Screening for cervical cancer: a new scope for general practitioners? Results of the first year of colposcopy in general practice.

A survey was carried out over one year of all the women who attended a colposcopy clinic in a general practice. During the year 1254 women underwent cytological screening in the practice and 197 of these underwent colposcopy. Of 79 women with abnormal smears that suggested cervical intraepithelial neoplasia, 62 (79%) were confirmed by biopsy to have cervical premalignancy. In addition, the remaining 118 women with normal or inflammatory smears underwent colposcopy either because of their history or because they requested the investigation. A general underestimate of cervical intraepithelial neoplasia when cytology alone was used was discovered. Seven out of 28 women with inflammatory smears were found to have important cervical premalignancy. Mildly dyskaryotic smears led to a falsely reassuring estimate of the degree of severity of cervical lesions. Seven out of 13 patients who underwent colposcopy because they were thought to be at high risk of neoplasia because of a history of genital warts, unexplained recurrent cystitis, heroin abuse, or immunosuppression had cervical intraepithelial neoplasia proved at biopsy. This report shows that both in screening for and in the follow up of known cervical disease a normal smear cannot guarantee normal pathology. Diagnostic colposcopy is a valuable complementary investigation that could be carried out in a general practice.     

Cytological screening for cervical cancer and human papillomavirus in general practice.

In a retrospective study of cervical screening in a general practice in Birmingham 156 out of 1913 smears taken over three years showed some abnormality. Smears from 65 women showed severe non-specific inflammation, and 91 women had various grades of cervical intraepithelial neoplasia, of whom 53 were aged under 30 and 13 over 40. Of 35 women with clinical evidence of human papillomavirus, 21 had normal results on cervical testing and 14 abnormal results. The incidence of genital warts among sexually active young people is growing, but the association of human papillomavirus with abnormal cervical smears is not clear. The efficacy of screening in the United Kingdom must be improved by actively encouraging younger patients to attend for regular screening.     

Review of cervical smears from 76 women with invasive cervical cancer: cytological findings and medicolegal implications

OBJECTIVE: To review cervical smears from 76 women which were taken prior to the diagnosis of invasive cervical cancer and to determine the appropriateness of the cytology reports issued on the smears. METHODS: Cervical smears, clinical records, cervical smear history and cytology reports from 76 women with invasive cervical cancer were reviewed. After microscopic review of the cervical smears, the cases were divided into two groups: Group 1 comprised 50 women who were found to have had at least one false-negative (F/N) smear report prior to the diagnosis of invasive cervical cancer. Group 2 comprised 26 women for whom no evidence of F/N reporting was found. RESULTS: A total of 209 cervical smears from the 50 women in group 1 were available for review (range 2-12 smears per woman); 100 of the 209 smears were considered to have been reported appropriately. Ninety-seven smears which had been reported originally as negative or inadequate were found, on review, to contain numerous severely dyskaryotic cells and were reclassified as F/N smears. All of the 50 women had at least one F/N smear and 29 had two or more. Twelve smears from eight women contained only a few (<200 severely dyskaryotic cells). Forty women developed invasive squamous carcinoma and 10 developed invasive adenocarcinoma. The stage at diagnosis ranged from 1A to stage 4. Seventy-one smears from the 24 women in group 2 were available for review (range 1-15 smears per woman). In two cases included in group 2, no smears were provided for review as the smears had been lost or mislaid. Review of the 71 smears confirmed the accuracy of the original cytological classification of the smear. Nineteen women were diagnosed with squamous cancer, two microinvasive cancer, one glassy cell, two adenocarcinomas, and one with adenosquamous carcinoma. One women was found to have an embryonal rhabdomyosarcoma of the corpus uteri involving the cervix. DISCUSSION/CONCLUSION: The medicolegal implications are discussed in the light of the above findings. Evidence of breach of duty of care was presented in all 50 cases in group I although causation was not established in every case. There was no evidence of failure of duty of care in terms of the standard of the cervical cytology reports issued or standard of clinical management in 17 of the 26 cases in group 2. However, in seven of the 26 cases in group 2, clinical management of the case was substandard due to failure to investigate symptoms of irregular bleeding regardless of a negative cytology report (two cases), failure to act upon a suspicious smear report or consecutive inadequate smear reports (two cases), failure of follow-up after treatment of CIN3 (two cases) and histological misdiagnosis (one case).     

