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1.  Adherence to recommendations for early repeat cervical smear tests. 
BMJ : British Medical Journal  1989;298(6688):1605-1607.
OBJECTIVE--To assess adherence to recommendations for an early repeat cervical smear test in women with reports of cytological abnormalities, and to evaluate the impact of reminder letters to medical practitioners when such smear tests are overdue. DESIGN--Observational study. SETTING--Cytology (gynaecological) service for Victoria, Australia. SUBJECTS--Two groups of women who had abnormal cervical smears during 1985. Women in group A had some evidence of an important dysplasia and were advised to have a repeat smear in three months' time whereas women in group B had a less serious abnormality and were advised to have a repeat smear test in six months' time. In all, 971 of the 1036 women in group A and 1401 of the 1464 women in group B were eligible to have a repeat smear analysed by the service. INTERVENTION--If a repeat smear had not been received within three months of the recommended date a reminder letter generated by the service's computer was sent to the medical practitioner who had taken the smear. END POINT--Thirty six months after the report on the abnormal smear was issued. MEASUREMENTS AND MAIN RESULTS--In all, 870 (90%) of the women in group A and 1154 (82%) of the women in group B had a repeat smear test. The mean time to a repeat test was 3.0 months (95% confidence interval 0.5 to 16.4) in group A and 6.0 months (1.2 to 30.3) in group B. The reminder letter to the practitioner potentially increased the rate of return for a repeat smear test by 18% in group A and 24% in group B. Adherence to the recommendation for a repeat test increased with increasing age. CONCLUSIONS--Achieving high rates of follow up smear tests and appropriate management in women with cytological abnormalities is critical to the impact of a screening programme for cervical cancer. The reminder system used in this study was not labour intensive or expensive and provided a fail safe mechanism for ensuring that reports of abnormal smears were not overlooked.
PMCID: PMC1836856  PMID: 2503146
2.  Human papillomavirus in false negative archival cervical smears: implications for screening for cervical cancer. 
Journal of Clinical Pathology  1995;48(8):728-732.
AIM--To assess the value of detecting human papillomavirus (HPV) DNA in false negative archival cervical smears in population based screening programmes for cervical cancer. METHODS--Cytomorphologically classified false negative archival Pap smears (n = 27) taken from 18 women up to six years before cervical cancer was diagnosed were blindly mixed with 89 smears from hospital patients with a variety of gynaecological complaints and tested for HPV by the polymerase chain reaction (PCR). Corresponding cervical cancer biopsy specimens were also available for HPV analysis. Neither the examining cytopathologist nor the molecular biologist was aware of the study design. RESULTS--HPV DNA was detected in the smears of 16 patients with cervical cancer missed previously by cytology. HPV 16 and 18 were found predominantly in those smears taken up to six years before the diagnosis of cervical cancer. The smears of the two remaining patients were reclassified as inadequate for cytology or contained no suitable DNA for PCR. In 15 patients the same HPV type could be found in the smears and the cervical cancer biopsy specimens. CONCLUSIONS--The results indicate that high risk HPV types can be detected in archival smears classified as false negative on cytology and that cytological screening errors may be reduced if combined with PCR testing for HPV.
PMCID: PMC502799  PMID: 7560199
3.  Attendance at Cervical Cancer Screening and Use of Diagnostic and Therapeutic Procedures on the Uterine Cervix Assessed from Individual Health Insurance Data (Belgium, 2002-2006) 
PLoS ONE  2014;9(4):e92615.
To assess the coverage for cervical cancer screening as well as the use of cervical cytology, colposcopy and other diagnostic and therapeutic interventions on the uterine cervix in Belgium, using individual health insurance data.
The Intermutualistic Agency compiled a database containing 14 million records from reimbursement claims for Pap smears, colposcopies, cervical biopsies and surgery, performed between 2002 and 2006. Cervical cancer screening coverage was defined as the proportion of women aged 25–64 that had a Pap smear within the last 3 years.
Cervical cancer screening coverage was 61% at national level, for the target population of women between 25 and 64 years old, in the period 2004–2006. Differences between the 3 regions were small, but varied more substantially between provinces. Coverage was 70% for 25–34 year old women, 67% for those aged 35–39 years, and decreased to 44% in the age group of 60–64 years. The median screening interval was 13 months. The screening coverage varied substantially by social category: 40% and 64%, in women categorised as beneficiary or not-beneficiary of increased reimbursement from social insurance, respectively. In the 3-year period 2004–2006, 3.2 million screen tests were done in the target group consisting of 2.8 million women. However, only 1.7 million women got one or more smears and 1.1 million women had no smears, corresponding to an average of 1.88 smears per woman in three years of time. Colposcopy was excessively used (number of Pap smears over colposcopies = 3.2). The proportion of women with a history of conisation or hysterectomy, before the age of 65, was 7% and 19%, respectively.
