Rationale for stopping cervical screening in women over 50.

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.     

Feasibility of cytology-based cervical cancer screening in rural Cameroon

OBJECTIVE: To determine the prevalence of cervical cancer and its precursors in a rural population in Cameroon and to evaluate the feasibility of a cytology-based screening program in such areas. STUDY DESIGN: A prospective study was conducted in the rural town of Bafang. Following an advocacy campaign, 750 women were recruited. After a clinical examination, all women had a Pap smear with the Cervex Brush. Each sample had two preparations, conventional and liquid based. The conventional smears were interpreted in Bafang. Cytologically abnormal cases, those with clinical inflammation and/or macroscopic cervical lesions, had a colposcopic examination and directed biopsy. HSIL and colposcopically abnormal cases were treated with large loop excision of the transformation zone (LLETZ). The liquid-based preparations and histopathology were performed in Geneva and the results sent to Cameroon for patient follow-up. RESULTS: Mean age and parity of the women screened were 43.7 years and 7.8, respectively. The conventional smears showed 3.6% cervical abnormalities: 2% (15/740) ASCUS/LSIL and 1.6% (12/740) HSIL. The liquid-based preparations showed 12.6% (91/722) cervical abnormalities: 10.1% (73/722) ASCUS/LSIL and 2.5% (18/722) HSIL. Fifty percent of samples in both preparations showed evidence of inflammation. Histology was performed on 64 colposcopically directed punch biopsies and LLETZ specimens. The histologic diagnoses agreed with the cytologic findings in 60% (14/23) of conventional smears and 85% (12/14) of liquid-based preparations. CONCLUSION: There is a high rate of cervical intraepithelial neoplasia in the unscreened rural population of Cameroon. The situation is complicated by a high rate of cervical infection. A population-based cytologic screening program for cervical cancer would not be feasible in rural Cameroon because of high cost, low quality and limited technical facilities. Rural Africa requires an algorithm using a simple, low-cost technique of mass screening and an improved cytology service only to triage selected patients.     

The Cytological Prediction of Cervical Intraepithelial Neoplasia In Colposcopically Directed Biopsies

The tissue sections and preceding cervical smears of 1262 women who had colposcopic cervical biopsies were reviewed and the reports correlated. Close correlation between the cytological and histological findings, to within one histological grade of cervical intraepithelial neoplasia (CIN), was noted in 86% of cases. However, the biopsy was negative, or contained evidence of wart virus infection only, in 24% of cases where dyskaryotic cells had been observed in the cervical smear. Of particular concern was the fact that negative histological findings were recorded in 13% of cases where the smear contained cells showing a moderate dyskaryosis and in 1.26% of cases where the smear showed severe dyskaryosis. This suggests that colposcopically directed biopsies do not always reflect the underlying pathological changes in the cervix. Management of these cases is discussed. In 45 women with a normal cervical smear prior to biopsy, histology revealed seven cases of CIN 3 and one case of invasive squamous carcinoma. This indicates that referral for colposcopy is advisable whenever there is clinical suspicion of cancer, even if the cervical smear report is normal.     

Cervical intraepithelial neoplasia grade III (CIN III) and invasive cervical carcinoma: the yawning gap revisited and the treatment of risk

In a 3-year study of the population of Southampton and south-west Hampshire there were 10 times as many cases of CIN III compared with invasive squamous carcinoma (700 compared with 70). The peak incidence of CIN III per 1000 screened women years was in those aged 25-29 years, which was 20 years earlier than the peak incidence of invasive cervical cancer per 1000 women years at risk. Ninety percent of CIN III was diagnosed in women under 50 years. There were 14 cases of cervical glandular intraepithelial neoplasia grade III (CGIN III), three coexisting with CIN III, all in women aged under 50 years: the gap between intraepithelial and invasive lesions was not seen for glandular neoplasia. Although referral was for at least moderate dyskaryosis in 86.8% of women with CIN III or CGIN III, most had been screened previously, either having had mild abnormalities requiring repeat cytology (39.8%) or negative cytology (34.5%). Only 12 women aged > or = 50 years had previous negative cytology: 21.4% compared with 35.6% of women aged < 50 years (P = 0.034). The results of this study suggest that the best opportunity for preventing invasive squamous cell carcinoma lies in screening women aged 20-39 years when the incidence of CIN III in the screened population is highest and before the peak incidence of invasive disease. The results also indicate the importance of repeated screening and follow up of minor cytological abnormalities in the detection of CIN III. The benefit of screening must be regarded as a treatment of risk, since it is almost certain that a high proportion of CIN III regresses or persists unchanged.     

