after multivariate adjustment. Recent studies have also indicated that smoking may be more closely related to high-grade lesions of the cervix and vulva. These data provide evidence of an association between HPV, smoking, and cancer. Progression of dysplasia likewise seems to be associated with smoking. Several groups have attempted to discern whether the connection between smoking and cervical cancer is from local immunosuppression and/or from direct carcinogenic effects.

High-risk human papillomaviruses (HR-HPV) are the necessary cause of cervical carcinomas. To determine whether HPR-HPV DNA detection in primary routine screening could represent a sensitive and reliable technique for the detection of high-grade squamous intraepithelial lesions (HGSIL), laboratory analysis using 2 cytologic techniques (conventional and liquid-based), HPV testing with Hybrid Capture II assay (HC-II), followed by colposcopic examination of women with abnormal cervical finding and/or persistent HR-HPV infection, was conducted in 7932 women who had routine cervical examination. The sensitivity of HPV testing for detecting a histologically proven HGSIL was 100%, higher than that of conventional (68.1%) and liquid-based (87.8%) cytology. The low specificities of 85.6% and 87.3% of HPV testing slightly increased to 88.4% and 90.1% if HPV testing was reserved for woman >30 years old. The quantitative approach provided by the HC-II assay for the assessment of the viral load was not reliable for predicting HGSIL in normal smears. HR-HPV testing could be proposed in primary screening in association with cytology. With conventional cytology it significantly improves the detection of HGSIL. With the use of the same cervical scrape for HPV testing and liquid-based cytology, HR-HPV testing would allow to select positive samples treated in a second time for cytology which gives a good specificity., (Copyright 2001 Cancer Research Campaign.)

GENERAL DATA: There is now considerable evidence that high risk human papillomaviruses (HPV), such as HPV 16, are closely associated with cancer of the cervix. HPVs that are primarily transmitted through sexual contact, are found in over 99% of the cases of invasive cervical cancer. Although most women can be infected during their sexual life, a small minority is at risk for developing cancer. The long latency period between primary infection and cancer emergence suggests that additional factors are involved in the process of tumor development: sexual behavior, immune status, genetic predispositions, nutritional status, tobacco use, socio-economical level. NATURAL HISTORY: HPVs infect epithelial cells of the transformation zone of the cervix. As with other sexually transmitted diseases, the incidence of HPV infection is highest among young women. However, this viral infection is more often than not transient, because most individuals develop an effective type-specific immune response. Approximately 1% of the population has genital warts and 4% of women have cervical precancerous lesions: low grade squamous intraepithelial lesion (LGSIL) or high grade SIL. These last lesions preferentially observed in women aged 35-40 yrs are at high risk of progression towards an invasive cancer. ONCOGENIC POTENTIAL OF HPV: Pre-malignant and malignant cells arise as a result of HPV DNA integration in the host cellular genome, and overexpression of the viral E6 and E7 oncogenes. Cells acquire a proliferative advantage by escaping growth control exerted by p53 and p 105Rb. Both cellular proteins are indeed inactivated respectively by E6 and E7 proteins. Aneuploidy and karyotypic abnormalities are also key events in the tumor progression. A PREVENTABLE DISEASE: Cervical cancer is more than ever a preventable disease. While waiting for clinically applicable vaccination programs, strategies to prevent cervical cancer include 1) improved screening covering the widest possible population and using HPV testing, 2) close management and follow-up of women with precancerous lesions.

Between September 1991 and September 1993, husbands of women with and without cervical neoplasia and commercial sex workers in one brothel and one massage parlor in Bangkok, Thailand, were interviewed; serologic tests for sexually transmitted infections were performed; and cervical and penile scrapings were tested for human papillomavirus (HPV) DNA. The risks of cervical carcinoma in monogamous women and of oncogenic HPV in their husbands were associated with the men's having unprotected intercourse with prostitutes. The prevalence of oncogenic HPV was higher in commercial sex workers than in women attending gynecologic and family planning clinics. Oncogenic HPV prevalence declined with age in human immunodeficiency virus (HIV)-negative, but not in healthy HIV-positive, commercial sex workers and was weakly associated with hepatitis B antigenemia, suggesting that persistence of HPV infection is due to subtle changes in immunity. Associations of HPV with recent pregnancy and oral contraceptive use suggest that hormonal factors may increase the risk of cervical neoplasia by enhancing persistence of HPV infection. The prevalence of high-grade squamous intraepithelial lesions was strongly related to oncogenic HPV types and weakly to HIV infection only in their presence. Commercial sex workers in Bangkok are reservoirs of oncogenic HPV, and cervical cancer in monogamous Thai women develops in part as a result of transmission of these viruses to them by their husbands from prostitutes.