The screening coverage increased slightly from 59% in 2000 to 61% in 2006. The screening intensity remained at a high level, and the number of cytological examinations was theoretically sufficient to cover more than the whole target population.
PMCID: PMC3972167  PMID: 24690620
4.  Annual Papanicolaou screening for 5 years among human papillomavirus-negative women 
BMC Cancer  2013;13:379.
Primary human papilloma virus (HPV) screening is more effective than cytology in reducing the risk of cervical cancer, but screening intervals should be extended in HPV-negative women. However, some Markov models predicted that long intervals are associated with an excess risk of cervical cancer. The aim of this analysis was to estimate the real-life risks and benefits of annual Papanicolaou (Pap) screening in HPV-negative women with normal cytology.
Women with negative Hybrid Capture 2 (HC2) results and normal cytology at the time of inclusion in the Hannover HPV screening trial underwent annual Pap smears for 5 years. A subgroup was randomly selected for retesting with cytology, HC2, and colposcopy 60–68 months after recruitment.
Of 4236 women included, 3406 had at least one Pap smear, but only 1185 attended all five annual screening visits. The proportion of women with at least one abnormal smear was 14.4% in 60 months. The probability of abnormal smears increased continuously over time. No case of ≥ CIN2+ was observed during 5 years. Of 605 women selected for subgroup analysis, 292 agreed to be retested (48.3%). The rate of high-risk HPV at 60–68 months was 3.0% (9/296).
The long-term risk of high-grade neoplasia after an initial negative HC2 test and normal cytology result was low, while the rate of false-positive abnormal Pap smears was significant and increased constantly over time. Pap smear screening of HPV-negative women more frequently than every 5 years could be potentially harmful and seems to be of little clinical value.
PMCID: PMC3751119  PMID: 23937771
Annual papanicolaou smear; Cervical cancer screening; Human papillomavirus (HPV); HR-HPV DNA test; Screening intervals
5.  Diagnosis and treatment of cervical intraepithelial neoplasia in general practice. 
BMJ : British Medical Journal  1989;299(6707):1083-1086.
OBJECTIVE--To audit the first five years of a colposcopy and treatment service for cervical dysplasia established within a general practice. DESIGN--A cervical smear register was established to determine which women were "at risk" of dysplasia. The results of colposcopy and treatment of dysplasia were analysed. SETTING--A large rural general practice with community hospital facilities in mid-Wales. PATIENTS--4437 Women at risk in a total practice population of 14,100. INTERVENTIONS--Colposcopy of women with dyskaryotic smear results, persistent inflammatory smear results, or vulval warts. Treatment of women with proved dysplasia by electrodiathermy of the cervix or cone biopsy. RESULTS--138 Women with dysplasia were diagnosed over five years: 36 mild, 97 moderate or severe, and five with microinvasion. Despite a 78% smear rate of at risk women over five years, nine invasive cancers still occurred. CONCLUSIONS--The results of treatment are acceptable. Cervical dysplasia has become very common, the risk of a dysplasia in women aged 20-39 who had smear tests being one in 14 over five years.
PMCID: PMC1837948  PMID: 2511973
6.  Risk of Cervical Pre-Cancer and Cancer Among HIV-Infected Women With Normal Cervical Cytology and No Evidence of Oncogenic HPV Infection 
U.S. cervical cancer screening guidelines for HIV-uninfected women 30 years of age and older have recently been revised, increasing the suggested interval between Pap tests from three years to five years among those with normal cervical cytology (the Pap test) who test negative for oncogenic human papillomavirus (HPV). Whether a three-year or five-year screening interval might be used in HIV-infected women who are cytologically normal and oncogenic HPV-negative is unknown.
To determine the risk of cervical pre-cancer or cancer defined cytologically (high-grade squamous intraepithelial lesions or greater [HSIL+]) or histologically (cervical intraepithelial neoplasia 2 or greater [CIN-2+]), as two separate endpoints, in HIV-infected women and HIV-uninfected women who at baseline had a normal Pap test and were negative for oncogenic HPV.
Design, Setting and Participants
Participants included 420 HIV-infected women and 279 HIV-uninfected women with normal cervical cytology at their enrollment in a multi-institutional cohort, between October 1, 2001 and September 30, 2002, with follow-up through April 30, 2011. Clinical sites were in the Bronx, Brooklyn, Chicago, Los Angeles, San Francisco, and Washington, DC. Semi-annual visits included Pap testing and, if indicated, cervical biopsy. Cervicovaginal lavage specimens from enrollment were tested for HPV DNA using PCR. The primary analysis was truncated at five years of follow-up.
