Atypical glandular lesions of the cervix and risk of cervical cancer.

INTRODUCTION: Cytology screening has been effective in reducing risks for cervical squamous cell carcinoma but less so for adenocarcinoma. We explored the association of atypical glandular cells or absence of glandular cells in cytology, and subsequent histological diagnoses and cancer risk. MATERIAL AND METHODS: All women in Norway with atypical glandular cells of undetermined significance (AGUS), adenocarcinoma in situ (ACIS) and normal/benign cells, but absence of endocervical or metaplastic cells (NC-NEC) in their first cytology during 1992-2014 (NC-NEC; 2005-2014), recorded in the Cancer Registry of Norway, were included (n = 142 445). Histology diagnoses (stratified by age) within 1 and 3 years after cytology were examined. The Nelson-Aalen cumulative hazard function for gynecological cancer risk was displayed. RESULTS: The majority of AGUS and particularly ACIS were followed with histology within 1 and 3 years. Cervical intraepithelial neoplasia (CIN) lesions were more common in women <35 than in women ≥35 years. Cervical adenocarcinoma followed 13% of ACIS after 1 and 3 years. After ACIS and AGUS, cervical adenocarcinoma was the most frequent cancer subtype. Cumulative risks of cervical adenocarcinoma following ACIS, AGUS and NC-NEC were 3.5%, 0.9% and 0.05%, respectively, after 22, 22 and 9 years of follow-up. CONCLUSIONS: There was a high-risk of glandular malignancies after AGUS and ACIS in cytology. If effective treatment of pre-cancer and early cancer is available, cytology screening provides some level of prevention of adenocarcinoma. Lack of glandular cells did not entail a higher cancer risk.

Adverse Pregnancy Outcomes After Treatment for Cervical Intraepithelial Neoplasia.

OBJECTIVE: To explore associations between specific treatments for intraepithelial or early invasive cervical lesions and adverse pregnancy outcomes. METHODS: We conducted a population-based cohort study in which treatment data from the Cancer Registry of Norway were linked to the Medical Birth Registry of Norway to identify adverse pregnancy outcomes. All women (n=545,243) with singleton births (N=943,321) in Norway during 1998-2014 were included; 9,554 of births were in women treated before delivery. Hazard ratios (HRs) with 95% confidence intervals (CIs) were derived from Cox regression models. RESULTS: There was a significant association between preterm birth and previous treatment of cervical lesions overall (9.7 compared with 5.3%; HR 1.8, 95% CI 1.7-2.0). The strongest associations were seen for cold knife (13 compared with 5.3%; HR 2.6, 95% CI 1.3-5.3) and laser conization (12 compared with 5.3%; HR 2.3, 95% CI 2.0-2.5). The association was stronger for preterm birth at earlier gestational ages and increased with amount of tissue excised. Furthermore, the association weakened with calendar year of treatment. There was also an association with increased risks of spontaneous abortion (0.5 compared with 0.2%; HR 2.5, 95% CI 1.7-3.7), and the strongest associations were seen for laser conization (0.6 compared with 0.2%; HR 3.0, 95% CI 1.8-5.3) and a loop electrosurgical excision procedure (LEEP) (0.4 compared with 0.2%; HR 2.3, 95% CI 1.3-4.0). CONCLUSION: Treatment with major excisional procedures, including LEEP, was associated with increased risks of preterm birth and spontaneous abortion. The risk of preterm birth was highest at early gestational ages and for those with the largest amount of tissue excised. Women should be informed about their future risk of adverse pregnancy outcomes, particularly preterm birth, after excisional treatment for cervical lesions.

Prospective seroepidemiologic study of human papillomavirus and other risk factors in cervical cancer.

BACKGROUND: Several sexually transmitted infections (STI) have been reported to interact with human papillomavirus (HPV) in the etiology of cervical cancer. A large cohort study is required to obtain a both unbiased and stable estimate of their effects. METHODS: Four major biobanks in the Nordic Countries containing samples from about 1,000,000 subjects were linked with nation-wide cancer registries. Serum samples from 604 women with invasive cervical cancer (ICC) diagnosed on average 10 years after sampling and 2,980 matched control women were retrieved and analyzed with serology for key STI. RESULTS: Exposure to HPV16 was the strongest risk factor for cervical cancer [OR = 2.4; 95% confidence interval (CI), 2.0-3.0], particularly for squamous cell carcinoma (OR = 2.9; 95% CI, 2.2-3.7). HPV18 was strongly associated with increased risk for adenocarcinoma (OR = 2.3; 95% CI, 1.3-4.1). Baseline seropositivity for HPV16 did not confer any increased risk for HPV18 DNA-positive cancer and conversely HPV18 seropositivity had no association with HPV16 DNA-positive cancers. HPV6 had no effect on its own (OR = 1.1; 95% CI, 0.9-1.3), but had an antagonistic effect on the risk conferred by HPV16 (P < 0.01). Herpes simplex virus 2 had little or no association (OR = 1.1; 95% CI, 0.8-1.4). Previous exposure to Chlamydia trachomatis, as indicated by serum antibodies, had a strongly increased risk for cervical cancer (OR = 1.9; 95% CI, 1.5-2.3). CONCLUSIONS: A large prospective study has assessed the role of different STIs in cervical cancer. IMPACT: Prospective evidence supports cofactor role of some STI in cervical cancer.

Factors associated with non-attendance, opportunistic attendance and reminded attendance to cervical screening in an organized screening program: a cross-sectional study of 12,058 Norwegian women.

BACKGROUND: Cervical cancer incidence and mortality may be reduced by organized screening. Participant compliance with the attendance recommendations of the screening program is necessary to achieve this. Knowledge about the predictors of compliance is needed in order to enhance screening attendance. METHODS: The Norwegian Co-ordinated Cervical Cancer Screening Program (NCCSP) registers all cervix cytology diagnoses in Norway and individually reminds women who have no registered smear for the past three years to make an appointment for screening. In the present study, a questionnaire on lifestyle and health was administered to a random sample of Norwegian women. The response rate was 68%. To address the predictors of screening attendance for the 12,058 women aged 25-45 who were eligible for this study, individual questionnaire data was linked to the cytology registry of the NCCSP. We distinguished between non-attendees, opportunistic attendees and reminded attendees to screening for a period of four years. Predictors of non-attendance versus attendance and reminded versus opportunistic attendance were established by multivariate logistic regression. RESULTS: Women who attended screening were more likely than non-attendees to report that they were aware of the recommended screening interval, a history of sexually transmitted infections and a history of hormonal contraceptive and condom use. Attendance was also positively associated with being married/cohabiting, being a non-smoker and giving birth. Women who attended after being reminded were more likely than opportunistic attendees to be aware of cervical cancer and the recommended screening interval, but less likely to report a history of sexually transmitted infections and hormonal contraceptive use. Moreover, the likelihood of reminded attendance increased with age. Educational level did not significantly affect the women's attendance status in the fully adjusted models. CONCLUSIONS: The likelihood of attendance in an organized screening program was higher among women who were aware of cervical screening, which suggests a potential for a higher attendance rate through improving the public knowledge of screening. Further, the lower awareness among opportunistic than reminded attendees suggests that physicians may inform their patients better when smears are taken at the physician's initiative.

Awareness of human papillomavirus in a cohort of nearly 70,000 women from four Nordic countries.

OBJECTIVE: To assess the fraction of women who have heard of human papillomavirus (HPV) in four Nordic countries (Denmark, Iceland, Norway, and Sweden) and to study the correlates of this awareness, just before the vaccines were released. DESIGN: Population-based cross-sectional study by means of a questionnaire. Setting. Denmark 2004-2005. Population. A total of 69,147 women participated (participation rate of 65%) in the study. METHODS: A random sample of women from the general female population (18-45 years) in Denmark, Iceland, Norway, and Sweden were invited to answer a self-administered questionnaire regarding HPV and lifestyle habits. MAIN OUTCOME MEASURES: Having heard of HPV. RESULTS: Overall, a total of 32.6% had ever heard about HPV. Respectively, only 25.1% of Danish women, 33.0% Norwegian women, 32.5% Swedish women, and 41.0% Icelandic women had heard about HPV. The most important correlates associated with ever having heard of HPV were a history of genital warts (odds ratios, OR=2.57; 99% confidence intervals, CI: 2.38-2.76) and educational level (OR=2.06; 99% CI: 1.92-2.21). Other correlates associated with awareness of HPV were being single during pregnancy, never having been pregnant, former use of hormonal contraceptives and condom use. CONCLUSIONS: Our data suggest that at least two-thirds of Nordic women have never heard of HPV. These data are important for developing and evaluating strategies to inform and educate the population about HPV infection and disease.

Papanicolaou smear history in women with low-grade cytology before cervical cancer diagnosis.

BACKGROUND: The purpose of the current study was to examine the screening histories of women diagnosed with invasive cervical cancer (ICC) in 2000 who had previous Papanicolaou (Pap) smears deemed to be unsatisfactory or with low-grade findings that did not lead to biopsy. METHODS: A total of 252 Pap smears from 47 women taken between 1992 and 2000 were included in the study; 247 smears were reexamined at the laboratory of origin before the study and all 252 were then reexamined independently by 2 experienced cytotechnicians and 2 cytopathologists. RESULTS: Of the 47 cases of ICC, 35 were squamous cell carcinoma, 10 were adenocarcinoma, and 2 were other types. On reexamination at the laboratory of origin, 24 cases were upgraded and in the study group 27 cases were upgraded to diagnoses requiring biopsy. On reexamination at the laboratory of origin, it was found that the first high-grade squamous intraepithelial lesion (HSIL) could have been diagnosed on average 4.2 years earlier than it was originally (95% confidence interval [95% CI], 3.3-5.1 years). On reexamination by the study group the first diagnosis of HSIL was made in smears dating from 5.4 years before the diagnosis of ICC (95% CI, 4.5-6.2 years). CONCLUSIONS: The study confirms that unsatisfactory and low-grade Pap smears imply a risk of developing high-grade lesions at a later date and shows that in a screening program a subgroup of smears may be diagnosed as unsatisfactory or low grade despite the presence of high-grade findings that are detectable on reexamination.

Screening histories of women with CIN 2/3 compared with women diagnosed with invasive cervical cancer: a retrospective analysis of the Norwegian Coordinated Cervical Cancer Screening Program.

OBJECTIVE: This study compares the screening history for women with cervical intraepithelial neoplasia (CIN) 2/3 or adenocarcinoma in situ (ACIS) with women with different stages and subtypes of cervical carcinoma. METHODS: An analysis of the Norwegian Coordinated Cervical Screening Program comparing all cases with a CIN 2/3/ACIS (N=8586) with all ICC (N=777) in the period 2000-2002. All Pap smears since 1992 were used to characterise detection mode and screening history. Multinominal regression models estimated the risk associated with detection mode and adequate Pap smear history. RESULTS: A wide range of age at diagnosis, from 16 to 92 years of age was observed regardless of the stage of the disease. Fifty five percentage of the women diagnosed with CIN 2/3/ACIS had an adequate screening history. Of women diagnosed with SCC, 45.1% in stage I, and 10.5% in stage IV had an adequate history. The median age of women with CIN 2/3 (34 years) and squamous cervical carcinoma (SCC) stage I (37 years) given an adequate Pap smear history was not significantly different. For women with ACC, the proportion with adequate screening history was roughly 50% for all stages. After adjustment for detection mode and age, the OR for being diagnosed with ICC stage I compared to CIN 2/3 was 1.2 (95% CI: 1.0-1.5), while the OR of being diagnosed with ICC stage II-IV was 3.4 (95% CI: 2.3-4.8). CONCLUSIONS: Women with CIN 2/3 and ICC stage I were similar with respect to screening histories, i.e. detection mode and age at diagnosis, while women with ICC stage II-IV seldom had an adequate screening history and were diagnosed at a significantly higher age.