Elsevier

The Lancet Oncology

Volume 9, Issue 5, May 2008, Pages 425-434
The Lancet Oncology

Fast track — Articles
Natural history of cervical neoplasia and risk of invasive cancer in women with cervical intraepithelial neoplasia 3: a retrospective cohort study

https://doi.org/10.1016/S1470-2045(08)70103-7Get rights and content

Summary

Background

The invasive potential of cervical intraepithelial neoplasia 3 (CIN3; also termed stage 0 carcinoma) has been poorly defined. At the National Women's Hospital, Auckland, New Zealand, treatment of CIN3 was withheld from a substantial number of women between 1965 and 1974 as part of an unethical clinical study. The resulting variation in management allows comparison of the long-term risk of invasive cancer of the cervix in women whose lesion was minimally disturbed with those who had adequate initial treatment followed by conventional management. We aimed to estimate the long-term risk of invasive cancer in these two groups of women. A judicial inquiry referred for independent clinical review in 1988 all women for whom there remained doubt about the adequacy of their management.

Methods

Between February, 2001, and December, 2004, medical records, cytology, and histopathology were reviewed for all women with CIN3 diagnosed between 1955 and 1976, whose treatment was reviewed by judicial inquiry and whose medical records could be located, and linkages were done with cancer and death registers and electoral rolls. To take into account the probability that the CIN3 lesion had been completely removed, we classified adequacy of treatment by type of procedure, presence of CIN3 at the excision margin, and subsequent cytology. The primary outcome was cumulative incidence of invasive cancer of the cervix or vaginal vault. Follow-up continued until death or Dec 31, 2000, whichever came first. Analyses accounted for procedures during follow-up.

Findings

1229 women whose treatment was reviewed by the judicial inquiry in 1987–88 were included. Of these, 48 records (4%) could not be located and 47 women (4%) did not meet the inclusion criteria. At histopathological review, a further 71 (6% of 1134) women were excluded because the review diagnosis was not CIN3. We identified outcomes in the remaining 1063 (86% of 1229) women diagnosed with CIN3 at the hospital in 1955–76. In 143 women managed only by punch or wedge biopsy, cumulative incidence of invasive cancer of the cervix or vaginal vault was 31·3% (95% CI 22·7–42·3) at 30 years, and 50·3% (37·3–64·9) in the subset of 92 such women who had persistent disease within 24 months. However, cancer risk at 30 years was only 0·7% (0·3–1·9) in 593 women whose initial treatment was deemed adequate or probably adequate, and whose treatment for recurrent disease was conventional.

Interpretation

This study provides the most valid direct estimates yet available of the rate of progression from CIN3 to invasive cancer. Women with untreated CIN3 are at high risk of cervical cancer, whereas the risk is very low in women treated conventionally throughout.

Funding

Cancer Society of New Zealand, Wellington, New Zealand.

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

References (29)

  • C Paul

    The New Zealand cervical cancer study: could it happen again?

    BMJ

    (1988)
  • WA McIndoe et al.

    The invasive potential of carcinoma in situ of the cervix

    Obstet Gynecol

    (1984)
  • MRE McCredie et al.

    Review of cytologic slides from the National Women's Hospital, New Zealand, cohort of women with cervical intraepithelial neoplasia 3 diagnosed in 1955–1976

    Acta Cytol

    (2006)
  • Australian Bureau of Statistics. Census of population and housing. Table 1. Not indigenous persons. Selected...
  • Cited by (874)

    • Vaccines for HPV-associated diseases

      2023, Molecular Aspects of Medicine
    View all citing articles on Scopus
    View full text