Koilocytosis; an indication for conservative management

The management of women with mild dyskaryosis continues to be the subject of debate. The management of cases with such smears could be improved if additional morphological features were found to be indicative of low/high grade cervical intraepithelial neoplasia (CIN). Our own experience in the routine audit of the diagnostic accuracy of cervical smears had suggested that cases of dyskaryosis with koilocytosis were associated with a low risk of CINIII. Two hundred and forty-four cervical smears reported as showing evidence of wart virus infection were reviewed and their subsequent histories noted. Of these smears, 173 demonstrated clear evidence of koilocytosis. Irrespective of the initial grade of dyskaryosis, only 28 cases (16.2%) had underlying CIN or had progressed to CIN over a minimum follow-up period of 21 months. Only two cases (1.2%) showed evidence of CINIII. Koilocytosis is associated with a low risk of CIN and an especially low risk of CINIII. The management of women with koilocytic smears should be modified accordingly.     

Koilocytosis; an indication for conservative management

The management of women with mild dyskaryosis continues to be the subject of debate. The management of cases with such smears could be improved if additional morphological features were found to be indicative of low/high grade cervical intraepithelial neoplasia (CIN). Our own experience in the routine audit of the diagnostic accuracy of cervical smears had suggested that cases of dyskaryosis with koilocytosis were associated with a low risk of CINIII. Two hundred and forty-four cervical smears reported as showing evidence of wart virus infection were reviewed and their subsequent histories noted. Of these smears, 173 demonstrated clear evidence of koilocytosis. Irrespective of the initial grade of dyskaryosis, only 28 cases (16.2%) had underlying CIN or had progressed to CIN over a minimum follow-up period of 21 months. Only two cases (1.2%) showed evidence of CINIII. Koilocytosis is associated with a low risk of CIN and an especially low risk of CINIII. The management of women with koilocytic smears should be modified accordingly.     

How predictive is a cervical smear suggesting glandular neoplasia?

The prevalence of endocervical adenocarcinoma and its precursors has increased, in part due to increased diagnostic awareness of these lesions. To date, limited information has been published regarding the predictive value of glandular abnormalities in cervical smears. This study details the histological follow up of 418 cervical smears showing glandular abnormality, reported in our department over a six year period from 1993 to 1998. Histological follow up was available for 395 of the 418 smears (94.50%). The overall positive predictive value (PPV) for this group of smears was 72.66% for either significant glandular or squamous pathology (at least low grade cervical glandular intraepithelial neoplasia or CIN2 on follow up biopsy), and 55.70% for significant glandular pathology alone. Examination of subcategories of abnormal glandular smear showed that the PPV increased with the degree of abnormality reported within the smears.     

Outcome analysis of 4 years' follow-up of patients referred for colposcopy with one smear showing mild dyskaryosis

Objective: To assess the 4‐year outcome of patients after one smear showing mild dyskaryosis with respect to smear regression rate, prevalence of cervical intraepithelial neoplasia (CIN) and the effect of age. Methods: Retrospective analysis of patients diagnosed with initial mildly dyskaryotic smear during the year 2000 with a follow‐up period of 48 months. These women had not had any previous abnormal smears. Settings: Cytopathology Department and Colposcopy Unit, King’s College Hospital, London, UK. Results: We identified 524 patients of whom 375 patients with complete follow‐up data are included. The age range was 19–67 years with a median of 29 years. There were 207 patients aged 35 years or less (55%). At 6 months, 258 smears were performed and 47.8% of them were negative (95% CI: 41.6–54.0%). The total number of negative follow‐up smears in the first year was 198 out of a total of 397 smears performed (50%). This proportion has significantly increased between 1 and 4 years’ follow‐up to 67.5% (RR: 1.24; 95% CI: 1.14–1.35). Over the 4‐year period, 791 smears were performed and 477 were negative (60.3%; 95% CI: 56.9–63.7%). Of the 477 negative smears there were only 61 smears (12.8%; 95% CI: 10–16%), in 54 patients (14%; 95% CI: 11–18%) that reverted back to low‐grade cytological abnormality. In only one case the repeat smear showed high‐grade abnormality after initial negative follow‐up; however, on biopsy, histology showed CIN I. Out of the 375 patients, 70 required treatment with excisional biopsy (19%; 95% CI: 15.0–22.9%). Histology confirmed high‐grade CIN in only 41 cases giving a prevalence of 11% (95% CI: 8.1–14.5%). There were no cases of microinvasive or invasive cancer detected. Age (≤35 years versus >35 years) did not significantly affect either cytological or histological outcome. Conclusion: Sixty per cent of follow‐up smears after initial mild dyskaryosis subsequently became negative; of them 87.2% remained negative over the 4 year follow‐up. Treatment was only required in 19% of patients, with 11% prevalence of high‐grade CIN. Age did not affect the outcome. These results are reassuring and indicate that colposcopic referral may not be necessary after only one mildly dyskaryotic smear.     