Cervical disease in women referred to colposcopy following inadequate smears

The aim of this audit was to determine if inadequate cervical smears are associated with significant cervical pathology. Case records for 52 women with three consecutive inadequate smears referred for colposcopy to the Leicester Royal Infirmary (LRI) were retrieved. Sixteen women underwent large loop excision of the transformation zone (LLETZ) and cervical intraepithelial neoplasia (CIN) was identified in six cases. There were no cases of inadequate smears initiating the diagnosis in 100 consecutive women with invasive cervical cancer. Inadequate smears are associated with high rates of treatment for a low yield of CIN. To reduce morbidity associated with colposcopy it may be acceptable to repeat an inadequate smear after 6 months rather than arranging immediate recall.     

Long term risk of invasive cancer after treatment for cervical intraepithelial neoplasia grade 3: population based cohort study

Objective To study the long term risk of invasive cancer of the cervix or vagina after treatment for cervical intraepithelial neoplasia grade 3.Design Prospective cohort study.Setting Swedish cancer registry.Participants All women in Sweden with severe dysplasia or cervical carcinoma in situ (equivalent to cervical intraepithelial neoplasia grade 3) treated during 1958-2002 (n=132 493) contributing 2 315 724 woman years.Main outcome measures Standardised incidence ratios with risk of cancer in the Swedish general female population as reference, and relative risks in multivariable log-linear regression model, with internal references.Results Women with previous cervical intraepithelial neoplasia grade 3 had an increased risk of invasive cervical cancer compared with the general female population (standardised incidence ratio 2.34, 95% confidence interval 2.18 to 2.50). The increased risk showed a decreasing trend with time since diagnosis for women treated later than 1970 but the risk was still increased after 25 years. An effect of age was found, with an accentuated increase in risk for women aged more than 50. The excess risk for cervical cancer associated with previous cervical intraepithelial neoplasia grade 3 has steadily increased since 1958. For vaginal cancer the standardised incidence ratio was 6.82 (5.61 to 8.21) but this decreased to 2.65 after 25 years. Adjustments in the multivariable log-linear regression model did not substantially alter these results.Conclusions Women previously treated for cervical intraepithelial neoplasia grade 3 are at an increased risk of developing invasive cervical cancer and vaginal cancer. This risk has increased since the 1960s and is accentuated in women aged more than 50. The risk is still increased 25 years after treatment.     

A case-control study of cervical cancer screening in north east Scotland.

To estimate the relative risk of invasive cervical cancer in each succeeding year after a negative screening result the screening records of all women tested in the north east of Scotland were examined as the basis for a case-control study. The cases consisted of 115 women in whom invasive cervical cancer had been diagnosed in 1968-82 and who had appeared in the screening records at least once before diagnosis. For each patient five controls were selected from women of the same age who appeared in the screening records before the date of diagnosis in the patient. If the patient''s cancer had been detected by screening the controls were chosen from women of the same age screened the same year. A comparison was made between cases and controls of the number of negative smears taken before the diagnosis. The results showed a high relative protection (inverse of the relative risk) in the first two years after a negative test, falling steadily as time since the last negative test elapsed. Even after 10 years, however, a considerable residual effect was observed.     

