Cervical screening. Ian D Duncan

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1 DOI: /toag Cervical screening Ian D Duncan Since the introduction in the late 1980s of UK cervical screening programmes based on computerised call and recall, mortality from cervical cancer has fallen by one-third and incidence has dropped by two-thirds. Current methods of screening have probably reached the limits of their usefulness. However, encouraging new approaches involving liquid-based cytology and automation are in the advanced stages of development. Roles are also being researched for entirely different technologies, including human papillomavirus testing. It is anticipated that both sensitivity and specificity will improve. Keywords cancer, cervix, cytology, papillomavirus, screening Background Worldwide, cervical cancer is the second most common cancer to affect women.approximately new cases are reported per annum. Three out of every four of these cases affect women in developing countries and only one in four affects women in developed countries. It is generally accepted that this difference is largely due to cervical screening. Unlike other forms of screening in the oncology field, cervical screening aims to prevent cervical cancer and not to detect it. Two different approaches were developed during the second half of the 20th century as a result of earlier discoveries. In 1925, Hans Hinselmann, working in Germany, introduced colposcopy, 1 whereby a stereoscopic magnified view of the illuminated cervix was obtained with a binocular instrument mounted on a stand. In many developed countries women were encouraged to undergo annual gynaecological examination and colposcopy became part of this routine examination. Its use spread from Germany to South America and back to Spain and Italy. Primary colposcopic screening for cervical neoplasia is still commonplace in these countries but cervical cytology, introduced by Papanicolaou and Traut 2 in 1941, was adopted by the English-speaking world. This approach has the advantage that smear taking is an easier skill to acquire than colposcopic expertise, and the cytoscreeners and cytopathologists who examine the smears do not require the physical presence of the woman herself. Thus, cytology lends itself more to mass population screening. Colposcopy and cytology were initially seen to be in competition with one another. In reality they are complementary. Cytology has become the standard cervical screening tool in most countries where population-based cervical screening is practiced. Colposcopy tends to be reserved for those women identified as having abnormal cytological findings. Cervical screening is applied to individual women, who do benefit from it. However, reduction in the national incidence of and mortality from cervical cancer is a public health measure requiring mass participation, which in turn demands elaborate organisation. An age and sex register is essential and such registers are not universal. In many countries in the developing world they simply do not exist. Topography can also render countrywide cervical screening an insurmountable task. For such countries the World Health Organization advocates a policy of downstaging. Individuals well accepted within the community but having no medical training can be taught to recognise cervical cancer at an early symptomatic stage when treatment is still life saving. In the UK the issues and problems are quite different. UK cervical screening programmes In the late 1980s the Department of Health for England and Wales and the Scottish equivalent determined that computerised call and recall be undertaken.as a result, women between the ages of 20 and 64 years in England and Wales and 20 and 59 years in Scotland are invited to have a smear taken at least once every five years. The five-year interval was chosen because of the published results of an International Agency for Research on Cancer (IARC) working party that had studied ten different cervical screening programmes. 3 Compared with an unscreened population and assuming 100% uptake, it suggested that five-yearly screening of women aged years could reduce the incidence of Author details Ian D Duncan FRCOG, Reader and Honorary Consultant Gynaecologist/Oncologist, Maternal and Child Health Sciences, Ninewells Hospital, Dundee, Tayside, DD1 9SY, UK. ian.d.duncan@tuht.scot.nhs.uk 93