To distinguish risk factors for acquisition of cervical human papillomavirus (HPV) infection from the determinants of neoplasia among infected individuals we have conducted a three-arm case-control study nested within a large population-based cohort of women (the Manchester cohort) screened for HPV at entry using L1 consensus primer PCR. The study includes 181 HPV-positive controls who did not develop high-grade cervical intraepithelial neoplasia (CIN3) during follow-up, 203 HPV-negative controls, and 199 HPV-positive cases with histologically confirmed CIN3. Detailed information on sexual, reproductive and gynaecological history, oral contraceptive use and smoking was obtained at face-to-face interview. There was a striking division between risk factors for infection and those predictive of disease. Comparing the HPV-positive against the HPV-negative controls, the only risk factors for infection were number of sexual partners (OR for six or more = 3.89; 95% Cl = 1.99-7.62), a relatively recent new sexual relationship (OR for a new partner within the previous 2 years = 4.17; 95% Cl = 2.13-8.33), and a history of previous miscarriage (OR = 2.59; 95% Cl = 1.28-5.21). The determinants of CIN3 among infected women were, in contrast, early age at first intercourse (OR for 16 years old or less = 3.23; 95% Cl = 1.33-7.69), a long time since starting a new sexual relationship (OR for 6 years or more = 4.94; 95% Cl = 2.51-9.71), and cigarette smoking, with strong evidence for a dose- response (OR for current smoking habit 20+ per day = 2.57; 95% Cl = 1.49-4.45). Oral contraceptive use was not significantly associated with either HPV infection or CIN3., (Copyright 2000 Cancer Research Campaign.)

The authors assessed risk factors for cervical intraepithelial neoplasia (CIN) among southwestern American Indian women using case-control methods. Cases were New Mexico American Indian women with biopsy-proven grade I (n = 190), grade II (n = 70), or grade III (n = 42) cervical lesions diagnosed between November 1994 and October 1997. Controls were American Indian women from the same Indian Health Service clinics with normal cervical epithelium (n = 326). All subjects underwent interviews and laboratory evaluations. Interviews focused on history of sexually transmitted diseases, sexual behavior, and cigarette smoking. Laboratory assays included polymerase chain reaction-based tests for cervical human papillomavirus infection, tests for gonorrhea and chlamydia, wet mounts, and serologic assays for antibodies to Treponema pallidum, herpes simplex virus, and hepatitis B and C viruses. In multiple logistic regression analysis, the strongest risk factors for CIN II/III among American Indian women were human papillomavirus type 16 infection (adjusted odds ratio (OR) = 7.6; 95% confidence interval (CI): 2.4, 23.2), any human papillomavirus infection (OR = 5.8; 95% CI: 3.3, 10.0), low income (OR = 3.3; 95% CI: 1.7, 6.2), and history of any sexually transmitted disease (OR = 2.0; 95% CI: 1.1, 3.5). Unlike previous research, this study found no strong associations between CIN and sexual activity or cigarette smoking.

Introduction: The establishment of human papillomavirus (HPV) infection as a major cause of cervical neoplasia has resulted in major efforts to develop prophylactic HPV vaccines for prevention of cervical neoplasia. Cervical cancer and the other HPV-associated cancers constitute a major public health burden and eradication of the major causative infection is certainly the most appealing long-term preventive measure. Nevertheless, the effects of preventive HPV vaccination will need to be estimated and compared for (cost-) efficacy with other primary prevention and with secondary prevention programs. However, estimating the effects of preventing a causative exposure is complicated when the exposure is a transmissible infection. The spread of the epidemic is dynamic and may change over time depending e.g. on the changes in human behavior. Depending on the circumstances, prevention of an infection may have either greater or lesser effects than the prevention of a non-infectious exposure. Estimating the time trends in HPV infections and the underlying trends in the risk of cervical neoplasia is important for estimating effects of interventions., Method: A literature review on recent evidence on time trends in cervical neoplasia, compared with evidences on time trends in HPV infections and interactions between different types of HPV infections., Results: In Finland, there has between 1991 and 1995 been a 60% increase in the incidence of cervical cancer among women <55 years of age. Trends in detection rates of cervical cancer precursor lesions are consistent with an increase in the background cervical cancer risk. From the 1960s to 1980s, there has been a major increase in HPV seroprevalences over time in the Nordic countries. Increasing trends are also seen for other sexually transmitted diseases and smoking. Several studies indicate the existence of interaction between benign and oncogenic HPV types, thus making the relationship between the incidences in HPV infections and in cervical neoplasia complex., Conclusion: The increase in cervical cancer is paralleled by increases in HPV infection, other STDs and smoking and changes in screening practices, all of which may have contributed. Prediction of the effect on cervical cancer incidence of changes in HPV incidences is complicated by the existence of several risk factors, the protective effect of screening and by the population dynamics of HPV infections.