Assessment of the Accuracy of Cytology In Women Referred For Colposcopy and Biopsy: the Results of a 1 Year Audit

The results of weekly colposcopy review meetings have been audited for 1 year and cases where there was a discrepancy between the referral cervical smear and the initial colposcopy biopsy have been analysed. New referrals (n = 476) for colposcopy were studied. In the final outcome 80% of 326 women referred for moderate or severe dyskaryosis were found to have cervical intraepithelial neoplasia (CIN) grade II or III or invasive carcinoma. Three women found to have invasive carcinoma had been referred for severely dyskaryotic smears. Twenty women were referred for smears with cell changes suggesting glandular neoplasia: five were found to have adenocarcinoma in situ, whereas eight had CIN and seven had negative biopsies. The results justify the referral policy and demonstrate the need for further investigation when initial colposcopic biopsies are negative.     

Atypical glandular cells: criteria to discriminate benign from neoplastic lesions and squamous from glandular neoplasia

OBJECTIVE: To evaluate the presence of some criteria in cervical smears with atypical glandular cells and their correlation with histological patterns to identify pre-neoplastic and neoplastic lesions. METHODS: Seventy-three women referred with an atypical glandular cell smear, who had undergone conization or hysterectomy, were included in this study. Referral Pap smears were reviewed using the set of 27 cyto-morphological criteria that was correlated with the histological diagnosis. RESULTS: Histological results showed intraepithelial or invasive neoplasia in 35 (48%) cases and benign lesions in 38 (52%) cases. After logistic regression and decision tree analysis an increased nuclear/cytoplasmic ratio and the presence of dyskeratotic cells were strongly associated with intraepithelial or invasive neoplasia and the differential cyto-morphological criteria for glandular lesions were decreased cytoplasm, irregular nuclear membranes and the presence of nucleoli. CONCLUSION: The analysis of individual cyto-morphological criteria can better predict intraepithelial or invasive neoplasia and differentiate glandular from squamous lesions.     

CIN 2/3 and cervical cancer after an ASCUS pap smear. A 7-year, prospective study of the Norwegian population-based, coordinated screening program

OBJECTIVE: To estimate the risk of being diagnosed with cervical intraepithelial neoplasia (CIN) 2/3 or invasive cervical cancer (ICC) based on diagnostic and screening procedures performed after a diagnosis of atypical squamous cells of undetermined significance (ASCUS) and to compare this risk to that in women with a normal Pap smears. STUDY DESIGN: A 7-year, prospective, cohort study was performed in the Norwegian population-based, coordinated screening program. After excluding women in the midst of follow-up of an abnormal Pap smear or with a history of CIN 2/3 or ICC, the study population consisted of women 25-69 years of age with a normal (n = 526,661) or ASCUS Pap smear (n = 10,037) in 1995-1996. Risk estimates were calculated by logistic and parametric survival regression. RESULTS: Within 7 years of an ASCUS smear, 1,017 women (10.1%) were diagnosed with CIN 2/3 and 62 (0.62%) with ICC. Women with an ASCUS index Pap smear had a relative risk of 15-30 of being diagnosed with histologically verified CIN 2/3 or ICC within the first 2 years of follow-up as compared to women with a normal index smear. In long-term follow-up, women with an ASCUS index smear followed by a normal smear, which cancelled further clinical follow-up, were at > 3.5 times higher risk of both CIN 2/3 and invasive cancer as compared to women with a normal index smear. CONCLUSION: Pap smear follow-up of women with an ASCUS smear does not identify all women at higher risk of CIN 2/3 and ICC. Other diagnostic procedures should be implemented to improve the screening program.     

Cytology suggestive of glandular neoplasia: outcomes and suggested management

Eighty-three cases having a cervical smear result showing abnormal glandular cells were identified and matched up with the diagnostic histology result. Thirty-four (41.0%) were associated with malignancy and 26 (31.3%) with a cervical intraepithelial lesion without invasion. Thirty-eight (45.8%) had conditions of the cervix as follows: 12 cases had invasive disease of the cervix; nine (10.8%) adenocarcinoma of cervix and three (3.6%) squamous carcinoma of cervix. Nineteen (22.9%) had cervical intraepithelial neoplasia (CIN/SIL) alone and seven (8.4%) had cervical glandular intraepithelial neoplasia (CGIN) +/- CIN. There were 16 (19.3%) cases with malignancies of the uterine corpus and six (7.2%) had a malignancy arising from another primary site. Twenty-three (27.7%) had no malignant or pre-malignant condition. The risk of malignancy was related to age and ranged from 18.2% in those under 35 years to 67.9% in those 55 years and over. A protocol for the management of these cases is described.     

