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The history and importance of cervical screening

David Luesley
MA MD FRCOG
Professor of Gynaecological Oncology
University of Birmingham

The concept of an epithelial disorder that has the potential to develop into cancer dates back to the end of the last century, when Sir John Williams described noninvasive tissue resembling malignancy adjacent to an area of microinvasive carcinoma in a hysterectomy specimen. The term carcinoma-in-situ (CIS) was introduced in the 1930s. Retrospective studies on archived histological material found CIS lesions in women who subsequently went on to develop cervical cancer, and so the precursor nature of CIS to cervical cancer was established. Subsequent prospective studies confirmed these findings.

Cervical cytology
One of the most important features of precancerous lesions is the fact that they are not associated with symptoms and cannot be diagnosed by naked eye inspection of the cervix. The only method of detection is the application of a screening test. The test that is currently employed is the cervical smear. This test depends upon the recognition of abnormal, or dyskaryotic, cells from a sample taken by scraping the cervix with a specially designed spatula. The first illustrations of shed cells from tumours as seen under a microscope were published 150 years ago. These early observations were followed during the next 50 years by descriptions of cells from sputum, urine, cerebrospinal fluid, gastric washings and lymph node aspirates.

Babes in Bucharest and Papanicolaou in New York introduced diagnostic cytology of the female genital tract almost simultaneously, circa 1928. However, neither of these seminal observations made any major clinical impact, and it was not until Papanicolaou and Traut's later published works on uterine cancer detection in the 1940s that any significant momentum was gained.(1) Today it is generally considered that the cervical smear is one of the most effective health tools ever introduced. There is also little doubt that its effectiveness has been considerably improved over the past 20 years by the increasing use of colposcopy. The combination of smear and colposcope provides a very potent weapon in the quest to reduce deaths from cervical cancer. Further and more recent developments include liquid-based cytology, which greatly improves the quality of the examined specimen, reducing the number of unsatisfactory tests and enhancing the performance.

When the Pap smear was introduced in the 1940s and abnormalities investigated it became obvious that there were changes not amounting to CIS but still showing similar features. These lesser changes were initially referred to as "dysplasia", but because it was an imprecise term covering a range of abnormalities, from normal to CIS, many other terms were also in use. This caused confusion in management. Ralph Richart coined the term cervical intraepithelial neoplasia (CIN) and divided it into grades 1, 2 and 3. Grades 1 and 2 corresponded to mild and moderate dysplasia respectively, and grade 3 combined severe dysplasia and CIS into one category.(2) The definition implied a continuum of change and emphasised to clinicians the concept of a single disease entity, which it was hoped would lead to more rational management. More recently the concept of a continuum of change from CIN 1 to cervical cancer has been challenged. The process seems to be a series of discrete events starting off with human papillomavirus (HPV) infection. Progression or regression depends on several factors. For practical purposes we now use a two-stage grading, with CIN 1 and warty atypia becoming low-grade CIN, where there is a significant chance for regression, and CIN 2 and CIN 3 being grouped together as high-grade CIN.

Preinvasive disease
Cervical precancer has a long natural history, which is one of the reasons why it is suitable to screen for. If a cancer is going to develop at all it will take several years to do so, even from a CIN 3 lesion. We don't know why some CIN 3 lesions become invasive while others stay as intraepithelial disease. We're not even very sure how many CIN 3 lesions will become invasive, as prospective studies are unethical. However, the best prospective data we have where women with inadequately treated CIN 3 were followed up without intervention found that 36% developed an invasive tumour after 20 years.(3)

At the other end of the spectrum, we know that up to 50% of women with minor cytological abnormalities will regress to normal if left untreated. On the other hand, you could look at the figures and say that women with mild dyskaryosis have a 16-47 times increased incidence of invasive disease compared with the general female population.(4,5)

Screening
Screening by offering women smear tests at regular intervals began in the 1960s, and its beneficial effect in reducing deaths from cervical cancer was first demonstrated in British Columbia. Over the ensuing three decades, structured screening programmes were introduced throughout most of the Western world. The NHS introduced a structured national screening programme in 1988. Before this, cervical screening varied depending on the area of the country. The regions still have a degree of autonomy in planning their screening programme, but there is now a National Coordinating Network to ensure the adoption of common standards and working practices. Regions are required to offer screening to women aged 20-64 on a maximum five-yearly cycle. Most regions now screen women every three years, but the emphasis remains on coverage rather than frequency: it is far better to screen 100% of eligible women every five or even 10 years than to screen 50% every two or three years. The women who don't get screened are likely to be those most at risk of the disease.