Introduction: Cervical cancer is frequently associated with infection from various types of human papillomavirus (HPV) with high a oncogenic potential (high-risk types). Commercial systems for HPV typing are available, but the question as to when HPV typing should be performed has not yet been solved., Objectives: To assess the value of HPV typing in a clinical setting in a population with opportunistic screening., Study Design: Cytology, histology and HPV status of 593 patients from a high-risk collective were evaluated retrospectively. For HPV typing, the hybrid capture (HC) system was used., Results: Infection with high-risk types of HPV was associated with more severe cervical lesions. Women with PAP III or PAP IIID who were infected with high-risk HPV were at increased risk for high-grade cervical lesions (CIN III+) (p = 0.006). Conization influenced HPV status: of 63 patients who were HPV high-risk positive before conization, 4 remained positive afterwards., Conclusion: HC appears to be a useful system to triage women with PAP III or IIID and to detect patients with residual HPV infection after conization. However, because of high costs and no significant increase in the sensitivity of cytology, the use of HPV typing in routine cervical screening cannot be recommended in countries with opportunistic annual cytological screening.

Human papillomaviruses (HPVs) are the major aetiological agents of cervical carcinoma. In this review, epidemiological and molecular data are combined to present a model for HPV-induced cervical carcinogenesis. The impact of current knowledge regarding diagnostic and therapeutic approaches is shown, i.e. the use of HPV tests in cervical cancer screening, in the management of atypical smears of uncertain diagnosis and in smears indicative of mild dysplasias, as well as in follow-up examinations during and after therapy. In addition, the value of the two most frequently used HPV detection systems, polymerase-chain reaction (PCR) and hybrid capture (HC) analysis, is discussed.

The reliability of the Hybrid Capture II (HC-II; Digene, Silver Spring, MD, U.S.A.) assay was tested in detecting 18 human Papillomavirus (HPV) types for the screening of cervical lesions. Cytology, HPV testing, colposcopy, and biopsy were used to monitor 204 women with normal smears at the first entry. The median follow-up was 15 months (range, 4-27 months). The primary endpoint was clinical progression defined as the presence of a cervical intraepithelial lesion at the biopsy. In the patient population of 204 HPV-infected women, 81 (39.7%) had a persistent HPV infection at two or three examinations with a final histologic diagnosis of 14 high-grade and 13 low-grade squamous intraepithelial lesions (SIL) within 4 to 22 months. Women with regressive HPV infection did not develop any lesion during the same period. The evaluation of the viral load of high-risk HPV by the HC-II did not represent a sensitive approach to predict the persistence or the apparition of high-grade lesions. Thus, persistent high-risk HPV infection detected with HC-II represents a reliable tool to select populations at risk for the development of high-grade cervical lesions.

Increased risk for cervical intraepithelial neoplasia (CIN) in human immunodeficiency virus (HIV)-infected women may be explained by repeated positivity of human papillomavirus (HPV) infection facilitated by HIV infection and related immunosuppression. As part of a longitudinal study with semiannual examinations, 268 women in Baltimore, Maryland (of whom 184 were HIV+), provided 1,426 cervicovaginal lavage specimens tested for HPV DNA by a polymerase chain reaction-based assay between 1992 and 1998. HPV positivity and time to HPV clearance according to HIV serostatus and CD4+ cell count were compared using models for correlated binary data and survival analysis. Of the 187 participants who had at least one positive measurement, the probability of subsequent HPV positivity among HIV- women and HIV+ women with CD4+ > or =200 and <200 cells/microl was 47.5%, 78.7%, and 92.9% (p < 0.001). Within-women HPV results were correlated (i.e., clustered) in each group (p < 0.01). Compared with HIV-participants, the relative incidence of HPV clearance was 0.29 and 0.10 among HIV+ women with CD4+ > or =200 and <200 cells/microl (p < 0.001). At the end of follow-up, 11 women had biopsy-confirmed CIN. The association of HIV and CIN (p = 0.014) was fully explained by repeated HPV positivity induced by HIV infection (p = 0.648). Reversal of immunosuppression following potent antiretroviral therapy must be expected to have a dramatic impact on HIV-related CIN.

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.