Main Outcome Measure
The five-year cumulative incidence of cervical pre-cancer and cancer.
No oncogenic HPV was detected in 369 (88%; 95% CI, 84%-91%) of the HIV-infected women and 255 (91%; 95% CI, 88%-94%) of the HIV-uninfected women with normal cervical cytology at enrollment. Among these oncogenic HPV-negative women two cases of HSIL+ were observed; an HIV-uninfected woman and an HIV-infected woman with a CD4 cell count of 500/μL or greater. Histologic data were obtained from four of the six sites. There were six cases of CIN-2+ in N=145 HIV-uninfected women (cumulative incidence = 5% [95% CI, 1%-8%]) and nine cases in N=219 HIV-infected women (cumulative incidence = 5% [95% CI, 2%-8%]). This included one case of CIN-2+ in N=44 oncogenic HPV-negative HIV-infected women with CD4 cell counts less than 350/μL (cumulative incidence = 2% [95% CI, 0%-7%]), one case in N=47 women with CD4 cell counts of 350 to 499/μL (cumulative incidence = 2% [95% CI, 0%-7%]), and seven cases in N=128 women with CD4 cell counts of 500/μL or greater (cumulative incidence = 6% [95% CI, 2%-10%]). One HIV-infected and one HIV-uninfected woman had CIN-3, but none had cancer.
The five-year cumulative incidence of HSIL+ and CIN-2+ was similar in HIV-infected women and HIV-uninfected women who were cytologically normal and oncogenic HPV-negative at enrollment.
PMCID: PMC3556987  PMID: 22820789
7.  Prophylactic cytological investigation for cervical cancer in relation to stage at diagnosis: a study of 420 women in Denmark 
Despite widespread cervical smear testing 500-600 cases of cancer of the cervix are still diagnosed each year in Denmark, with over 200 deaths. The distribution of the different stages of cancer among 420 women who were diagnosed during 1983 was correlated with the number of previous cervical smears, whether done purely for screening reasons or for minor gynaecological problems. Of the women with cancer 56% had never been screened, and among these 42% were diagnosed at stage 1; 19% had been screened once; 61% of them at stage 1. The remainder (25%) had been screened at least twice, and 81% of them were diagnosed at stage 1. Among the patients who had been screened at least twice, with the last screening not more than three or five years ago, about 90% were diagnosed at stage 1 and the rest at stage 2.
The introduction of cervical smear testing will thus mean a considerably better stage distribution among cases which develop invasive cancer of the cervix, and both case fatality and mortality rates will be reduced by organized programmes, which have better participation rates than disorganized use of cervical smears.
PMCID: PMC1711521  PMID: 3256647
8.  Risk of cervical cancer associated with mild dyskaryosis. 
BMJ : British Medical Journal  1988;297(6640):18-21.
In a survey of 1781 patients who had mild dyskaryosis in a cervical smear taken between 1965 and 1984 invasive cancer occurred in 10 women. In four cancer was diagnosed soon after presentation, and in three it developed some years after default from follow up. Invasion occurred in one patient during cytological surveillance and in a further two after referral for colposcopic supervision. A poor correlation was found between a single cervical smear showing mild dyskaryosis and biopsy results. This was, however, improved by a series of smears. During initial surveillance cervical smear results reverted to normal in 46% of our patients within two years. During longer term follow up none of these patients developed invasive cancer, and life table analysis showed that three quarters had not relapsed after 14 years. We also found no evidence to suggest that preinvasive disease is more rapidly progressive in younger women. Our results indicate that cytological surveillance is acceptably safe provided that biopsy is advised if dyskaryosis persists.
PMCID: PMC1834182  PMID: 3408902
9.  Visual inspection of cervix with acetic acid (VIA) in early diagnosis of cervical intraepithelial neoplasia (CIN) and early cancer cervix 
To study the place of visual inspection of cervix with acetic acid in screening for CIN and cancer cervix and to compare and correlate the efficacy of VIA with cervical cytology in early detection of cancer cervix.
This cross sectional study took place in the Gynaecology out patient department (GGOPD) of NSCB Medical College, Jabalpur between June 2005 and September 2006. Out of the total 16,400 women who attended GOPD during this period, 750 women were screened for CIN and early cancer cervix. VIA and pap smears were done concurrently and their sensitivity and specificity compared. For ethical reasons all those who were found positive were subjected to colposcopy and further management as per standard guidelines.
