50 years of age, the CR of CIN2+ is significantly lower compared to younger women, irrespective of the number of previous negative screening episodes. Combining the effect of age and the effect of the number of previous negative smears in the case of a CIN2+ diagnosis every 1 true-positive CIN2+ we may expect between 1 and 6.3 false-positive cases in the worst scenario, according to the combination in .
The present study is based on a large multicentric cohort and a great amount of person-years; nevertheless a number of points in the study design need to be discussed.
Ideally, the protective effect of cervical screening should be estimated on the risk of invasive carcinoma. Nevertheless, we chose CIN2+ as the outcome because in the whole cohort (287
330 women, 1110 CIN2+ cases), we found few invasive carcinomas (n
=61) only. Incidence of cervical cancer in the study population is not comparable to that of the general population as women are selected for having performed at least two cytological screening tests, the first negative. Moreover, screening protocol addresses women with CIN2+ diagnosis to treatment.
Usually DR is calculated per smear as it is used to estimate a lesion prevalence, whereas here it was calculated as cases on person-years to take into account the screening history and the effect of previous tests on diagnosis.
We stratified the cohort choosing 50 years of age as cutoff. Even though the age groups have different lengths (25 and 15 years), this choice was based on previous studies showing a strong risk reduction for CIN2+ after 50 years of age (Gustafsson et al, 1995
; Gram et al, 1998
; International Agency for Research on Cancer, 2005
). Also, our results show that DR of CIN2+ decreases significantly from 4.17 in the 45–49 age group to about 2 after 50 years of age (). When stratifying for 5-years age classes and previous screening episodes, after two, the DR before 50 years is doubled compared to older women (data not shown). To verify that the use of two groups of 25 and 15 years length would not affect our study conclusions, we estimated CR using 25–44 and 45–64 age groups, and the results show that the risk in younger women is at least threefold higher than that in older ones (the ratio ranging from 3.3 to 6.3).
As shown in , one critical point in cervical screening is the specificity of cytohistological diagnosis.
We estimated the joint probability of a false-positive CIN2+ diagnosis within a screening episode, as it depends on the probability of being a false-positive case at both the primary and the assessment test, for the adopted diagnostic category.
Histological diagnosis reproducibility might be as questionable as cytological diagnosis. Studies of cervical biopsies have shown fair-to-poor interobserver and intraobserver agreement in reporting (Robertson et al, 1989
). We assumed histological specificity to be at least 0.94 according to the findings of ASCUS-LSIL Triage study (Stoler and Schiffman, 2001
), which reviewed 2237 original histological slides.
According to these assumptions, the ratio between true-positive and false-positive results is almost above 10 under 50 years of age, whereas among older women, for each real case identified, one false positive is also diagnosed. After four tests, at least three false-positive cases are diagnosed every true positive (). These considerations hold also in the case of two 20-year age groups, that is 25–44 and 45–64 (data not shown). Yet, in our results, the effect is even stronger, thus demonstrating that the screening benefits over 50 years is uncertain.
False-positive results are associated with unnecessary assessment and its complications, adverse effects of treatment, unnecessary treatment, adverse effects of labelling or early diagnosis, anxiety and costs generated by investigations and treatment (International Agency for Research on Cancer, 2005
). Hence an effort to increase specificity is needed, especially in older age groups.
A different CIN2+ DR is reported among the participating centres, likely due to real incidence differences and not due to diagnostic variability among laboratories. Actually, data on reproducibility that are available for cytological diagnosis in Italy showed that agreement was generally good (Montanari et al, 2003
As the cohort includes women coming from six different Italian screening programmes, with different periods of observation, the CIN2+ DRs must be taken with caution. For this reason, we have performed an analysis on the Florence and Turin data only, as they contribute for 75% of the observed women. The estimates of the DRs, ratios and trends are very similar to those calculated on the whole cohort.
Centres with the highest CIN2+ incidence (Ravenna, Ferrara and Mantova) gave a limited contribution to the cohort as to person-years but they provided a great number of cases; this could have reduced the stronger effect observed in a previous analysis (Armaroli et al, 2005
). Thus, decision makers should take into account the local CIN2+ prevalence when implementing local intervention strategies, as in single areas, the probability of being a case might be higher than that of being a false positive.
Women who undergo screening more frequently may have a lower risk of cervical disease because of a healthier lifestyle and a better access to treatment (Ronco et al, 1991
). In the present study, DRs are low also because women were selected as having had at least one negative smear before the index test. Moreover, survival within the cohort is subordinated to not having shown a previous high-grade cervical lesion, as follow-up is stopped when a CIN2+ lesion occurs, that is the probability of being positive to the last Pap smear is conditional to having accumulated previous negative test.
Detection rates are affected by the duration of sojourn time and by the proportion of lesions that regress. Moreover, the sensitivity of smear test for long-sojourn time lesions as CIN2 (International Agency for Research on Cancer, 1986
) depends on the number of smear tests performed during the sojourn time; on the other hand, frequent testing increases the DR of those significant lesions. This last effect may explain the observed risk reduction when the number of screening episodes increases, particularly after four negative tests.
Few cases of preinvasive lesions were diagnosed ex novo
in well-screened women aged over 50 years (two or more 3- to 5-yearly negative screens) (Van Wijngaarden and Duncan, 1993
) or in women with three consecutive (at most 3-yearly) negative screens before 50 years age (Cruickshank et al, 1997
) or in women with at least three negative smear tests screens between 41 and 49 years of age (Gustafsson et al, 1995
In Turin (Italy), invasive carcinoma incidence during 1992–1998 was reduced by 75% in women who attended one screening at least, as compared to nonattenders (3.0 vs
000 person-years), the latter showing the highest incidence (Ronco et al, 2005
The results of the present study, in accordance with other reports, may suggest that the adequacy of a routine screening test to identify early lesions in women over 50 years of age with at least four previous negative screens is questionable; possible alternative strategies may be explored. Women might be involved in the decision whether to stop screening or to undergo just another smear test in their life after evaluating the individual risk of a CIN2+ at further screening through algorithms based on age, screening history and living area-specific DRs. Comparing the future individual risk of being a case or a false positive may support and strengthen individual choices. The decision of stopping screening may also be supported by a negative result of HPV testing.
Informing women about the risk related to changes in their and their partners' sexual habits (Brisson et al, 1994
) may allow spontaneous return to the usual screening protocols.
Such strategies agree with the IARC recommendations for implementation on cervical cancer screening (International Agency for Research on Cancer, 2005
) and with the IARC Working Group statement that there is little benefit from screening old women who have always tested negative in an organised screening programme. In particular, for women over 50 years of age, the Working Group recommend a 5-year screening interval.
The results of our study support the opinion that the benefit arising from cytological screening is uncertain in older women. Ethical and practical considerations subsequent to screening intensity reduction must be taken into account. A possible consequence might be an increase in invasive lesion incidence, compared to a major resource saving. Estimates of unprevented cervical cancers are in the magnitude of about two cases per 100
000 person-years (Sherlaw-Johnson et al, 1999
). It is thus desirable to evaluate if benefits arising from saved resource allocation to more cost-effective interventions would make acceptable to reduce or to stop screening in 50-year-old or older women with a negative documented screening history.