Genital herpes simplex.

Genital herpes is a sexually transmitted disease caused by the herpes simplex virus. Following the initial infection the virus becomes latent in the sacral ganglia. Approximately 80% of patients are then subject to milder but unpredictable recurrences and may shed the virus even when they are asymptomatic. The disorder causes concern because genital herpes in the mother can result in rare but catastrophic neonatal infection and because of a possible association between genital herpes and cancer of the cervix. No effective treatment is as yet available. Weekly monitoring for virus by cervical culture from 32 weeks'' gestation is recommended for women with a history of genital herpes and for those whose sexual partner has such a history.     

An audit of cervical cytology in HIV‐positive women

O. E. O. Hotonu, J. Hussey, M. S. T. Basta, V. Wadehra, P. Cross and M. L. Schmid
An audit of cervical cytology in HIV‐positive women Objective: To investigate whether a cohort of human immunodeficiency virus‐positive (HIV+) women were having annual cervical cytology as recommended by the English National Health Service cervical screening programme (NHSCSP) guidelines. Methods: An audit of cervical cytology in an HIV+ cohort of 187 women by obtaining their last cervical cytology result and recall from local cytology services. Results: Of the 187 women in the audit, two were ineligible, leaving 185 women, 167 (90.3%) of whom were aged 25–64 years and eligible for screening. Of the 185 women, 126 (68.1%) had a cytology history, 50 (27%) had never had cervical cytology and nine (4.9%) had inadequate details to ascertain whether or not they had a cytology history. Of the 126 with a cytology record, 34 (27%) had a current cytological abnormality, which was low grade in 25 (19.8%) and high grade in nine (7.1%). Among women aged 25–64 years attending the clinic, these percentages were significantly higher than expected for England as a whole (P < 0.001). Of 126 women with a cytology record, 29 (23%) were overdue for their recall date and of these the previous test was abnormal in 14 (48.3%). Cytology tests were taken within the community setting in 61 (48.4%), whereas 65 (51.6%) were seen either at an HIV sexual health clinic or were under colposcopy follow‐up. Of 91 women with negative cytology only 50 (54.9%) were recommended for repeat in 12 months. Conclusion: This audit demonstrates a high rate of cytological abnormalities among HIV+ women compared with the screening population at large. Implementation of NHSCSP guidelines has been difficult and requires improved care pathways between HIV clinics, primary care and laboratories.     

An Audit of Cervical Cancer Deaths In Nottingham

Death certificates were reviewed and 57 women were identified whose primary cause of death was cervical cancer. Their cervical smear records were reviewed from laboratory files. Only nine had participated in the cervical cancer screening programme before the diagnosis of cervical cancer was made. One woman had an abnormal smear as a result of cervical screening but failed to attend for follow-up.
The problem of false negative smears is also addressed and the value of review of negative smears for the purposes of cytology audit is emphasized.     