Out of the 750 women screened VIA was positive in 122 (16.26%) women and cytology was positive in 39 (5.2%) cases of the true positive (27 cases). The difference between the two tests was statistically significant (P=0.000001) VIA being highly sensitive (93.1%) buy less specific than cytology.
The high sensitivity of VIA shows that the test could be valuable in detection of precancerous lesions of the cervix.
PMCID: PMC3394489
cervical carcinoma; screening; VIA cytology
10.  Molecular mapping of high-grade cervical intraepithelial neoplasia shows etiological dominance of HPV16 
Women with high-grade cervical intraepithelial neoplasia (HGCIN) frequently present with multiple cervical lesions, and multiple concomitant Human papillomavirus (HPV) genotype infections. To elucidate HPV genotype attribution in different regions on the cervix, we performed molecular mapping of cervical disease in women with HGCIN. Thirteen subjects referred to colposcopy for abnormal cervical cancer screening results were included. A cervical smear and biopsies from four different areas on the cervix were collected. HPV genotyping using Linear Array (for cytology) or SPF-10-LiPA25 (for histology) were performed in 13 smears, 52 whole sections from biopsies, and 138 tissue regions isolated with laser capture microdissection (LCM). Twelve subjects had a diagnosis of CIN3 and one subject had a diagnosis of CIN2 based on the worst histology found in four biopsies. Eight of the 13 smears (62%) showed multiple genotype infections. Four of 13 women (31%) had multiple HPV infections in their biopsies. After performing LCM-PCR, only one woman (8%) had two different carcinogenic HPV types in morphologically distinct, but colliding HGCIN lesions. HPV16 was identified as the causal type in all women with HPV16 in cytology. A large proportion of other HPV types found in cervical smears were not detected at the tissue level. Using tissue-based genotyping and LCM-PCR analysis, we were able to attribute an individual HPV type to each area of CIN lesions. We demonstrate that HPV16 is even more etiologically dominant than previously thought, based on various genotype attribution models.
PMCID: PMC3382014  PMID: 22419273
CIN; HPV; colposcopy; LCM; genotyping
11.  Cytology history preceding cervical cancer diagnosis: a regional analysis of 286 cases 
British Journal of Cancer  2011;104(4):685-692.
Despite programmed screening in the Netherlands, the decrease in incidence of cervical carcinoma lags behind. We analysed screening results preceding carcinoma cases, timeliness in case of follow-up, and FIGO (International Federation of Gynaecology and Obstetrics) stages as efficiency parameters for screening were taken.
We analysed 286 women with cervical cancer between 2005 and 2007 for cytology history preceding carcinoma, hierarchically arranging cytology history (if present) into three groups: ‘screened', ‘work-up', and ‘underscreened' (>6 yrs before diagnosis). For screen- and work-up smears, we analysed timeliness. FIGO stage was measured in relation to cytology history.
A total of 105 out of 286 (36.7%) women with cervical carcinoma were screened preceding the diagnosis. Delayed time intervals in case of abnormal cytology were 43.5% for borderline/mild dyskaryosis (BMD) and 38.0% for BMD (moderate dyskaryosis or worse; P=0.51). A total of 108 out of 286 (36.4%) women were underscreened, and 73 out of 286 (25.5%) were unscreened. Advanced carcinoma or FIGO stage ⩾2B in screened women was 16.0 vs 48.7% in work-up, underscreened, or unscreened (P<0.001).
Women with cervical cancer are underscreened and have poor timeliness in case of abnormal cytology. Being un- or underscreened correlates significantly with higher cervical cancer stages, especially in older women (aged ⩾49 years; P<0.001). Improvement of attendancy is needed to meet the standard of quality for screening programmes.
PMCID: PMC3049583  PMID: 21266976
population-based screening programme; non-compliance; cervical intraepithelial neoplasia; cervical carcinoma
12.  Outcome of "Atypical Squamous Cells" in Cervical Cytology: Follow-up Assessment by Loop Electrical Excision Procedure 
Korean Journal of Pathology  2012;46(4):359-364.
We have retrospectively assessed the incidence and outcome of women diagnosed during a hospital-based cytology screening program with "atypical squamous cells (ASC)" and followed-up with loop electrical excision procedure (LEEP).
We analyzed 173,947 cases of cervical smears' follow-up cytology and histology findings. Previous or archival cytology with LEEP results were retrieved for 390 women with ASC of undetermined significance (ASC-US) and 112 with ASC, cannot exclude high-grade squamous intraepithelial lesion (ASC-H).