2 Crude rate per person years at risk invasive cancer by 84%. Three-yearly screening could reduce the incidence by 91%, employing 15 rather than 9 tests and annual screening could reduce the incidence by 93% but requires 45 tests. The National Health Service Cervical Screening Programme National Coordinating Network (NHSCSP NCN) was established in 1989 encompassing the 14 English Health Authorities, the three Celtic nations and the private sector. The programme has gone from strength to strength. In 1994, the NHSCSP NCN became simply the NHSCSP and in 1997 the NHSCSP assumed responsibility for England alone, with Scotland, Wales and Northern Ireland developing their own programmes along similar lines Figure 1. Trends in cervical cancer mortality, Scotland, Successful screening and cancer prevention Despite media attention being largely devoted to its shortcomings, cervical screening in the UK is highly successful. In July 1992, the Department of Health set a target within the Health of the Nation 4 initiative to lower the incidence of invasive cervical cancer at least 20% below the 1986 level to no more than 12.8 cases/ women by the year This target was achieved nine years ahead of schedule in 1991, when it fell to 12.7, 5 and the downward trend has continued. It is estimated that the incidence of cervical cancer fell 42% between 1988 and Deaths from cervical cancer had been falling in England by 1 2% each year from the mid-1950s. Mortality fell faster to around 7% per year, from 6.1 per women in 1988 when computerised call and recall was introduced to 2.8 per women in Similar results have been achieved in the remainder of the UK (Figure 1). Success is mainly due to population coverage. A target of 80% of eligible women to be screened at least once every five years was also incorporated into the Health of the Nation initiative and has been exceeded every year since In the proportion of the target population screened was 81.2%, with London at 75.7%, the only government office region below 80%. 5 In 2002 the number of deaths in England from cervical cancer fell below one thousand for the first time, to Room for improvement Success not withstanding there is still room for improvement. As with all such processes, cervical screening is not 100% accurate and never can be. Regrettably false negatives occur and women develop cervical cancer despite participating in the programme.these false negatives can lead to medical litigation on behalf of the patient and frustration and sometimes guilt on the part of the laboratories. This can be counter-productive in the recruitment of both cytoscreeners and cytopathologists. Improving the sensitivity of cervical screening is a goal but so also is improving the specificity. Although the latter is much less likely to make the headlines, lack of specificity is much more costly for the country as a whole. Clearly, the majority of women found to be screen-positive on cervical cytology would not go on to develop cervical cancer were they not to have been detected, investigated and, in many cases, treated.were it not so, in the absence of cervical screening, we would currently be witnessing an epidemic of enormous proportions far in excess of the number of cases encountered before screening was introduced. It would seem that as well as detecting truly precancerous lesions we are also detecting conditions which are self-limiting and which are only mimicking precancer. Improving specificity It is unethical to subject women to cervical screening if they are not at any risk of developing cervical cancer and this applies at both ends of the target age range. High-grade cervical intraepithelial neoplasia (CIN) undoubtedly does occur in teenagers. It is, however, at a very early stage in its pathogenesis, thus allowing ample time for its detection once the woman has left her teens. In 2000 in England, 26 cases of cervical cancer were registered in women aged between 15 and 24 years and in 2002 only five deaths from cervical cancer were registered in this age group. 6 The NHSCSP has concluded that there is no justification for screening teenagers and 94

3 recommended that calls should not be initiated before a woman s 25th birthday. 6 In England, the screening of teenagers has dropped from in to in (Figure 2). 5,7 It is noteworthy that, of those teenagers, (87.9%) were tested opportunistically outside the NHSCSP. 5 The age at which screened women are discharged from the programme is arbitrary. Currently, the NHSCSP in England discharges women at the age of 64 years. In Scotland, however, women are discharged at the earlier age of 59 years. In the neighbouring Scottish Regions of Tayside and Grampian, the population is relatively stable and well-organised screening programmes have been in place since the 1960s. In 1993, retrospective case analyses demonstrated that, in the Dundee and Angus Districts of Tayside, CIN typically occurs in younger women. 8,9 It was further shown that the incidence of CIN over the age of 50 years in women screened every three years was so low that consideration might be given to lowering the age at which well-screened women could be discharged. It was reported that 15.5% of smear tests were done to detect 3.4% of cases of CIN and that a total of smear tests were required in women over 50 years to detect one new case of CIN3 over a four-year period.this was supported by a study from Grampian Region showing that only one case of CIN 3 and one case of invasion were detected over a five-year period in approximately 9000 women with adequate smear histories prior to the age of 50 years. 