Management of women with mild and moderate cervical dyskaryosis.

OBJECTIVE--To compare the outcomes in women with mild and moderate dyskaryosis after increasing periods of surveillance and thereby to define a rational protocol for managing such women. DESIGN--Prospective study with randomisation of women to one of four treatment groups, each with a different period of surveillance; one group in which the women were given immediate treatment and three other groups in which the women were under surveillance for six, 12, and 24 months. SETTING--A dedicated colposcopy clinic in Aberdeen, Scotland. SUBJECTS--902 women who presented with a mildly or moderately dyskaryotic smear for the first time. INTERVENTIONS--Cytological and colposcopic examinations at intervals of six months until the allocated period of surveillance was completed, at which time biopsy was performed. Women with severe dyskaryosis were withdrawn from surveillance and a biopsy was performed. MAIN OUTCOME MEASURES--The histological findings after punch biopsy or large loop excision of the transformation zone, and the trends in cytological appearances of serial cervical smears. RESULTS--793 women completed the study. In all, 769 women had an adequate final smear, of which 197 were normal cytologically, 328 were still mildly or moderately dyskaryotic, and 244 were severely dyskaryotic. Seventeen of the 67 (25%) women with one repeat smear showing non-dyskaryosis had cervical intraepithelial neoplasia grade III compared with only one of the 31 (3%) women with no dyskaryosis in four repeat cervical smears (P < 0.0001). None of the women had invasive cancer. Of 158 women whose index smear showed mild dyskaryosis and who were allocated to the group under surveillance for two years, only 40 had not defaulted or still had dyskaryotic smears by the end of the two years. CONCLUSION--Cytological surveillance, although safe, is not an efficient strategy for managing women with mildly abnormal smears. Women with any degree of dyskaryosis in a smear should be referred for colposcopy.     

Predicting mortality from cervical cancer after negative smear test results.

OBJECTIVE--To assess the relative protection against death from cervical cancer after two or more negative smear test results and compare it with the protection against invasive cancer estimated by an International Agency for Research on Cancer (IARC) working group in an analysis of data from 10 large screening programmes. DESIGN--Comparison of risk of death from cervical cancer after two or more negative smear results with the risk in unscreened women by using a model constructed with data from the British Columbia screening programme. MAIN OUTCOME MEASURES--Mortality from and incidence of invasive cancer. RESULTS--In women with two negative smear results estimates of protection against cervical cancer were about 50% higher when lethal invasive cancer was used as the criterion rather than all invasive cancer. This difference was due to these women being more likely to attend for further tests at which invasive cancer could be detected: screen detected cancer has a better prognosis than clinically diagnosed cancer. Screening intervals could be longer than three years: screening women aged 35-64 every five years was predicted to result in a 90% reduction in mortality from cervical cancer. CONCLUSION--Because protection from mortality is higher than protection from disease and because of the high costs and negative side effects of frequent screening, screening intervals should be longer than three years.     

Changing cytologic detection rates for cervical intraepithelial neoplasia and invasive cancer in a population lacking a mass screening program

The secular trends in the detection rates for cervical intraepithelial neoplasia (CIN) and invasive carcinoma were evaluated for a population lacking a mass screening program. For the period from 1980 through 1987, 185,659 Papanicolaou smears from 176,511 women were examined. The average annual age-adjusted detection rate for invasive cervical cancer declined from 3.7 x 10(-3) in 1980 to 1.4 x 10(-3) in 1987. The rate of cytologic findings consistent with CIN 3 and verified by histology increased from 0.7 x 10(-3) to 2.6 x 10(-3), and the rate of findings consistent with CIN 1 and CIN 2 increased from 4.3 x 10(-3) to 7.2 x 10(-3). The yield of Papanicolaou smear diagnoses consistent with CIN 3 was substantial (more than one case per 1,000) for women up to 60 years old, but was insignificant for older women.     