On the follow-up cytology, of the 390 women initially diagnosed with ASC-US, 130 (33.3%) had no follow-up records of smears before LEEP; smears of 18 (4.6%) were negative for cytologic abnormalities, 193 (49.5%) were ASC-US, 24 (6.2%) were ASC-H, 111 (28.5%) were low grade squamous intraepithelial lesion (SIL), and 44 (11.4%) were high grade SIL. LEEP findings in these 390 women showed that 183 (46.9%) were negative, 73 (18.7%) were graded as cervical intraepithelial neoplasia (CIN) 1, 25 (6.4%) as CIN 2, 102 (26.2%) as CIN 3, and 7 (1.8%) had carcinoma. LEEP was performed in 112 women initially diagnosed with ASC-H; 36 (32.1%) were negative, 4 (3.6%) were graded as CIN 1, 7 (6.3%) as CIN 2, 60 (53.6%) as CIN 3, and 5 (4.5%) with carcinoma.
Patients with ASC-H smears were at increased risk of SIL or carcnoma compared with patients with ASC-US. Careful follow-up is required in ASC patients.
PMCID: PMC3479825  PMID: 23110028
Cervix uteri; Cytology; Loop electrical excision procedure; Atypical squamous cell
13.  Histologic and clinical characteristics associated with rapidly progressive invasive cervical cancer: a preliminary report from the Yale Cancer Control Research Unit. 
Histologic and clinical characteristics associated with rapidly progressive invasive cervical cancer are presented in this preliminary report from a population-based study involving all patients in Connecticut diagnosed with cervical cancer from March 1, 1985. Rapidly progressive invasive cervical cancer, i.e., invasive cancer diagnosed within three years of a true negative Pap smear, is more likely to occur in younger women with high annual incomes (61 percent greater than $40,000) who report a greater frequency of benign gynecologic conditions (uterine leiomyomata, vaginitis) compared to a control cervical cancer group. These preliminary data suggest that as many as 35 percent of the rapidly progressive cervical cancers are likely to be adenocarcinomas. Because they are mostly endocervical in origin, they may not be detected cytologically if scrapers or cotton swabs are used to sample the endocervical canal. New cytologic screening techniques using brushes may identify these lesions earlier and should routinely be employed in cytologic screening for cervical neoplasia. The difficulty in early detection of this form of the disease requires that physicians rapidly assess patients with unexplained pelvic and lower abdominal pain, vaginal discharge, or abnormal vaginal bleeding since early recognition is the only chance for cure. Further analyses of this population of women will be made to identify additional risk factors when the study data are complete.
PMCID: PMC2589083  PMID: 2596124
14.  Value of high-risk human papillomavirus 16 deoxyribonucleic acid testing with cytological entities in peri and postmenopausal women 
Genital human papillomavirus (HPV) infection is a sexually transmitted disease that is caused by HPV. Some types of HPV, called high-risk (HR) types may cause cell changes that sometimes lead to cervical cancer. HPV screening has been proposed for symptomatic female population; however, Pap test is the main stay in low resource setting.
To detect HR HPV 16 positivity in perimenopausal and postmenopausal women and its association with cytological entities diagnosed on Pap smear.
Materials and Methods:
Pap smears and cervical scrapes were collected from 230 women consisting of 120 perimenopausal women approaching menopause and 110 postmenopausal women with a cervix after cessation of menstruation and processed as per routine procedure for detection of HR-HPV 16 deoxyribonucleic acid (DNA). Cytologically abnormal HPV 16 negative cases were also tested for other HR-HPV types.
Among the perimenopausal women 12 (10%) cases were positive for HR-HPV 16 consisting of 6 (5%) abnormal cases and 108 (90%) were HPV 16 negative consisting of 5 (4.1%) abnormal cases. However, among 110 postmenopausal women 14 (12.7%) were positive for HPV 16 DNA consisting of 6 (5.4%) abnormal cases and 96 (87.2%) were HPV 16 negative consisting of 4 (3.6%) abnormal cases. HPV 16 negative abnormal cases (9) were positive for low risk-HPV 6/11 consisting of atypical squamous cells (3) and low-grade squamous intraepithelial lesions-HPV (6).
There is not much variation in HPV 16 positive cases in peri and postmenopausal women. By combining HPV DNA testing with Pap smear more cases having potential for pre-cancer lesions may be detected; however, HPV test cannot replace the Pap smear in low resource setting.
PMCID: PMC3793357  PMID: 24130412
Human papillomavirus 16 deoxyribonucleic acid; menopause; Pap smear; uterine cervix
15.  Detection of abnormal cervical cytology in Papanicolaou smears 
Cervical cytology by Papanicolaou (Pap) smears is an effective means of screening for cervical premalignant and malignant conditions. Cervical intra-epithelial neoplasia (CIN) and cervical cancer remain important health problems for women worldwide.