Differences between papanicolaou smears with correct and incorrect diagnoses

A case control study of women with carcinoma in situ (CINIII) was undertaken comparing Papanicolaou smears for which false negative reports had been issued with slides for which true positive reports had been made. the number of abnormal cells was the strongest differentiating factor. Where there were less than 50 abnormal cells on the slide, the odds of a false negative report being issued was 23.7 times greater (95% confidence interval 3.7-150) than when there were 200 or more abnormal cells. In false negative slides, the abnormal cells were likely to be not represented throughout the slide, present only as single cells rather than as groups, small in size and with finely granular normochromatic nuclei. We conclude that there are intrinsic differences between true positive and false negative slides. Given these characteristics, rapid rescreening of slides that are considered negative may not be an effective method of reducing the false negative rate.     

A pilot study of cervical screening in an inner city area—lessons for a national programme

The objectives of this study were to examine aspects of organization of a proposed national screening programme based in general practice. The target population of women aged 25–59 years and their general practitioners (GPs), in a defined inner city area, was identified from a population register of persons eligible for free medical services; a computerized system was developed for invitations and record linkage of cytology results. Smears were examined in one laboratory and follow up of women with abnormal smears was undertaken by one gynaecologist. A random sample of non‐responders was surveyed by questionnaire. Response following two invitations was only 20%. Practices with male doctors only had significantly lower reponse rates ( P <0.001) than those with a female doctor/nurse. A survey of non‐responders showed that over 20% of addresses were incorrect and 16% of those interviewed were ineligible for smear tests. A preference for a female to undertake smears was expressed by 67%, and 77% believed that the purpose of the cervical smear was to detect cancer. An accurate population register, health promotion, support for GP practices, provision of alternative venues for smear tests, development of computer systems, accurate data entry and fail‐safe follow up are aspects of a cervical screening service which must be addressed prior to setting up a national service.     

Cervical cytology/histology discrepancy: a 4‐year review of patient outcome

E. L. Moss, A. Moran, G. Douce, J. Parkes, R. W. Todd and C. E. W. Redman Cervical cytology/histology discrepancy: a 4‐year review of patient outcome Objective: To investigate the diagnosis, review and management of women identified as having a cytology/histology discrepancy. Methods: A review of all patients diagnosed with a discrepancy between referral smear and cervical histology was performed between January 2003 and December 2004. Cases were followed for a minimum of 4 years and patient management and outcome reviewed. Results: A significant discrepancy was identified in 79 cases, 0.1% of all smears (n = 80 926) analysed during the study period. A discrepancy between cytology and histology, obtained from large loop excision of the transformation zone (LLETZ), was confirmed by multidisciplinary review in 42 cases (53.2%). In 37 cases (46.8%) the cytological and/or histological diagnosis was revised; the cytology was significantly more likely than the histology to be amended (chi square P = 0.005), most often because cytology had been overcalled. Of the confirmed discrepancy cases, 33 (78.6%) were due to high‐grade squamous cell or glandular abnormalities on cytology with a negative, inflammatory or human papillomavirus (HPV) infection on histology (HGC/NH). HGC/NH cases were managed by cytological follow‐up in 29 (87.9%), of which 72.4% of the smears were negative when performed at least 6 months post‐excision. During the 4‐year follow‐up period six women with a confirmed HGC/NH underwent a repeat cervical excision (hysterectomy or LLETZ), and of these, HPV effect was seen in two cases but no cervical intraepithelial neoplasia was detected in any of the histological specimens. Conclusion: Cytology overcall was responsible for the majority of cytology/histology discrepancies. A confirmed discrepancy is not an indication for a further excisional biopsy but follow‐up is essential because a small percentage of patients may have disease that has been missed.     

Review of negative and low‐grade cervical smears in women with invasive cervical cancer after the first 3 years of the national cervical screening programme in Slovenia

