Fast track — ArticlesNatural history of cervical neoplasia and risk of invasive cancer in women with cervical intraepithelial neoplasia 3: a retrospective cohort study
Introduction
Cervical cancer is the second most common cancer affecting women worldwide.1 Cytological screening programmes aim to detect precursor lesions, known as cervical intraepithelial neoplasia (CIN), and treat these to prevent the onset of invasive cancer. Cervical screening has not been assessed by randomised trials, so controversy has remained for half a century about the effectiveness of different screening policies. Assumptions about the natural history of CIN underpin recommendations about frequency of cervical screening, yet uncertainty surrounds the estimates of invasive potential of CIN.2
A unique opportunity has arisen from a clinical study of the natural history of cervical carcinoma in situ (CIS) at the National Women's Hospital, Auckland, New Zealand, in which treatment of curative intent was withheld or delayed for many women who were first diagnosed between 1965 and 1974.3, 4 CIS is now included, together with severe dysplasia, in the definition of CIN grade 3 (CIN3; full thickness involvement of the epithelium with dysplastic cells, but with no signs of invasion into the stroma; also termed stage 0 carcinoma of the cervix).5 That clinical study was initiated by G H Green who obtained permission from senior medical staff at the hospital to attempt to verify his premise that CIS was not a precursor of invasive cancer.3 From 1965, some women with CIS received no treatment of curative intent after a diagnostic biopsy, often no more extensive than punch or wedge, the purpose of which was to confirm the diagnosis and exclude invasive cancer.6 Women were followed up with regular clinical, cytological, and sometimes colposcopic examinations, but persistent abnormalities were frequently not considered an indication for treatment. Additionally, treatment of curative intent was withheld from some women diagnosed with CIS in the years before 1965, despite cytological evidence of persistent or recurrent disease. The clinical study was not a randomised clinical trial, not all women with CIS were under Green's care, and no records exist of which women were chosen for that study which, however, was never formally ended. In response to the concerns of some clinicians in 1973, a working party was set up and, from the time of its report in 1975,4 few women with CIS were referred to the study. Therefore, the decade 1965 to 1974 can be taken as the operative period of recruitment to the study, although some women remained without curative treatment after 1975.
A judicial inquiry held in 1987–88 concluded that the study was unethical because treatment was withheld without consent, monitoring of outcomes was inadequate, and the study was not ended when clinicians raised concerns.4, 7 Additionally, the judicial inquiry referred for independent clinical review in 1988 all women for whom there was any doubt about the adequacy of their management. One of the recommendations from the inquiry was that the histological and other material at the National Women's Hospital “should be available for properly planned and approved research and teaching”.4 The opportunity to learn from this experience is enhanced by the fact that meticulous records were kept and many women had repeated cervical smears and biopsies, with the latter often intended for diagnosis rather than cure.4
An independent analysis by McIndoe and colleagues8 in 1984 that used data from women diagnosed at the hospital over the period 1955–76, assessed the risk of cancer of the cervix or vaginal vault in women with, and those without, persistent positive cytology 2 years after the diagnosis of cervical CIS. Their estimate of risk in women with evidence of persistent disease has become a standard reference on the invasive potential of CIN3.
We have extended this approach by reviewing inclusion criteria, histological diagnoses, and cytological findings; updating diagnostic criteria and terminology; taking into account both initial and follow-up treatment; and extending the period of follow-up. We estimated the invasive potential of CIN3 by establishing the long-term risk of invasive cancer of the cervix or vaginal vault in women with persisting disease as defined by positive cytology within 2 years after initial treatment (first aim) and in women who had minimum disturbance of their lesion (ie, punch or wedge biopsy; second aim). We also aimed to estimate the long-term risk of cancer in women who received adequate treatment initially and conventional management thereafter (third aim), approximating current clinical practice
Section snippets
Patients and procedures
We considered for inclusion all women diagnosed histologically with CIS alone or CIS with microinvasion at National Women's Hospital between Jan 1, 1955, and Dec 31, 1976, the main period of concern to the judicial inquiry.4 These comprised: those whose names were on the clinic register at National Women's Hospital (n=1194), or who were included in the McIndoe lists, referred to in Appendix 3 of the New Zealand Cervical Cancer Inquiry report4 (an additional n=35). Between February, 2001, and
Results
Between February, 2001, and April, 2002, medical records were reviewed for 1181 (96%) of the 1229 women; hospital staff could not locate the remaining 48 records. We excluded another 47 women, because there was no histopathology report for the initial diagnostic biopsy (n=3), the initial diagnosis of CIS was made outside the National Women's Hospital (n=34), diagnostic material had been removed from the National Women's Hospital (n=3), or there was a previous or concurrent diagnosis of invasive
Discussion
Our analysis provides the most direct estimates yet available of the rate of progression from CIN3 to invasive cancer. In women who had minimum disturbance of their lesion (punch or wedge biopsy) initially and no subsequent adequate treatment, 31% developed cancer within 30 years. This probably underestimates the true invasive potential of CIN3, because even a small diagnostic biopsy might be curative for some women.15 If we focus on the subset of this group who had persistent disease after
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