Cervix intraepithelial neoplasia grade III (CIN III) is an intraepithelial proliferative process with different levels of severity depending on both the extension of the proliferation in the epithelium and the presence of cellular atypia. Human papillomavirus (HPV) has been clearly associated with such lesions. The results of a preliminary study are described on the local application of cidofovir, an acyclic nucleoside phosphonate derivative with broad-spectrum anti-DNA virus activity for the treatment of CIN III. Cidofovir 1% in gel was applied three times, every other day, on the cervix of each of 15 women with biopsy proven CIN III. Within 1 month after the start of treatment, the cervix was removed surgically. Histology and human papillomavirus polymerase chain reaction (HPV-PCR) were carried out. In 7 of the 15 patients the histology showed a complete response, whereas 5 patients had a partial response characterized by the persistence of CIN II-III lesions, 1 patient had a dysplasia of lower grade (CIN I), and 2 patients did not show differences in the histology. Complete response was confirmed by PCR in 4 of the 7 patients, with complete response histologically. Cidofovir was not toxic to the normal epithelium. Cidofovir 1% gel was able to inhibit partially or completely cervical dysplasia lesions after only three applications (every other day). This effect was specific and tissue other than the dysplastic epithelium was not affected by the treatment., (Copyright 2000 Wiley-Liss, Inc.)

Minority women in the United States experience a disproportionately high burden of the more than 2 million yearly cases of squamous intraepithelial lesions of the cervix. Risk factors for squamous intraepithelial lesions of the cervix are infection with the sexually acquired human papillomavirus (HPV), an early age at first intercourse, history of multiple sexual partners, oral contraceptive use, high parity, lower socioeconomic status, poor diet, immunosuppression, and promiscuous male sexual partners. Although Hispanics are the largest growing minority population in the United States, few HPV risk factor studies have either included or focused on Hispanics in the United States. To determine risk factors for HPV infection among Mexican-American women, we conducted a cross-sectional study from 1992-1995. Nine hundred and seventy-one women, 18-47 years of age, with cytology results were included in this analysis. Overall, 13.2% of participants were HPV positive by the Hybrid Capture tube method for high-risk types 16, 18, 31, 33, 35, 45, 51, 52, or 56. Age [adjusted odds ratio (AOR) = 0.3 for ages >36 years compared with ages 18-20] and duration of oral contraceptive use (AOR = 0.4 for > or =4 years relative to nonusers) were inversely associated with these high-risk types of HPV infection. Marital status (AOR = 1.9 among single women compared with married) and lifetime number of sexual partners (AOR = 2.3 for women > or =5 partners relative to monogamous women) were positively associated with an increased risk. Participants born in Mexico were significantly (P < 0.05) older, had fewer sex partners, and older age at first intercourse. Despite this lower behavioral risk profile, women born in Mexico were significantly more likely (AOR = 1.9; CI = 1.2-3.2) to have an HPV infection compared with United States-born, Mexican-American women after adjustment for potential confounders. Collectively, these results suggest that an unmeasured factor, such as the sexual behavior of the male partner, may be influencing HPV risk. Further research is needed to define this factor and to assess cultural norms of sexual behavior.

Background: Little is known about the natural history and the malignant potential of low-grade cervical intraepithelial neoplasia associated with human papillomavirus (HPV) infection. Cervical cancer remains the second most frequent cause of death in women across the world. Epidemiologic and molecular studies have shown that human papillomavirus (HPV) is associated with cervical carcinogenesis. In this prospective study we examined the behavior of low-grade cervical intraepithelial lesions associated with HPV infection over a 6-year period., Material and Methods: During 1992, women with Papanicolaou smears reporting koilocytotic atypia (HPV effect) with or without grade 1 cervical intraepithelial neoplasia (HPV +/- CINI, low grade squamous intraepithelial lesions, LgSIL), along with colposcopic impression of LgSIL were included to the study. Between 1992 and 1998 all women underwent repeat Papanicolaou smears, colposcopic evaluation and HPV DNA testing every six months. HPV typing of cervical scrapes was done by PCR., Results: A total of 330 women completed at least 6 years of follow up. Among women with high-risk HPV types (16/18), the presence of dysplasia (grade 1 cervical intraepithelial neoplasia) was significantly correlated with the progression of the lesion; 29% of cases with HPV + CINI (15 out of 75) progressed to more severe lesions versus only 9% of cases with HPV infection (18 out of 225), P < 0.001, chi-square test. The incidence of histologically confirmed progressive lesions was significantly greater in women with mild dysplasia (18 out of 75, 24%) compared to women without dysplasia (13 out of 255, 5%), P < 0.001, chi-square test., Conclusions: In our study HPV typing was not predictive of the evolution of low-grade intraepithelial lesions associated with HPV infection. Standard cytologic screening and colposcopy are the most effective means of monitoring low-grade lesions.