10 The Tayside study was extended over a further four years. 11 Had the policy suggested in 1993 been implemented (i.e. women with a history of three negative smears, the most recent taken no more than three years previously, being discharged at the age of 50 years) only 13 women with CIN or microinvasive disease would have gone undetected. Refining these criteria further, had such women only been discharged with a negative exit smear performed at age 50 years then only three cases would have gone undetected over a three-anda-half year period (two of CIN3 and one of microinvasive disease). The study has been advanced even further with data from 1997 through This unpublished work has shown that during these last three years had the further amended policy been adopted only three women all with CIN2 would have gone undetected.were such findings to be confirmed on a wider scale, significantly fewer smears would have to be performed and well-screened women could be reassured at an earlier age that the likelihood of their developing invasive cervical cancer was absolutely minimal. Improving sensitivity Cervical screening programmes based upon traditional cytology screening are rapidly approaching their limitations. Both false negative and false positive results are unavoidable. This fact is now being widely publicised. New approaches must be considered.when a cervical smear is taken, only a proportion of the cells scraped from the cervix are actually transferred to the slide and these may be partly obscured by both red and white blood cells. Liquid-based cytology (LBC) involves the taking of the smear using a plastic device from which the cells wash off more readily than from a wooden spatula (Figure 3). The device is rinsed in a buffered methanol solution for transfer to the laboratory. A degree of self-separation can be achieved by centrifugation and, if necessary, several optimal thin-layer smears can be made and the remainder of the cells stored. Thin-layer cytology based upon a liquid sample has the potential to reduce both the number of false negatives and unsatisfactory smears and lends itself to automation (Figures 4 and 5). Currently, pilot studies are being carried out at several sites in England to determine the cost effectiveness of this approach. In Scotland, the completion and review of pilot studies informed the decision taken by the Health Minister to implement LBC across the nation by April In England, following further pilot studies the National Institute for Clinical Excellence (NICE) has recommended replacing the conventional smear test with LBC. This recommendation has been welcomed by the NHSCSP and the Department of Health and rollout of LBC is expected in the next five years. 6 Numbers screened (000s) Figure 2. Reduction in NHSCSP teenage cervical screening

4 Figure 3. Cells wash off plastic devices better than wooden spatulae Figure 4. Liquid-based cytology specimen showing severe dyskaryosis; note the clean background (courtesy of Dr Sheila Nicoll, Consultant Pathologist, Ninewells Hospital, Dundee) Human papillomavirus testing Cost effectiveness is an important consideration and a liquid-based sample also lends itself to another form of testing, namely for high-risk human papillomavirus (HPV) subtypes. It is widely accepted that there is a causal relationship between certain subtypes of HPV and cervical neoplasia. 13 More than 100 subtypes are recognised and these can be categorised as of low, intermediate and high oncogenic risk, the archetypes of the high-risk category being HPV 16 and 18. Studies have shown that high-risk HPV is present in more than 99.7% of cervical carcinomas worldwide.walboomers et al. 13 were among the first to show that high-risk HPV was always present in preceding abnormal smears in women subsequently developing cervical cancer and that persistent infection with one of the 15 high-risk HPV subtypes is essential for the maintenance of CIN and the subsequent development of invasive cancer. Meijer and Walboomers 14 have suggested that when women become sexually active many of them acquire an infection with high-risk HPV. Some 80% of these women will clear this infection without developing cervical lesions while the remainder go on to develop CIN. Most of these women will also regress when the high-risk HPV is cleared. Some women cannot clear the virus and develop a persistent high-risk HPV infection and CIN. In the presence of certain cofactors, such as activated oncogenes or in the absence of tumour suppression genes, this may subsequently result in invasive cervical cancer. Thus, the detection of high-risk HPV in cervical smears is potentially a powerful tool for detecting those women at risk of developing cervical cancer. Clearly, however, HPV testing also has the potential for detecting vast numbers of women with a temporary infection that is of no consequence. The high prevalence of this temporary infection in women under the age of 30 years makes HPV screening of this age group inappropriate