Outcomes of screening to prevent cancer: analysis of cumulative incidence of cervical abnormality and modelling of cases and deaths prevented

ObjectiveTo determine the frequency of different outcomes in women participating in cervical screening.DesignAnalysis of screening records from 348 419 women, and modelling of cases of cervical cancer and deaths with and without screening.SettingCervical screening programme in Bristol.ResultsFor every 10 000 women screened from 1976 to 1996, 1564 had abnormal cytology, 818 were investigated, and 543 had abnormal histology. One hundred and seventy six had persistent abnormality for two years or more. In the absence of screening 80 women would be expected to develop cancer of the cervix by 2011, of whom 25 would die. With screening 10 of these deaths would be avoided. Comparison of cumulative abnormality rates with numbers expected to develop cancer in the absence of screening suggests that at least 80% of high grade dyskaryosis and of high grade dysplasia would not progress to cancer. The lifetime risk of having abnormal cytology detected could be as high as 40% for women born since 1960.ConclusionsScreening is labour and resource intensive. It involves treatment for many women not destined to develop invasive cancer. The increased intervention rate for cervical abnormality in England is due to change in practice, not a cohort effect, and is probably the reason for the marked fall in incidence and mortality during the 1990s. For other cancers there is scope for major iatrogenic harm from screening because of invasive tests and treatments.

What is already known on this topic

Since the mid-1980s incidence of and mortality from cervical cancer in women born since the 1930s in England and Wales has fallen; screening is the most likely explanationFor each death prevented many women have to be screened and many are treated who would not have developed a problem

What this study adds

In the NHS cervical screening programme around 1000 women need to be screened for 35 years to prevent one deathOver 80% of women with high grade cervical intraepithelial neoplasia will not develop invasive cancer, but all need to be treatedFor each death prevented, over 150 women have an abnormal result, over 80 are referred for investigation, and over 50 have treatmentBefore the 1988 relaunch of screening with strict quality standards, for each death prevented there were 57 000 tests and 1955 women had abnormal results     

Preliminary results of a district call scheme for cervical screening organised in general practice.

A recognised problem with the cervical screening programme in the United Kingdom is the failure to include women who have never had a cervical smear test, who are a high risk group. The implementation of a district based call scheme in East Berkshire in 1986 is described whereby women aged 20-64 with no record of a cervical smear test who were judged to be eligible for testing by their general practitioner were sent a personal invitation from their general practitioner to attend for a test. A list of high risk unscreened women was kept by each practice, and a duplicate sent to the cytology laboratory to update the central records. Six months after each batch of invitations had been sent the resulting number of women having a smear test was assessed. Forty three of 51 practices approached agreed to participate in the five year scheme. During the first year lists were sent to the 43 participating practices. The first list was returned to the cytology laboratory by 37 practices and the second by 33; practices varied in their responses, however, some needing considerable persuasion to return the lists. Of 972 identified unscreened women from the total 3757 women listed in the lists of the family practitioner committee, 247 (25%) had a cervical smear test in response to the invitation, representing an overall increase of 7% in the screened population. The preliminary findings of the five year study have shown that screening can be improved by a systematic call scheme. Coordinated support from the area health authority in health education, monitoring of screening, and feedback of data from the scheme to practices is required to reduce the proportion of unscreened women.     