To study the role of Pap smear in detecting premalignant and malignant lesions of cervix; and to determine the prevalence of various lesions.
Materials and Methods:
This study is based on 300 patients who attended the out-patient Department of Obstetrics and Gynaecology. Pap smears were prepared from patients presenting with complaints like vaginal discharge, post-coital bleeding, inter-menstrual bleeding, dyspareunia, and pain lower abdomen. After fixation and staining, each smear was carefully examined.
Epithelial cell abnormalities were found in 5% smears, atypical squamous cells of undetermined significance (ASCUS) in 0.3%, squamous intraepithelial lesion (SIL) in 3.4% which includes low grade squamous intraepithelial lesion (LSIL) (2.7%) and high grade squamous intraepithelial lesion (HSIL) 0.7%. Invasive carcinoma was seen in 1.3% cases. Mean age of the patients with diagnosis of LSIL was 32.3 years and for HSIL, it was 40.5 years. The mean age of the patients with invasive carcinoma was 57 years.
Premalignant and malignant lesions of cervix are not uncommon in our set up and can be diagnosed early by Pap smears.
PMCID: PMC3307451  PMID: 22438616
Cervical cancer; cervical intraepithelial neoplasia; papanicolaou smear
16.  Rationale for stopping cervical screening in women over 50. 
BMJ : British Medical Journal  1993;306(6883):967-971.
OBJECTIVE--To investigate whether the currently recommended age at which to stop cervical screening (64) can be lowered and what criteria should be used for safely doing so. DESIGN--Retrospective case analysis study. SETTING--Dundee and Angus districts of Scotland. SUBJECTS--Women diagnosed as having cervical intraepithelial neoplasia and microinvasive or invasive cancer of the cervix in 1989 and 1990 (798 cases). MAIN OUTCOME MEASURE--History of cervical cytology results according to age (age groups of five years) and screening interval (three years and five years). RESULTS--Cervical intraepithelial neoplasia was most common in women under 45 (711 cases in women of 45 and under v 38 cases in those of 46 and over). Cervical intraepithelial neoplasia occurring de novo was not seen in women over 50 who had been screened every three years. Microinvasive or invasive cancer of the cervix was diagnosed in 26 women over 50. None of these women had participated adequately in the cervical screening programme. CONCLUSION--Cervical intraepithelial neoplasia typically occurs in younger women. All women over 50 with an adequate history of negative results on smear testing every three years may be safely discharged from further screening if these findings are confirmed in other populations.
PMCID: PMC1677423  PMID: 8490472
17.  Rare association of human herpesvirus 6 DNA with human papillomavirus DNA in cervical smears of women with normal and abnormal cytologies. 
Journal of Clinical Microbiology  1996;34(6):1589-1591.
We investigated by nested PCR the possible association of human herpesvirus 6 (HHV-6) and human papillomavirus (HPV) genomes in the cervixes of 109 women with normal and abnormal cytological smears. HPV DNA was detected in 8.33% of 24 women with normal cytologies and in 41.1% of 85 women with abnormal cytologies; the proportion of HPV DNA was directly related to the severity of the lesions. HHV-6 DNA was found in only one patient, who had a cytological pattern of koilocytosis. The HHV-6 genome was classified by restriction enzyme analysis as variant B. The study indicates that detection of the HHV-6 genome in the cervixes of women with a wide spectrum of gynecological complaints is a rare event and rules out the possible association between HHV-6 and HPV genomes in cervical cancer lesions.
PMCID: PMC229073  PMID: 8735129
18.  Effect of an antepartum Pap smear on the coverage of a cervical cancer screening programme: a population-based prospective study 
Almost one-third of Norwegian women aged 25–69 years invited to have a Pap smear do not attend during the recommended period, and thus constitute a population with high-risk of cervical cancer (CC). Since the incidence of precancerous lesions of the cervix peak with occurrence of pregnancies within the same decade in women aged 25 to 35 years of age, antepartum care presents an opportunity to offer a Pap smear thereby increasing the coverage of the programme. The study objective was to describe the effect of the antepartum Pap smear on the coverage of a cytological CC screening programme.
Among 2 175 762 women resident in Norway in 31.12.1996, all women who gave birth in 1996–7 were identified from the Medical Birth Registry of Norway. Attendance to the cervical cancer screening was assessed by linkage to the Cytology Registry separately for the pregnant and non-pregnant women cohorts. The results were stratified by age, history of previous Pap smear and history of invitation to the CC screening programme. Logistic regression was used to estimate the relative probabilities of having a Pap smear adjusted for age, screening history, and time since invitation, for pregnant and non-pregnant women, respectively.