The activation of HPV-specific T cells within the cervical microenvironment is likely to play an important part in the natural history of cervical intraepithelial neoplasia (CIN). The extent and the type of T cell activation will depend critically on the expression of MHC, costimulatory cell surface molecules and cytokines by keratinocytes and Langerhans cells within the cervical lesion. Expression of MHC class II (HLA-A-DR and -DQ), costimulatory/adhesion molecules (CD11a/18, CD50, CD54, CD58 and CD86) and cytokines (tumour necrosis factor-alpha (TNF-alpha) and IL-10) was therefore investigated by immunohistochemistry in normal squamous epithelium (n = 12), low-grade (n = 23) and high-grade (n = 18) squamous intraepithelial lesions of the cervix. CIN progression was associated with de novo expression of HLA-DR and CD54, and increased expression of CD58 by keratinocytes. However, significantly, there was no expression of any adhesion/costimulation molecule by epithelial Langerhans cells in any cervical biopsy studied. Furthermore, TNF-alpha, a potent activator of Langerhans cells, was expressed constitutively by basal keratinocytes in normal cervix (12+/12). but expression of this cytokine was absent in a number of CIN samples (20+/23 for low-grade, 12+/18 for high-grade CIN). Conversely, the suppressive cytokine IL-10 was absent in normal epithelium (0+/12), but was up-regulated in a number of CIN lesions (12+/23 for low-grade; 8+/18 for high-grade CIN). The restricted expression of costimulation/adhesion molecules and the nature of the cytokine microenvironment within the epithelium may act to limit effective immune responses in some CIN lesions.

Purpose: There is strong evidence that papillomavirus infections (HPV), especially infections with HPV 16/18, are involved in the development of dysplasia and cancers. Cervical cancer is thought to be increased in women with systemic lupus erythematosus (SLE)., Methods: To assess this risk we studied cervical smears from 11 women with SLE and determined the prevalence of HPV infection by in situ hybridization., Results: Dysplasia was found in 9% of women with SLE and in 0.03% of control subjects (non significant difference). Dysplasia was found to be six times more frequent in women with SLE (18% versus 3%, P < 0.01). HPV prevalence in normal smears was 37.5% in women with SLE versus 14.7% in control subjects (non-significant difference). Identified HPV genotypes were those for which intermediate or high risk is well established. No correlation was found between infection or dysplasia risk and the lymphocyte count or a previous treatment with cyclophosphamide., Conclusion: We conclude that women with SLE would be at increased risk of HPV infection, dysplasia and cervical cancer. We suggest that women with SLE should be regularly tested for cervical cancer by colposcopy, especially in case of HPV 16 infection.

A cytological examination of 425 sexually active females aged 13-17 established cervical HPV infection incidence at 30.3 +/- 2.2% while that of cervical dysplasia--4.5 +/- 1.0%. The risk factors for HPV infection included low education and income level (p < 0.05), number of sexual partners exceeding three (p < 0.05), poor hygienic standards of woman (p < 0.05) and those of partner (p < 0.001) and smoking of more than 5 cigarettes per day (p < 0.001). The risk factors of cervical epithelial dysplasia were number of partners of 5 or more (p < 0.001), poor hygienic standards of male partner (p < 0.001) and smoking of 10 cigarettes and more per day (p < 0.001), etc.

There was planed a cycle of works devoted to the title problem. The aim of the first of them was evaluation in our material influence of HPV infection on dysplasia progression of cervical squamous epithelium in correlation to the detected HPV type.

Genital human papillomavirus (HPV) infection is the major causal factor of cervical intraepithelial neoplasia (CIN). The potential role of nutrition as an additional, independent risk factor for CIN has not been appropriately addressed in the context of HPV. This case-control study evaluated the etiologic role of HPV in terms of viral type and load and examined the association between CIN and plasma levels of micronutrients adjusting for HPV. Cases (n = 378) with histo-pathologically confirmed CIN and controls (n = 366) with no history of abnormal Pap smears were recruited from colposcopy and gynecology clinics, respectively. Risk of CIN was significantly increased among women who were infected with multiple HPV types (odds ratio [OR] = 21.06), a high viral load (OR = 13.08) and HPV 16 (OR = 62.49). After adjusting for HPV positivity and demographic factors, there was an inverse correlation between plasma alpha-tocopherol and risk of CIN (OR = 0.15). Plasma ascorbic acid was protective at a high level of > or = 0.803 mg/dl (OR = 0.46). CIN was not associated with plasma retinol and beta-carotene levels. The effect of genital HPV infection on CIN development is highly influenced by oncogenic viral type and high viral load. Vitamins C and E may play an independent protective role in development of CIN that needs to be confirmed in prospective studies.