A. Repše‐Fokter, A. Pogačnik, V. Snoj, M. Primic‐Žakelj and M. S. Fležar
Review of negative and low‐grade cervical smears in women with invasive cervical cancer after the first 3 years of the national cervical screening programme in Slovenia Objective: The purpose of the study was to perform a national review of negative, low‐grade and inadequate smears reported during the latest screening period before cervical cancer diagnosis in 2006, after the first 3 years of the screening programme. Methods: Among 162 new cervical cancer cases there were 47 (29%) without previous cytology, 47 (29%) with one high‐grade smear prior to diagnosis and 68 (42.0%) with at least one previous negative, low‐grade, atypical or inadequate smear 1–40 months before diagnosis. Of the latter 68 cases, 37 patients with 59 smears (together with 118 control slides) were included in the review as 31 had smears reported at laboratories no longer operating. Findings were related to the last cytology report before diagnosis as well as to histological type and stage of the cancer. Results: In our study group, 19 (51%) of 37 patients had squamous cell carcinoma, 15 (41%) adenocarcinoma and 3 (8%) adenosquamous carcinoma, compared with 121 (75%), 26 (16%), 12 (7%), respectively, and 3 (2%) other types, for all carcinomas. Twenty‐one of 37 women also had high‐grade cytology prior to diagnosis of cancer. Women with previous cytology (with or without recent high‐grade smears) were more likely to have stage I cancers than those without cytology (P < 0.0001). The expert group upgraded 17/33 smears in the patients with squamous carcinomas, which was more than in those with adeno‐ and adenosquamous carcinomas (5/24, P < 0.05). Conclusion: As expected, a higher proportion of smears preceding adenocarcinomas were true negative. Under‐diagnosed smears were not related to cancer stage or last cytology report before diagnosis.     

The interaction of high and low-risk human papillomavirus genotypes increases the risk of developing genital warts: A population-based cohort study

Cervical cancer is among the most common type of cancers in women and is associated with human papillomavirus (HPV) infection. Genital warts are also reported to be linked with HPV infection types 11 and 6. In turn, clinical characteristics and morphological features of warts may be useful in the prediction of prognosis and in making treatment decisions. Thus, we have investigated the association of high and low-risk HPVs genotype with genital wart risk, as well as pathological and cytological information in cases recruited from a population-based cohort study of 1380 patients. Patients infected with HPV genotype 6 or 11 had an increased risk of having warts, with OR of 2.34 (95% CI: 0.955-5.737, P = 0.06). Also, this association was enhanced in the presence of high plus low-risk HPV for having genital wart (OR: 2.814; 95%: 1.208-6.55, P = 0.017) and cases having high-risk HPV (OR: 2.329; 95% CI: 1.029-5.269, P = 0.042). Moreover, we observed patients with genital warts having CIN2/3, indicating the importance of informing the physician to the patient to prevent more severe lesions. Our data demonstrated that patients with both low/high-risk HPV types had an increased risk of developing genital warts and persistent infection with HPV was a necessary precursor for the increase in cervical lesions.     

P‐26CONVENTIONAL V THIN LAYER TECHNIQUES: A COMPARATIVE STUDY OF BRONCHIAL SPECIMENS USING CONVENTIONAL AND TWO LBC METHODS,THINPREP AND SUREPATH

Introduction: There is ongoing debate about the terminology used in the classification of dyskaryosis, including whether BNA smears should be classified according to whether koilocytes are present or not. We explored the effect of koilocytosis in the management experiences and clinical outcomes of women with a single BNA smear. Methods: This study includes 410 women aged 20–59 years, resident in Tayside who had an ‘baseline’ BNA smear between 31/10/1999 and 31/10/2002 who were eligible for the TOMBOLA trial but who did not participate. Recommended follow‐up for these women was a repeat smear in six months. Up to three‐years follow‐up data was collected on subsequent cytological smears, colposcopy examinations and any related histology. The baseline smear was re‐read for the presence or absence of koilocytes. Women were classified according to their clinical outcomes during their three years. Results: 47% (192/410) of women were classified as having koilocytosis at baseline. The mean age was lower among these women (25 years) compared to those without koilocytosis (35 years). 55% (105/192) of women with koilocytosis at baseline had one or more negative smears and no further abnormal smears, compared to 63% (137/218) of those without koilocytosis, the difference was not statistically significant. 28% (53/192) of women with koilocytosis at baseline were referred to colposcopy after subsequent low‐grade or high‐grade smears compared to 19% (42/218) of those without koilocytosis; the difference was statistically significant. 14% (27/192) of women with koilocytosis at baseline were diagnosed with CIN2/3 or worse during follow‐up compared to 10% (21/218) of women without koilocytosis; the difference was not statistically significant. Discussion: Our results suggest that the presence or absence of koilocytosis has little impact on the clinical outcomes of women with a BNA smear.     

