Does levonorgestrel-releasing intrauterine system increase breast cancer risk in peri-menopausal women? An HMO perspective.

PURPOSE: To evaluate the association between levonorgestrel-releasing intrauterine system (LNG-IUS) use and breast cancer (BC) risk. METHODS: A cohort of all Maccabi Healthcare Services (MHS) female members aged 40-50 years between 1/2003 and 12/2013 was used to identify LNG-IUS users as "cases," and 2 age-matched non-users as "controls." Exclusion criteria included: prior BC diagnosis, prior (5 years pre-study) and subsequent treatment with other female hormones or prophylactic tamoxifen. Invasive tumors were characterized by treatments received (chemotherapy, hormonal therapy, trastuzumab, or combination thereof). RESULTS: The analysis included 13,354 LNG-IUS users and 27,324 controls (mean age: 44.1 ± 2.6 vs. 44.9 ± 2.8 years; p < 0.0001). No significant differences in 5-year Kaplan-Meier (KM) estimates for overall BC risk or ductal carcinoma in situ occurrence were observed between groups. There was a trend towards higher risk for invasive BC in LNG-IUS users (5-year KM-estimate: 1.06% vs. 0.93%; p = 0.051). This difference stemmed primarily from the younger women (40-45 years; 0.88% vs. 0.69%, p = 0.014), whereas in older women (46-50 years), it was non-significant (1.44% vs. 1.21%; p = 0.26). Characterization of invasive BC by treatment demonstrated that LNG-IUS users had similar proportions of tumors treated with hormonal therapy, less tumors treated with trastuzumab, (7.5% vs. 14.5%) and more tumors treated with chemotherapy alone (25.8% vs. 14.9%; p = 0.041). CONCLUSIONS: In peri-menopausal women, LNG-IUS was not associated with an increased total risk of BC, although in the subgroup of women in their early 40's, it was associated with a slightly increased risk for invasive tumors.

Risk Factors for Cervical Cancer and CIN3 in Jewish Women in Israel - Two Case Control Studies.

PURPOSE: The aim of the study was to identify risk and protective factors/markers for cervical cancer and cervical intraepithelial neoplasia 3 (CIN3) in Israeli Jewish women in order to settle the discrepancy of low incidence rate of cervical cancer and relatively high incidence rate of CIN3. MATERIALS AND METHODS: We conducted two case control studies, which examined the association between potential risk and protective factors/markers for cervical cancer or CIN3 using self administered detailed questionnaires. RESULTS: For studying cervical cancer, 40 cases and 40 matched controls were interviewed. In the univariable and multivariable analyses older age, depression or anxiety and ever smoking seemed to act as independent risk factors/markers, while older age at first intercourse was protective. For studying CIN3, 99 cases and 79 controls were interviewed. Multivariable analysis has demonstrated that being born in Israel, depression or anxiety and ever smoking were independent risk factors/markers for CIN3. CONCLUSIONS: The risk factors/markers studied, that were associated with cervical cancer or CIN3 among Jewish women in Israel, are similar to those reported in other parts of the world, and do not explain the observed discrepancy of high in-situ cervical cancer rates and low invasive cervical cancer incidence in Israel.

Recent trends of cervical cancer and Cervical Intraepithelial Neoplasia 3 (CIN3) in Israel.

PURPOSE: This study describes time trends of cervical cancer and Cervical Intraepithelial Neoplasia 3 (CIN3) in Israel in the years 1986-2010 and characterizes these patients by demographics. METHODS: A retrospective survey based on cervical cancer and CIN3 data documented in the computerized system of the second largest Health Maintenance Organizations (HMO) in Israel, "Maccabi Healthcare Services" (MHS) between 1986 and 2010. RESULTS: 737 cervical cancer patients and 3,459 patients of CIN3 were reported between 1986 and 2010. The mean age of women with cervical cancer was significantly higher (mean 49.1 years) than that of CIN3 patients (mean 36.3 years) (p-value < 0.0001). The annual age-adjusted incidence rate of cervical cancer increased significantly from 1.6 per 100,000 in 1986 to 3.7 per 100,000 in 2010 (p for trend = 0.0001) and for CIN3, from 3.9 per 100,000 in 1986 to 40.4 per 100,000 in 2010 (p for trend = 0.0001). For cervical cancer, using the Joinpoint software we demonstrated an increase in the age-adjusted incidence rate between 1986 and 2003 and since then, a decrease was observed. Cervical cancer and CIN3 were mostly common in the Tel Aviv District. CONCLUSIONS: Although quite low to begin with, the incidence rates of cervical cancer and CIN3 in Israel may be further lowered by implementing an organized screening program and introduction of the HPV vaccine into the national immunization program.

Prevalence and correlates of human papillomavirus genotypes among patients with cervical cancer and cervical intraepithelial neoplasia 3 in Israel.