Although genital human papillomavirus (HPV) infection is well established as the etiologic agent for cervical intraepithelial neoplasia (CIN), little is known about the cofactors involved in the development of high-grade lesions or the progression of low-grade to high-grade lesions. In our study of HPV-infected women with CIN (163 CIN I, 51 CIN II and 44 CIN III), women with CIN II or III were compared with those with CIN I for risk factors associated with high-grade lesions. After controlling for age, education, ethnicity and frequency of Pap smear screening, infection with HPV 16, but not high viral load or infection with multiple types, was associated with high-grade lesions (OR for CIN II = 11.96, OR for CIN III = 23.74). Risk of CIN III, but not CIN II, increased with number of cigarettes smoked per day (ORs = 1.49 and 3.35 for < or = 10 and > 10 cigarettes per day, respectively) and decreased with frequency of condom use during sex (ORs = 0.60 and 0.32 for women who used condoms occasionally/sometimes and most/all of the time, respectively). There were no associations between high-grade lesions and plasma levels of micronutrients (retinol, beta-carotene, alpha-tocopherol and reduced ascorbic acid). Our results indicate that infection with HPV 16 is associated with high-grade lesions. Additional cofactors, such as cigarette smoking, may be required as a carcinogen to advance HPV-infected cells toward neoplastic progression.

Background: This cross-sectional study was designed to evaluate the role of cigarette smoking and high-risk HPV types as risk factors of CIN 2 and 3 in young, sexually active Brazilian women., Materials and Method: A series of 100 consecutive women with abnormal Pap smears were recruited, subjected to colposcopy, punch biopsy, and questionnaire for their social, sexual and reproductive factors. Of these, 77 women between 20 and 35 years of age (median 26.5 years) with biopsy-confirmed CIN 1 or CIN 2 and 3, were enrolled in this study. Representative samples from the exocervix and endocervix were obtained for HPV testing with the Hybrid Capture HPV-DNA assay, including the probes for the oncogenic HPV types (16, 18, 31, 33, 35, 45, 51, 52 and 56)., Results: The overall rate of CIN 2 and 3 was 23/77 (29.8%). The women with CIN 1, 2 and 3 did not differ from each other with regard to their age, race, schooling, marital status, lifetime number of sexual partners, age at first intercourse, use of oral contraceptives, or parity. However, current cigarette smoking was strongly associated with CIN 2 and 3 (p<0.001), and among smokers, the risk of high-grade CIN increased in parallel with the time of exposure (years of smoking) (p=0.07). HPV-DNA of the oncogenic types was detected in 43 (56%) women, the risk of being HPV DNA-positive was significantly higher in CIN 2 and 3 as compared with CIN 1 (p=0.037). Importantly, the prevalence of high-risk HPV types was significantly higher in cigarette smokers than in non-smokers (p=0.046)., Conclusions: The results indicate that the severity of CIN lesions was clearly related to two fundamental risk factors: 1) high-risk HPV types, and 2) current cigarette smoking. These two risk factors were closely interrelated in that the high-risk HPV types were significantly more frequent in current smokers than in non-smokers, suggesting the possibility of a synergistic action between these two risk factors in cervical carcinogenesis.

The objective of this study was to compare the use of molecular hybridization by hybrid capture methodology for human papillomavirus (HPV) with the use of demographic and lifestyle variables as intermediate triage in patients with cytological mild dyskaryosis. The study was designed as a prospective study using regression tree analysis of demographic data in consecutive patients who were subjected to colposcopic evaluation at the colposcopy clinic at the First Department of Obstetrics and Gynaecology, University of Milan (Milan, Italy). A total of 177 women were subjected to colposcopy because of a single routine Pap smear showing mild dyskaryosis. A structured interview, sampling for HPV testing for the detection of viral DNA by hybrid capture methodology, and colposcopic evaluation with cervical biopsies were performed for each subject. The accuracies of molecular hybridization for HPV and of the classification model based on the demographic and lifestyle variables in predicting patients with histologically high-grade cervical intraepithelial lesions were measured. The classification model based on the demographic and lifestyle variables showed comparable results with molecular hybridization for HPV (specificity, 0.75 versus 0.73; sensitivity, 0.61 versus 0.67, respectively). The use of demographic and lifestyle variables appears to be a simple and economic possibility for triaging patients with mild dyskaryotic smears in a screening program.

Human papillomavirus (HPV) infection has been recognized as the major cause of cervical cancer [1]. The transformation zone of the cervix is the most frequent target of the high risk HPV types. In our study infection with HPV16 and 18 was investigated in the cervical scrapes of 28 subjects with cervical intraepithelial neoplasia. The DNAs isolated from the samples were amplified by dot-blot hybridization with fragmented digoxygenin labelled probes. Eighteen of 28 patients (64.3%) were found positive for HPV-16, eleven (39.3%) were found positive for HPV-18 and six patients (21%) were infected with both HPV types. This method is practical and sensitive for determining patients with a higher risk of developing HPV-related cancer.

The purpose of this study was to investigate whether Epstein-Barr virus (EBV) is associated with acetowhite lesions of the portio cervix, demonstrating koilocytosis and/or cervical intraepithelial neoplasia (CIN) I-III. The study group comprised 37 women admitted to the Department of Gynaecology and Obstetrics, Sahlgrenska University Hospital, Göteborg because of pathological colposcopy or cytology of the portio cervix. Colposcopically, all exhibited acetowhite lesions of the portio cervix. Cells were sampled with a cytobrush for examination for EBV and human papillomavirus (HPV) DNA by polymerase chain reaction (PCR) and a biopsy was taken for histopathology. Biopsies from 5 patients positive for EBV by PCR in cervical cell samples were examined by an in situ hybridization technique for EBER (Epstein-Barr virus encoded RNA), RNAs expressed in latent EBV infection. The control group consisted of women attending the Department of Dermato-Venereology at the same hospital for STD check-up. These had a normal cytology and no signs of acetowhiteness of the portio cervix. In the study group, EBV DNA was found in 30% and HPV DNA in 51%. In the control group 57% exhibited EBV DNA and 23% HPV DNA. EBV was not found to be a predictive factor in the development of koilocytosis and/or CIN I-III. HPV was a predictive factor in acetowhite, koilocytotic lesions. No expression of EBER was found in the 5 biopsies examined by in situ hybridization.

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-cancer screening programmes using cytomorphological criteria could be more efficient if the screening included objective individual risk factors for women with normal cytology, such as a test for high-risk human papillomavirus (HPV). The value of a PCR-based test for high-risk HPV types was studied in a cohort of 1622 women presenting in a routine triannual population-based screening programme. Women were included in the study when they had no previous history of cervical dysplasia; and their initial Pap smear was read as normal (Pap 1 or 2). The mean age of the women was 42 years (range 34-54 years) and mean follow-up time was 40 months (range 5-73 months). Women were referred for colposcopically directed biopsies if they had had 2 successive cervical smears read as Pap 3a (mild to moderate dyskaryosis) or one read as > or = Pap 3b (severe dyskaryosis). Women with histologically confirmed cervical intraepithelial neoplasia grade III (CIN III) were considered positive cases. All women were tested for 14 high-risk HPV genotypes. Of the 86 high-risk HPV-positive women, 6 developed CIN III, whereas only 1 of the 1536 HPV-negative women did. The women with normal Pap smears containing high-risk HPV genotypes were 116 times (95% CI, 13-990) more at risk of developing CIN III, in contrast to women without high-risk HPV. These results support the view that the interval between successive smears in cervical-cancer screening can be increased considerably for women with cytomorphologically normal and high-risk HPV-negative cervical smears as determined by PCR.

Sexual behavior has been consistently identified as a major risk factor for cervical cancer. Population-based studies have demonstrated that risk related to sexual activity is mediated by human papillomavirus (HPV) infection. We conducted a case-control study of 199 cases with low-grade squamous intraepithelial lesions or high-grade squamous intraepithelial lesions as defined by cytology and 1000 control women selected from an ongoing prospective cohort study in Copenhagen, Denmark. Furthermore, 131 women with equivocal smears (atypical squamous cells of undetermined significance) were examined as a separate borderline case group. At enrollment, all women had a personal interview and a gynecological examination including cervical swabs for HPV testing and a Pap smear. HPV testing was performed using a combination of general primer 5/6-mediated and type-specific polymerase-chain-reaction-based methods. Cervical HPV infection was by far the most significant risk factor for cervical squamous intraepithelial lesions. The relationship with HPV was observed for all grades, while strength of association was greater for more severe lesions. The importance of the previously identified epidemiological risk factors for cervical neoplasia was also demonstrated. However, most of the effect of these factors could be explained by taking HPV infection into account, except for schooling and smoking. Non-use of barrier contraceptives and smoking were the only significant risk factors in HPV-positive women. In HPV-negative women, a residual effect existed for different measures of sexual activity, and use of oral contraceptives and smoking constituted significant risk determinants Overall, 66% of cases could be attributed to HPV; however, if the results were restricted to histologically confirmed high-grade lesions, the proportion of cases that could be attributed to HPV infection increased to 80%.

Background: A persistent genital infection with an oncogene-type of human papillomavirus (HPV) is considered to be essential for the development of most cervical carcinomas. Therefore, HPV analysis has been proposed as a possible complementary cytological screening program. The authors have developed a technique to analyze archival Pap smears, which has enabled them to study the relation between persistent HPV infection and the development of cervical cancer., Methods: Nested polymerase chain reaction was used to demonstrate the presence of HPV DNA, and sequencing of the obtained amplimer was performed to establish HPV type. The authors analyzed a series of 88 smears taken 1.5 to 7 years prior to the diagnosis of an HPV-containing cervical carcinoma (12 invasive adenocarcinomas, 18 invasive squamous carcinomas, and 58 squamous carcinoma in situ), which were compared with age-matched controls with no tumor development., Results: HPV DNA was present in a majority of the smears preceding a cancer, with an odds ratio of around 15 for all tumor groups. Infections with a persisting HPV type were demonstrated in most samples from a series of eight patients, from who multiple smears were available, covering the 7-year period preceding the cancer diagnosis., Conclusions: Persisting infection can be demonstrated in exfoliated cells many years before cancer is diagnosed. The results are complementary to those obtained with cytology, that is, HPV is detected also in those at-risk patients whose Pap smears are morphologically normal. However, the results are still insufficient to justify a general recommendation to use HPV testing for health control purposes.

Twenty-nine samples from 28 cases of vulvar squamous cell carcinoma, of which 13 fulfilled the criteria of the bowenoid subtype (mean age 45 years, range 31-68) and 16 of the usual subtype of invasive squamous cell carcinoma (ISCC) (mean age 67.5 years, range 34-83) were investigated for human papillomavirus (HPV) DNA, TP53 alterations, and mdm2 and bcl-2 gene product deregulation. Microscopically all the bowenoid subtype cases (group I) showed a high-grade intraepithelial (VIN 3, carcinoma in situ) lesion associated with early invasive carcinoma in six cases and overt invasive carcinoma in one. By contrast, no evidence of early carcinoma was present in the ISCCs (group II). By in situ hybridization and/or Southern blot hybridization or polymerase chain reaction (PCR), HPV DNA was detected in all cases of group I and in four of 16 cases (25%) of group II, two only by Southern blot after PCR. By single-strand conformation polymorphism and immunocytochemistry only wild-type TP53 and absence of detectable p53 product, respectively, were found in all cases of group I, i.e., in high-risk HPV-positive carcinomas, whereas mutations and/or p53 overexpression accounted for 75% in group II, i.e., in mainly HPV-negative carcinomas. The TP53 gene mutations observed in invasive carcinomas were significantly related to node-positive cases (p = 0.04). Taken together and in agreement with in vitro data, these results support the view that an alteration of TP53, gained either by interaction with viral oncoproteins or by somatic mutations, is a crucial event in the pathogenesis of vulvar carcinomas, but that TP53 mutations are mainly associated with disease progression. Finally, a preliminary immunocytochemical analysis seems to speak against the possible involvement of both MDM2 and BCL-2 gene products in the development of vulvar carcinoma.

Epidemiologic and laboratory data suggest that cervical cancer typically arises from a series of causal steps. Each step can be studied separately in the hope of better etiologic understanding and improved cancer prevention. The earliest identified etiologic step is infection of young women with specific types of venereally transmissible human papillomaviruses (HPVs). Cervical HPV infections often lead to low grade squamous intraepithelial lesions (mildly abnormal Pap smears). Human papillomavirus infections and their associated lesions are extremely common among young, sexually active women. The infections typically resolve spontaneously even at the molecular level within months to a few years. Uncommonly, HPV infections and/or low grade lesions persist and progress to high grade lesions. The risk factors for progression are mainly unknown but include HPV type and intensity, cell-mediated immunity, and reproductive factors. Nutritional factors or co-infection with other pathogens may also be involved at this apparently critical etiologic step between common low grade and uncommon high grade intraepithelial lesions. Except for advancing age, no epidemiologic risk factors have been found for the next step between high grade intraepithelial lesions and invasive cancer. At the molecular level, invasion is associated with integration of viral DNA. Based on worldwide research, the steps in cervical carcinogenesis appear to be fundamentally the same everywhere, with a central role for HPV infection. The importance of etiologic cofactors like smoking, however, may vary by region.