69% of the pregnant women had a Pap smear during one year of follow-up since beginning of the pregnancy with the majority taken during the antepartum period. Irrespectively of age or history of having a Pap smear, pregnant women were 4.3 times more likely to have a Pap smear during follow-up compared to non-pregnant women. 63.2% of the pregnant women had a smear as response to the invitation letter compared to 28.7% of the non-pregnant women, OR = 2.1 (95% CI 1.9 to 2.4). As an indication of "over-screening", 5397 pregnant women (57.8%) with a smear shortly before the start of follow-up also had a new Papsmear, compared to 83 023 (32.3%) in non-pregnant.
Pap smear screening during pregnancy increases the coverage of the CC screening programme. The contribution of the antepartum Pap smear to "over-screening" exists but its effect is modest in countries where women on average become pregnant after the start of recommended age of screening.
PMCID: PMC1790705  PMID: 17244348
19.  Screening hospital patients for uterine cervical cancer. 
Journal of Clinical Pathology  1983;36(6):611-615.
Women patients admitted to a district general hospital with non-gynaecological conditions were offered a cervical smear test. In three years 2296 women were tested. Serious uterine pathology was detected in 13 patients (5.7 per 1000) and significant cytological abnormalities (dyskaryosis of all grades) in 46 (20.0 per 1000). Of the women screened 963 (41.9%) had never had a smear test before and 1608 (70.0%) were over 39 yr. The results show that cervical screening of non-gynaecological patients in hospital reaches many of the women at risk for cervical cancer who do not otherwise have smears taken and reveals considerable uterine pathology.
PMCID: PMC498336  PMID: 6853729
20.  Improving the effectiveness of cervical cancer screening 
A review of 100 cases of invasive cervical cancer was designed to assess what changes in cervical screening services might be most effective in reducing mortality. In 68 cases there had apparently never been screening: no system of individual invitation existed for unscreened women. In 10 cases the last smear was reported as normal over five years earlier: a five-year recall system existed but was inefficient. In 13 cases suspicious cervical smear reports had not been followed up adequately. Two cases might have been diagnosed earlier, in spite of `normal or inflammatory' smears, if the symptoms had been fully elicited. For the remaining seven cases one or more smear was reported as normal within five years of diagnosis of invasive cancer. Overall, 15 cases might have been picked up earlier if suitable opportunities for screening which did arise had been exploited. It was concluded that a substantial proportion of these 100 women might have received treatment at an earlier stage solely by the rigorous implementation of the present screening policy.
PMCID: PMC1959890  PMID: 6492026
21.  Cervical Dysplasia 
Canadian Family Physician  1983;29:787-793.
Invasive squamous carcinoma of the cervix is preceded by a series of premalignant changes described as mild, moderate, or severe dysplasia, and carcinoma in situ. These premalignant states are identified by cervical cytology, diagnosed by colposcopy and if effectively treated, can prevent invasive squamous carcinoma of the cervix. Because of the apparent biological variation of the premalignant states, even the most aggressive cervical screening program cannot be expected to eliminate all invasive squamous cancer of the cervix. Optimal results of a cervical screening program will be achieved when all women under 35 years of age and sexually active have an annual cytological smear; the cytology is screened by a laboratory with high quality control; the patient's positive cytology is accurately assessed by an experienced colposcopist, and the premalignant lesion is effectively treated.
PMCID: PMC2154141  PMID: 21283455
22.  Cervical cytology reported as negative and risk of adenocarcinoma of the cervix: no strong evidence of benefit. 
British Journal of Cancer  1995;71(4):894-897.
The relationship between negative cervical cytology reports and risk of adenocarcinoma of the cervix was evaluated in a case-control study of 113 cases and 452 controls. All cases and controls had received at least two negative cytology reports. There was no significant difference between the cases and controls in the number of negative cytology reports or in history of cervical abnormality; while a test for trend in the time since last negative cytology report was significant (P < 0.001), the estimated benefit was very modest. Although the estimates of relative protection were higher in women aged less than 35 years than in women aged 35-69 years, this difference was not statistically significant. These results suggest that cervical screening as practised in the 1970s and 1980s was much less effective in preventing adenocarcinoma than squamous carcinoma of the cervix.
PMCID: PMC2033741  PMID: 7710961
23.  Screening for cervical intraepithelial neoplasia in north east Scotland shows fall in incidence and mortality from invasive cancer with concomitant rise in preinvasive disease. 
BMJ : British Medical Journal  1994;308(6941):1407-1411.
