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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.

Salient epidemiological and molecular biological features of Epstein-Barr virus (EBV) infection correlate well with the natural history of carcinoma of the cervix. It is therefore hypothesised that the incorporation of EBV into the genome of cervical epithelial cells at an early age (teens) could be an important early event in cervical carcinogenesis.

A review of age-specific mortality-rates from cervical cancer in England and Wales and in Scotland in 1968--76 shows a decline, striking at some ages. In England and Wales, however, there has been an increase at ages 25--34 and, possibly, at 15--24. Signs of such an increase are also seen in Scotland for the age-groups 25--34 when figures for two regions with well-established screening programmes are removed. Indeed trends in these regions compared with those for the rest of Scotland support the benefit of cervical screening.

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.

9000 women aged 20 years and under who had cervical smears taken in the 10-year period 1967-76 were studied. The number of young women with abnormal smears rose, but this increase was in proportion to the number screened. Abnormal smears were found in 145 (1.6%) cases. Follow-up for periods of up to 10 years showed that in over half the cases subsequent smears had reverted to normal without treatment. 19 of the 145 patients progressed to have smears which were suggestive of malignancy: 16 of these were diagnosed histologically as carcinoma-in-situ, and the other 3 were histological dysplasias. At follow-up no cases of carcinoma-in-situ were found in women under 21. No cases of invasive cancer were found on the initial biopsy. One microinvasive cancer was found in a woman aged 26 on a second biopsy 6 1/2 years after the first atypical smear. The preclinical cases were detected from smears taken during pregnancy, or, in the case of the one possibly nulliparous girl, during a gynaecological consultation. These women did not attend family-planning clinics until after a pregnancy.

In 1971 the Aberdeen cytology service handled 22,291 cervical smears--threequarters from women participating in a screening programme and the rest from women with symptoms who were referred to hospital. As a result of screening, 56 preclinical cases of cancer of the cervix uteri were treated in hospital; 13 others were classified as less than preclinical. Of the gynaecological patients 20 had clinical cancer and 29 had less than preclinical lesions. From estimates of the costs of running the cytology service and of hospital inpatient costs it is possible to derive figures for detecting and treating preclinical cases and investigating and treating clinical cases. The cost to the Health Service of detecting and treating each preclinical case was slightly less (445 pounds) than that for impatient treatment of each clinical case (487 pounds). However, if mass screening were abandoned cytology would almost certainly continue for women referred to hospital with symptoms, and, if the costs of taking and examining these smears is taken into account, the cost per clinical case treated nearly doubles to 835 pounds. Had outpatient and other follow-up costs been included, the difference in service costs would be even greater. Comparison of these figures assumes the controversial point that preclinical cancer will always progress to invasive carcinoma if left untreated and takes no account of inflation and discounting.

From surveys conducted by the authors it is concluded that the best and most acceptable quality control methods in cytology are those from within the laboratory. Most of these have results which can be reported centrally. Where the overall control and codes of practice are high, there the results are the most reliable, as sources of error from whatever cause are quickly brought to light. These conclusions are illustrated by data from the five centres and correlated in the tables.