Cervical screening: management of patients referred for colposcopy with smear abnormalities less severe than dyskaryosis

The cervical smear and biopsy results were reviewed for 141 patients who were referred for colposcopy with either a technically unsuitable smear or with cervical smear abnormalities less severe than dyskaryosis. The number of referrals due to minor smear abnormalities more than doubled from 8.6% to 22.3% of the total colposcopy referrals over the 4 year period studied. The minor smear abnormalities were only associated with cervical intraepithelial neoplasia (CIN) in patients aged <50 years. In 19 (13.5%) of the 141 patients high-grade lesions (CIN II or CIN III) were diagnosed. There were no cases of invasive cancer. Furthermore, the increased number of patients being referred for colposcopy with minor cervical smear abnormalities highlights the increasing pressures on colposcopy services, with prolonged waiting times for all patients.     

Polymorphism in the Matrix Metalloproteinase-2 Gene Promoter is Associated with Cervical Neoplasm Risk in Mexican Women

Matrix metalloproteinase-2 (MMP-2) is an enzyme with proteolytic activity on matrix proteins, and previous studies have revealed a strong association between the MMP-2 −1306C→T polymorphism and the risk of several types of cancer. Our study looked at whether this polymorphism contributed to the development of cervical neoplasia by analyzing 54 patients with invasive squamous cell cervical cancer, 100 patients with cervical intraepithelial neoplasia, and 126 control subjects. The MMP-2 CC genotype was more frequent in the cancer patients when compared with the control group (OR 2.57; 95% CI 1.15–5.86). The association of cervical cancer with the CC genotype was more pronounced in women who had first coitus at an early age (OR 3.96; 95% CI 1.46–11.06). The CC genotype was associated with intraepithelial neoplasia only in women with first coitus at 19 years old or younger. The data suggest that the MMP-2 −1306C→T polymorphism contributes to the development of squamous cell cervical cancer in the population studied, especially in women who had first coitus at an early age.     

Dimethylhydrazine: a reliable positive control for the short sampling time in the UDS assay in vivo

Cervical cancer represents the second most common malignant neoplasia in women world-wide. In Mexico, cervical cancer is the most common female malignancy. It has been recently seen an increased frequencies of micronuclei (MN) lymphocytes and cervical epithelial cells of cervical cancer patients. The aim of this hospital-based unmatched case-control study was to investigate the association between progressive stages in development of cervical cancer and frequency of micronucleated cells in the cervical epithelium and peripheral lymphocytes of 40 women, grouped by disease stage. Women at the Obstetrics and Gynecology Hospital of the Instituto Mexicano del Seguro Social (IMSS) in Monterrey, Mexico were diagnosed and classified on the bases of the Papanicolaou (PAP) smear and colposcopy/biopsy into control, low-grade squamous intraepithelial lesions (LGSIL), high-grade squamous intraepithelial lesions (HGSIL), and invasive groups. Analysis of the MN data in both cell types revealed (a) homogeneity among women within each of the four groups with regard to MN frequency, (b) in general, a correlation between MN frequency and grade of cervical lesion, and (c) a positive linear trend between the MN frequency and increased cervical cancer risk. In conclusion, we suggest that MN are a useful biomarker of cancer risk. Nonetheless, these results should be validated by other researchers.     

Regular audit of colposcopic biopsies from women with a mildly dyskaryotic or borderline cervical smear results in fewer cases of CINIII

Two years after introducing mandatory review of cases in which the cervical smear was discrepant with subsequent colposcopic or histological finding, the predictive accuracy of a first abnormal smear and the need for treatment were analysed. The results were compared with performance figures prior to this form of audit policy. Over 12 months 415 women referred for colposcopy were studied. Three per cent of patients with a single borderline smear and 6% with mild dyskaryosis had cervical intraepithelial neoplasia grade III (CINIII) revealed in histopathological examinations after colposcopy. Only 25% with a borderline smear and 33% with mild dyskaryosis required treatment. Of women with moderate dyskaryosis, 18% had a biopsy showing CINIII and 46% were treated. Of women with severe dyskaryosis in their cervical smear, 61% were shown to have CINIII or invasive cancer on biopsy and 90% were treated. Regular audit improved cytological prediction of grade of epithelial abnormality found on biopsy, allowing accurate, safe surveillance for minor smear abnormalities.