OBJECTIVE--To assess the effect of screening for cervical intraepithelial neoplasia on the incidence of and mortality from invasive squamous cell carcinoma of cervix in north east Scotland and to discover why cases of invasive cancer still occur. DESIGN--(a) Analysis of data on cases of cervical intraepithelial neoplasia obtained from the cytology data bank; (b) analysis of data on 612 women presenting with invasive squamous cancer during 1968-91, obtained from cancer registry and hospital records; (c) analysis of death rates obtained from the registrar general's (Scotland) annual reports, the Information Services Division of the Home and Health Department (Scotland), and local records for 1974-91; (d) case-control studies on 282 cases of invasive cancer and 108 deaths which occurred in 1982-91. Cases were matched with two controls both for age and for having a negative smear test result at the time of presentation of the case. SETTING--North east Scotland (Grampian region, Orkney, and Shetland). SUBJECTS--Women (n = 306,608) who had had cervical smear tests between 1960 and 1991. RESULTS--There had been a substantial increase in cases of cervical intraepithelial neoplasia grade III since 1982. The incidence of invasive cancer has fallen since the start of screening in 1960, the fall occurring mainly in the well screened age group 40-69 years. There was a rise in women aged under 40 and over 70. Women with invasive disease seen between 1982 and 1991 mostly presented at stage I. Of these, half were unscreened, one third were poorly screened, 11% were found in retrospect to have had abnormal cells, 3% had recurrence of disease after treatment for cervical intraepithelial neoplasia grade III, and 3% were lost to follow up. Death rates had fallen, most noticeably in women aged 45-64, who had had the opportunity to be screened and rescreened. There was a disturbing rise in deaths among women under 45. Most deaths (65%) occurred in unscreened women. Case-control studies showed that the longer the time and absence of a smear test before presentation the higher was the risk of invasive cancer and of death. CONCLUSIONS--Screening has been effective in reducing the incidence of and mortality from cervical cancer in north east Scotland. Most cases and deaths occurred in unscreened women or in those who had had few smears at long intervals. An increase in cases of cervical intraepithelial neoplasia grade III in women screened for the first time occurred during 1982-91.
PMCID: PMC2540391  PMID: 8019250
Cervical cancer is the most common gynaecological cancer in developing countries. Visual Inspection with Acetic Acid (VIA) was introduced to screen for cervical premalignant lesions in developing countries due to the inability of many countries to implement high quality cytologic services. We sought to compare VIA performance among different health workers in Nigeria.
In a population-based project, seven health workers working who had been screening women with VIA for about two years at local government health centers in rural Nigeria were retrained in a two-week program using the IARC training manual. Women from a rural village who had never had cervical cancer screening were recruited into the study. Each woman had cervical cancer screening by VIA, liquid-based cytology and oncogenic human Papillomavirus (HPV) DNA testing.
Despite similar participant characteristics, across all age groups, providers had wide ranges of VIA results; 0–21% suspect cancer and 0–25% VIA positive. VIA was insensitive compared to a combination of cytology and HPV testing.
In our study, VIA was not reproducible nor was it sensitive compared to cytology and HPV testing.
PMCID: PMC3580031  PMID: 23354369
Cervical cancer; VIA; Liquid-based cytology; HPV DNA; Health workers
25.  Incidence of cervical cancer after several negative smear results by age 50: prospective observational study 
Objective To determine the incidence of cervical cancer after several negative cervical smear tests at different ages.
Design Prospective observational study of incidence of cervical cancer after the third consecutive negative result based on individual level data in a national registry of histopathology and cytopathology (PALGA).
Setting Netherlands, national data.
Population 218 847 women aged 45-54 and 445 382 aged 30-44 at the time of the third negative smear test.
Main outcome measures 10 year cumulative incidence of interval cervical cancer.
Results 105 women developed cervical cancer within 2 595 964 woman years at risk after the third negative result at age 30-44 and 42 within 1 278 532 woman years at risk after age 45-54. During follow-up, both age groups had similar levels of screening. After 10 years of follow-up, the cumulative incidence rate of cervical cancer was similar: 41/100 000 (95% confidence interval 33 to 51) in the younger group and 36/100 000 (24 to 52) in the older group (P=0.48). The cumulative incidence rate of cervical intraepithelial neoplasia grade I+ was twice as high in the younger than in the older group (P<0.001).
Conclusions The risk for cervical cancer after several negative smear results by age 50 is similar to the risk at younger ages. Even after several negative smear results, age is not a good discriminative factor for early cessation of cervical cancer screening.
PMCID: PMC2673344  PMID: 19395420

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