Cervical cancers diagnosed after negative results on cervical cytology: perspective in the 1980s.

OBJECTIVES--To assess the magnitude of the problem of interval cancers of the cervix (those that are diagnosed within a short time after negative screening test results) in the 1980s, to compare the nature of interval cancers in younger women with that in older women, and, by reviewing negative cervical smears, to determine the proportion of interval cancers that might represent the development of malignancy anew compared with the proportion that might be associated with difficulties in sampling or errors in reporting. DESIGN--An audit of the interval cases of cervical cancer that had been diagnosed within 36 months of a smear having been reported as negative by the Victorian Cytology Gynaecological Service among women registered with cervical cancer during 1982-6. SETTING--The Victorian Cytology Gynaecological Service, a free public sector cytology laboratory in Victoria, Australia. SUBJECTS--138 Women, all of whom had had cervical cancer diagnosed during the 36 months after having had a negative cervical smear. Subjects were divided into two age groups: younger women, aged less than 35; older women, aged 35-69. INTERVENTIONS--Negative slides were reviewed for evidence of optimal sampling and for the presence of cellular abnormalities that had been missed at the time of the original reporting. MAIN OUTCOME MEASURES--The number of interval cases of cancer of the cervix registered during 1982-6. The proportion of interval cases occurring in younger women and the proportion occurring in older women. Division of women into three risk categories based on clinical history and screening history that broadly corresponded to the probability that a diagnosis of cervical cancer might be expected during the 36 months after the issuing of a negative smear report. RESULTS--138 Of 1044 (13.2%) women who had been registered with cervical cancer during 1982-6 had had one or more negative smears during the 36 months preceding the diagnosis of cancer. Interval cancers comprised a larger proportion of registrations of cervical cancer in women aged less than 35 years than in women aged 35-69 (21.1% v 11.0%, p less than 0.01). Women with interval cancer who had had at least three negative smears during the 10 years before the diagnosis of cancer were commoner in the younger age group than in the older age group (7.0% v 2.5%, p less than 0.01). When, however, the number of observed cases of squamous cell carcinoma was related to the number of expected cases in the absence of screening, no significant difference was found between the two age groups (6.8% v 4.8%, p greater than 0.10). The rate of diagnosis of interval cancer per 100,000 negative tests was lower among younger women than among older women (10/100,000 v 16/100,000). Review of the negative slides showed that 11.9% were again considered to be negative with an optimal sample having been obtained as evidenced by the presence of endocervical cells or metaplastic cells, or both. CONCLUSIONS--Interval cancers might comprise a larger proportion of all registered cases of cervical cancer among younger women owing to the larger proportion of such cancers being prevented in this age group. Among women with interval cancer review of the negative slides showed that most were accounted for by suboptimal sampling or by errors of reporting.     

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.     

Detailed account of confounding factors in interpretation of FTIR spectra of exfoliated cervical cells

The confounding variables that can potentially lead to a misinterpretation of FTIR spectroscopy of exfoliated cervical cells is described. A detailed account of the spectral effects of the following variables in FTIR spectroscopic screening of exfoliated cervical cells is presented: polymorphs; Cell degradation; and impurities such as endocervical columnar cells, metaplastic cells, cervical mucus, red cells, and debris. The interpretation of the spectra of exfoliated cervical cells must be done with subtraction analysis, which includes these factors. This is essential to prevent unacceptable false-positive rates. The above techniques are subsequently applied to two clinic populations: a dysplasia clinic in follow-up patients with negative cytology and two general gynecology clinics with patients with negative cytology. In the dysplasia clinic group 250 sequential patients with negative smears were tested. Thirty had false-positive smears as defined by the IR spectroscopy using the above methodology. Twenty of those patients subsequently had one follow-up and six had a positive abnormal smear. In the community clinic group 656 sequential patients were examined who had negative smears, of which 27 had false-positive FTIR spectra.     

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.