OBJECTIVES: This study aimed to assess the prevalence of human papillomavirus (HPV) in Israeli patients with cervical cancer and cervical intraepithelial neoplasia 3 (CIN3), to describe the distribution of the virus genotypes among positive cases, to characterize patients positive to HPV and, in particular, patients positive to HPV-16 and/or -18, and to evaluate the possible contribution of implementing HPV vaccination in Israel. METHODS: Samples from 84 patients with cervical cancer and 886 patients with CIN3, archived at the Maccabi Institute of Pathology, were screened for HPV. DNA extraction was performed using DNeasy Blood and Tissue Kit/QIAGEN. HPV detection and typing were performed by multiplex polymerase chain reaction with primers E6/E7, using the f-HPV/Genomed kit. RESULTS: Of the samples from 84 patients with cervical cancer, 89.3% were positive for HPV. Among these positive samples, HPV-16 was found in 70.7% and HPV-18 was found in 9.3%. Of the samples from 886 patients with CIN3, 85.0% were positive for HPV. Among these positive samples, HPV-16 was found in 73.8% and HPV-18 was found in 1.1%. In the patients with CIN3, the prevalence of HPV genotypes 16 and/or 18 was higher among young women and decreased across age groups. In addition, age, being born in Israel, being born in Europe, and being born in the former Soviet Union were correlated with a low risk of being infected with genotypes 16 and/or 18. DISCUSSION: The prevalence of HPV-16 and -18 in patients with cervical cancer and CIN3 in Israel is high. It is expected that the implementation of routine vaccination against these types of HPV will significantly reduce the burden of these diseases in Israel.

Cervical Pap screening among Israeli women, 2005-2010.

PURPOSE: This study describes the distribution and the trends of cervical abnormalities in Israel, based on Pap smear results. METHODS: A retrospective analysis of cervical smears received by the Central Pathology Laboratory of Maccabi Healthcare Services between January 2005 and December 2010. RESULTS: In total, 711,541 Pap smears were screened in the study period. Cytological abnormalities were observed in 4.78% of the total smears screened. An increase was observed in the rate of positive results from 2.63% in 2005 to 6.78% in 2010 (p = 0.0026). The cervical abnormalities in the study period distributed as follows: atypical squamous cell (ASC)-2.72%, low-grade squamous intraepithelial lesion (LSIL)-1.54%, high-grade squamous intraepithelial lesion (HSIL)-0.34%, squamous cell carcinoma-0.01%, atypical glandular cells (AGC)-0.10%, adenocarcinoma in situ (AIS)-0.06% and invasive adenocarcinoma-0.01%. The increase was statistically significant for ASC (p = 0.0028), LSIL (p = 0.0069) and for HSIL (p = 0.0260). The mean ages at diagnosis of women with ASCUS, LSIL, HSIL, squamous cell carcinoma, AGC, AIS and adenocarcinoma were 37.8, 33.2, 38.6, 55.4, 41.1, 49.9 and 57.1 years, respectively. CONCLUSIONS: The increase in the rate of squamous cell abnormalities demonstrated in this study emphasizes the need of implementing an education and a screening program among Israeli women. HPV vaccine, sexual behavior, cytology performance and HPV test are primary and secondary prevention tools which may reduce morbidity and mortality in the future. In addition, based on the age at diagnosis of the different pathologies, the age group in which Pap test is performed in Israel should be expanded from 35-54 to 25-65 years.

Treatment of high-grade squamous intraepithelial lesions: a "see and treat" versus a three-step approach.

OBJECTIVE: The study's subject was to examine the correlation between histologic findings in patients with high-grade squamous intraepithelial lesion (HGSIL) who have undergone loop electrosurgical excisional procedure (LEEP) with and without prior colposcopically directed biopsy. STUDY DESIGN: This retrospective study included 144 patients with cytologic HGSIL, of which 62 were treated by a three-step protocol, in which LEEP was performed only if the colposcopically directed cervical biopsies were positive (CIN II-III), and 82 women who were treated by "see and treat" protocol, in which LEEP was immediately performed if colposcopy was suggestive of CIN II or III lesions. RESULTS: There were no differences in the final histological findings between the groups. CONCLUSIONS: The colposcopically directed LEEP after a HGSIL on PAP-smear may reduce the time interval between diagnosis and treatment with a similar accuracy of diagnosis compared to the standard three-step protocol.

Occurrence of cervical intraepithelial neoplasia in generally healthy women with exophytic vulvar condyloma acuminata.

AIM: To disclose possible association between exophytic vulvar condyloma acuminata and cervical intraepithelial neoplasia in generally healthy, sexually active women. METHODS: This retrospective study included 74 patients (study group) who were referred for laser vaporization therapy of exophytic vulvar condyloma acuminata, and 88 asymptomatic volunteers without evidence of exophytic vulvar condyloma acuminata (control group) who were referred for screening Papanicolaou (Pap) test cervical evaluation including colposcopy. The diagnosis of cervical intraepithelial neoplasia was based on Pap smear, colposcopy and/or biopsy. RESULTS: On Pap smear, atypical squamous cells of undetermined significance or low-grade squamous intraepithelial lesions were found in 10 (13.5%) women with exophytic vulvar condyloma acuminata and in 2 (2.3%) asymptomatic volunteers (p < 0.05). Cervical intraepithelial neoplasia was found in 8 women with exophytic vulvar condyloma acuminata and in none of the asymptomatic volunteers (p < 0.05). CONCLUSION: An association was found between exophytic vulvar condyloma acuminata and abnormal Pap smear or positive cervical biopsy, in generally healthy women.