Nationwide coverage is now around 85%. Over 4.5m smears are assessed annually in England to detect preinvasive changes and hopefully further reduce the 4,000 cases of invasive cervical cancer and the 1,300 deaths each year. Because of the extremely low incidence of invasive cervical cancer in women under 20 years, and because of the high prevalence of HPV infection at this age, screening of women under 20 is not justified. Similarly, at the other end of the spectrum, provided a woman has been adequately screened with negative smears, and provided she has not recently changed her partner, there is no justification for continuing with screening after 65. Indeed, some authors have questioned the validity of screening such women beyond 50 years.

Cervical cytology is not a perfect test: it is a screening test and as such there will be false-positive results (where there is a positive result but no disease is actually there) and false-negative results (such as the Kent and Canterbury story). The number of false-positive results varies from 7-27%, while the number of false-negatives is around 20%.(6) The public and the press have difficulty with this concept.

How many smears are abnormal?
About 92% of the smears taken are adequate for diagnosis, and just under 10% of these adequate smears are "not normal". Most smear abnormalities are at the minor end of the spectrum. Overall, 4.3% of smears are reported as borderline changes, 2.5% as mild dyskaryosis, 1% as moderate dyskaryosis and 0.7% as severe dyskaryosis. Only 0.15% of smears are reported as suspected invasion or glandular neoplasia.(7) In general, the proportion of normal smears increases in older women, but so does the proportion of abnormalities representing invasive cancer. Borderline changes and mild dyskaryosis are very common in young women; the proportion of moderate dyskaryosis is highest for women aged 20-29, and the proportion of severe dyskaryosis is highest in women aged 25-34.(7)

What happens when a smear is abnormal?
Women with minor changes have a repeat smear, six months following the first abnormality. If the smear remains abnormal then referral for colposcopy is recommended. More severe abnormalities (anything equal or worse than moderate dyskaryosis) are referred for colposcopic assessment without repeating the smear. Colposcopy allows a tissue diagnosis to be made by taking a biopsy under magnified conditions. If preinvasive disease is confirmed, treatment can be offered. Treatment aims to remove the abnormal areas of the cervix without compromising function.

Conclusion
Screening with cervical smears has made a huge impact in prevention of cervical cancer in countries where it has been systematically applied. A complex and robust healthcare infrastructure is a prerequisite, which in part explains why there has been little, if any, impact in resource-poor nations. The vast majority of deaths from cervical cancer occur in those countries.

References

  1. Papanicolaou GN, Traut HF. The diagnostic value of vaginal smears in carcinoma of the uterus. Am J Obstet Gynecol 1941;42:193-206.
  2. Richart RM. Influence of diagnostic and therapeutic procedures on the distribution of cervical intraepithelial neoplasia. Cancer 1966;19:1635-8.
  3. McIndoe WA, McLean MR, Jones RW, Mullins PR. The invasive potential of carcinoma in situ of the cervix. Obstet Gynecol 1984;64:451-8.
  4. Soutter WP, Wisdom S, Brough AK, Monaghan JM. Should patients with mild atypia in a cervical smear be referred for colposcopy? Br J Obstet Gynaecol 1986;93:70-4.
  5. Robertson JH, Woodend BE, Crozier EH, Hutchinson J. The risk of cervical cancer associated with mild dyskaryosis. BMJ 1988;297:18-21.
  6. Gay JL, Donalson LD, Goellner JR. False negative results in cervical ­cytologic studies. Acta Cytol 1985;29:1043-6.
  7. Raffle AE, Alden B, McKenzie E. Detection rates for abnormal cervical smears: what are we screening for? Lancet 1995;345:1469-73.

Resources
NHS National Cervical Screening Programme­- contains ­information, resources and contact addresses for publications
W:www.cancerscreening.nhs.uk/cervical
Cervical Screening Wales
W:www.velindre-tr.wales.nhs.uk/csw/
Marie Stopes International Cervical Screening
W:www.mariestopes.org.uk/sscervical_screening.html