5 The future for cervical screening Perhaps the most important aspect of HPV testing is its negative predictive value and the potential for reducing the frequency of screening for women who are high-risk HPV negative and who have normal cervical smears. Currently the role of HPV testing in the UK cervical screening programmes is not established but studies are proceeding using HPV testing in the management of women with low-grade abnormal smears. New technologies are waiting in the wings. It is feasible in the not too distant future that advances in molecular biology will produce new highly sensitive and specific staining techniques which will become universally adopted in liquid-based cytology. Physical approaches using such instruments as the TruScan TM (Polartechnics Ltd) continue clinical trials. They may well find a role in primary screening in countries where the topography and maintaining repeated contact with an individual are extremely difficult and an instant read out is highly desirable. In developed countries with established screening programmes such an approach is perhaps more suited to a role in the triage of women already with suspected abnormality. Traditional cervical screening programmes based on cytology alone are effective but even better results are demanded. Resources are clearly finite and the rapid rise in technology has made it abundantly clear that healthcare resources are especially so. Cost effectiveness and value for money are fundamental issues. In the UK, cervical cancer is now an uncommon disease and particularly so in young women. It may be that by 2010 sufficient evidence will have been gathered to change the face of the UK cervical screening programmes. It is anticipated that automated thin-layer liquid-based cytology and HPV testing will have found an established role. Screening may begin at the age of 25 years and be carried out, initially three yearly, using automated cytology with the addition of HPV testing at the age of 37 years.assuming that these tests are negative, the interval before the next screen might be increased to six years with repeat smear and HPV at 43 and 49 years and assuming that these are also negative the woman might then be discharged from the Cervical Screening Programme completely. Figure 5. Conventional smear showing severe dyskaryosis (courtesy of Dr Sheila Nicoll, Consultant Pathologist, Ninewells Hospital, Dundee) References 1. Hinselmann H. Verbesserung der Inspektionsmoglichkeit von Vulva,Vagina und Portio. Munch Med Wschr 1925;77: Papanicolaou GN,Traut HF.The diagnostic value of vaginal smears in carcinoma of the uterus Am J Obstet Gynecol 1941;42: Day NE, Moss S. Screening for squamous cervical cancer: duration of low risk after negative results of cervical cytology and its implications for screening policies. IARC Working Group on evaluation of cervical cancer screening programmes. BMJ 1986;293: Department of Health. Health of the Nation: a strategy for health in England (Cm. 1986) London: HMSO; National Statistical Service. Cervical Screening Programme, England: London: National Statistics; October 2003 [ 6. NHS Cervical Screening Programme. Modernising the NHS Cervical Screening Programme introduction of LBC and change in national policy. Press release, 22 October Patnick J. editor. A National Priority in Cervical Screening Programme Annual Review Sheffield: NHSCSP; Van Wijngaarden WJ, Duncan ID. Rationale for stopping cervical screening in women over 50. BMJ 1993;306: Van Wijngaarden WJ, Duncan ID. Upper age limit for cervical screening. BMJ 1993;306: Cruickshank ME, Angus V, Kelly M, McPhee S, Kitchener HC.The case for stopping cervical screening at age 50. Br J Obstet Gynaecol 1997;104: McKenzie CA, Duncan ID.The value of cervical screening in women over 50 years of age time for a multi-centre audit. Scott Med J 1998;43: Damoglou S, Duncan ID. Unpublished data. 13. Fiander A. Human papillomavirus vaccines. The Obstetrician 2004;2: Walboomers JMM, Jacobs MV, Manos MM, Bosch FX, Kummer A, Shah KV.The human papilloma virus is a necessary cause of invasive cervical cancer worldwide. J Pathol 1999;189: Meijer CJ,Walboomers JM. Cervical cytology after 2000: where to go? J Clin Pathol 2000;53: Nobbenhuis MAE,Walboomers JMM, Helmerhorst TJM, Rozendaal L, Remmink AJ, Risse AKJ. Relation of human papilloma virus status to cervical lesions and consequences for cervical cancer screening: a prospective study. Lancet 1999;354: