BMJ  2005;331:1183-1185 (19 November), doi:10.1136/bmj.38663.459039.7C

Primary care

Risk of cervical and other cancers after treatment of cervical intraepithelial neoplasia: retrospective cohort study

¹ Department of Obstetrics and Gynaecology, Helsinki University Central Hospital, Box 140, FIN-00029, Helsinki, Finland, ² Mass Screening Registry, Finnish Cancer Registry, Liisankatu 21 B, FIN-00170, Helsinki, Finland, ³ Finnish Cancer Registry, Liisankatu 21 B, FIN-00170, Helsinki, Finland

Abstract

Objective To study the long term risk of cervical and other cancers after treatment for cervical intraepithelial neoplasia.

Design Retrospective cohort study.

Setting University Hospital, Helsinki, Finland.

Participants 7564 women treated for cervical intraepithelial neoplasia during 1974 and 2001 and followed up through the Finnish cancer registry until 2003.

Main outcome measures Standardised incidence ratio for cervical cancer and other cancers.

Results During follow-up 22 cases of invasive cervical cancer occurred in women treated for cervical intraepithelial neoplasia (standardised incidence ratio 2.8, 95% confidence interval 1.7 to 4.2). The highest risk was during the second decade (10 cases observed: 3.1, 1.5 to 5.7). The standardised incidence ratio for cervical intraepithelial cancer type 1 was 3.1 (1.4 to 6.2) and for type 2 was 3.7 (0.9 to 10.7).

Conclusions The risk of cervical cancer in the first 20 years after treatment for cervical intraepithelial neoplasia is higher than in the average population. The risk of smoking related cancers is also increased.

Introduction

Worldwide, cervical cancer remains one of the leading causes of death from cancer among women.¹ In countries with organised screening programmes for cervical cancer, incidence rates and mortality have decreased by 60%-90%.² All treatments for cervical intraepithelial neoplasia have excellent short term results and the differences are minimal,³ but only a few articles have studied long term outcomes after treatment. In the largest of these studies, the authors observed 2116 women for eight years after treatment and found that the incidence of cancer was reduced by 95%.⁴ In none of the studies, however, could follow-up data be linked to national cancer and population registries, and thus data on incidence of disease and mortality in treated women was unknown.

We assessed the incidence of cervical and other cancers long term in women treated for cervical intraepithelial cancer in Finland by linking primary data with two Finnish registries.

Methods

Our study is based on data of women treated for cervical intraepithelial neoplasia at Helsinki Central University Hospital, Finland during 1974 and 2001. Records for each patient included name, personal identifier, date and method of treatment, and diagnosis on the basis of histopathology.

The primary data consisted of 22 939 visits or treatments of 7599 women. We linked these data with the Finnish population registry and the Finnish cancer registry⁵ to identify cases of cancer. Follow-up was from six months after the first visit until death, emigration, or 31 December 2003. We chose a lag period of six months before diagnosing invasive cancer to exclude cancer diagnosed at the initial visit. After exclusions, 7564 patients remained for analysis.

The women were treated by knife or laser conisation, laser vaporisation, cold coagulation, or loop diathermy. At the first visit 2446 women were diagnosed as having CIN 1 precancerous lesions, 1543 as having CIN 2, 1334 as having CIN 3, and 2241 as having cervical intraepithelial neoplasia not otherwise specified.

We used cancer incidence rates in the population of southern Finland to calculate the expected numbers of cancer cases, stratified by sex, five year age groups, and five year calendar period. We present the results as standardised incidence ratios (ratio of observed to expected numbers of cases) with 95% confidence intervals (calculated on the presumption that the number of observed cases followed a Poisson distribution).

The mean number of visits per woman was 3.0 (range 1-31 visits). The mean number of visits for women with CIN 1 and CIN 2 lesions was 2.7 and 2.9, respectively, and for women with CIN 3 lesions it was 3.4. The mean age at the first treatment was 34.9 years (range 14-88 years). At the beginning of follow-up 43% of the patients were younger than 30, 52% were aged 30-59 (the group usually targeted for screening), and 5% were older than 60. The total follow-up time was 97 556 woman years. The average follow-up time was 11.9 years (range 0.5-28.0 years).

Results

We identified 448 new cases of cancer among 7564 women treated for cervical intraepithelial neoplasia—96 more cases than expected (table 1). Of these 96 excess cases, 26 were gynaecological cancers (standardised incidence ratio 1.5, 95% confidence interval 1.2 to 1.9). The risks were increased for cancers of the cervix (2.8, 1.7 to 4.2), vulva (4.1, 1.5 to 8.9), vagina (12.0, 3.9 to 28.0), lung or trachea (2.5, 1.9 to 3.5), other smoking related (1.7, 1.3 to 2.3), anus (5.7, 1.2 to 17.0), and any cancer (1.3, 1.2 to 1.4). Of the 22 cases of invasive cervical cancer 11 were diagnosed 0.5-9 years after treatment (2.7, 1.4 to 4.8), 10 after 10-19 years (3.1, 1.5 to 5.7), and one after 20 years (1.4, 0.04 to 8.0) (table 2). The standardised incidence ratios of overall cancer increased linearly with treatment of cervical intraepithelial neoplasia. We found a strong correlation between an increased risk of lung cancer and long time since treatment.

View this table: [in this window] [in a new window]   Table 1 Numbers of observed and expected cases of cancer, and standardised incidence ratios with 95% confidence intervals, by primary site

 

View this table: [in this window] [in a new window]   Table 2 Cancer incidence in women by follow-up time since treatment for cervical intraepithelial neoplasia

 

CIN 1 and CIN 2 precancerous lesions were associated with the highest risk of developing into invasive cervical cancer (3.1, 1.4 to 6.2 and 3.7, 0.8 to 10.9; table 1).

Of the eight patients with CIN 1 lesions who subsequently developed invasive cancer, five returned for one follow-up visit, two returned for two visits, and one returned for three visits. The three patients treated for CIN 2 lesions that subsequently developed into invasive disease returned for one, two, and four visits. The three patients with CIN 3 lesions who subsequently developed invasive cancer had two, three, and five visits.

What is already known on this topic Long term outcomes after treatment for precancerous lesions of the cervix are poorly documented The highest risk of invasive cancer is during the 10 years after treatment It has been proposed that only a small proportion of low grade lesions would progress to invasive cancer if not treated What this study adds The risk of invasive cervical cancer exists at least 20 years after treatment for cervical intraepithelial neoplasia The peak of incidence of invasive cervical cancer cases is in the second decade after treatment Women with low grade lesions are also at increased risk of developing invasive cancer

Discussion

The incidence of invasive cervical cancer among women treated for cervical intraepithelial neoplasia was about 23 per 100 000 woman years. A previous large study on long term outcomes after treatment estimated the rate to be 85 per 100 000 woman years.⁴ In our study, follow-up of cancer incidence was based on a nationwide cancer registry, with systematic criteria for the reporting of invasive disease. We found that the relative risk of cervical cancer after treatment of preinvasive lesions was higher than that in the reference population, at least during the first and second decade of follow-up. This contrasts with that of the previous large study, which found that the risk of cancer did not increase during eight years' follow-up.

We also found that the risk of cervical cancer was increased in women diagnosed as having CIN 1 and CIN 2 lesions; the point estimates were higher than those for CIN 3 lesions. The explanation might lie in the general approach towards treatment and follow-up by grade of precancerous lesions. All lesions were treated without exception; however, patients with lower grade lesions (CIN 1 and CIN 2) are not followed-up in a similarly systematic and long lasting way as are patients with high grade lesions. Inadequate follow-up is a major factor, as suggested in the literature.^6-9

Treatment of cervical intraepithelial neoplasia is, however, effective. In an earlier study of CIN 3 lesions,¹⁰ it was estimated that 28-39% of cases without treatment would progress to invasive cancer. Our data contained 837 cases of CIN 3 lesions in women aged 30-59, thus on the basis of the previous estimate, 234-326 would develop into invasive cervical cancers, not the three observed. The treatment effect might have been nearly 100%.

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Cancer coding is on bmj.com

Contributors: IK contributed to the study conception and design, analysis and interpretation of the data, and drafting the manuscript. AA contributed to the study conception and design, interpretation of the data, and drafting and revising the manuscript. EP contributed to the analysis and interpretation of the data and drafting the article. PN contributed to the study conception and design, interpretation of the data, and drafting and revising the manuscript. He is guarantor.

Funding: This study was partially financed from a grant from the Finnish Cancer Organisation.

Competing interests: None declared.

Ethical approval: This study was approved by the ethical committee of obstetrics and gynecology E8 of the Helsinki-Uusimaa hospital district (decision No 150/E8/03).

References

1. International Agency for Research on Cancer. Cervical cancer screening. IARC handbooks of cancer prevention, vol 10. Lyon: IARC/WHO, 2005: 302.
2. Anttila A, Läärä E. In: Sankila R, Démaret E, Hakama M, Lynge E, Schouten LJ, Parkin DM, for the European Network of Cancer Registries. Evaluating and monitoring of screening programmes. Brussels/Luxembourg: European Commission, Europe Against Cancer Programme, 2000.
3. Martin-Hirsch PL, Paraskevaidis E, Kitchener H. Surgery for cervical intraepithelial neoplasia. Cochrane Database Syst Rev 1999;(3): CD001318. DOI: 10.1002/14651858.CD001318.
4. Soutter WP, de Barros Lopes A, Fletcher A, Monaghan JM, Duncan ID, Paraskevaidis E, et al. Invasive cervical cancer after conservative therapy for cervical intraepithelial neoplasia. Lancet 1997;349: 978-80.[CrossRef][ISI][Medline]
5. Teppo L, Pukkala E, Lehtonen M. Data quality and quality control of a population-based cancer registry. Acta Oncol 1994;33: 365-9.[ISI][Medline]
6. Andersson-Ellström A, Seidal T, Grannas M, Hagmar B. The pap-smear history of women with invasive cervical squamous carcinoma. A case-control study from Sweden. Acta Obstet Gynecol Scand 2000;79: 221-6.[CrossRef][ISI][Medline]
7. Sasieni PD, Cuzik J, Lynch-Farmery E, the National Co-ordinating Network for Cervical Screening Group. Estimating the efficacy of screening by auditing smears histories of women with and without cervical cancer. Br J Cancer 1996;73: 1001-5.[ISI][Medline]
8. Baldauf J-J, Dreyfuss M, Ritter J, Meyer P, Philippe E. Screening histories of incidence cases of cervical cancer and high grade SIL: a comparison. Acta Cytol 1997;41: 1431-8.[ISI][Medline]
9. Gornall RJ, Boyd IE, Manolitsas T, Herbert A. Interval cervical cancer following treatment for cervical intraepithelial neoplasia. Int J Gynecol Cancer 2000;10: 198-202.[CrossRef][ISI][Medline]
10. Hakama M, Räsänen-Virtanen U. Effect of a mass screening program on the risk of cervical cancer. Am J Epidemiol 1976;103: 512-7.[Abstract/Free Full Text]

(Accepted 21 October 2005)

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Is there a correlation between developing cancer and treatment method

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Long-lasting increased risk of cervical cancer after treatment of CIN: explanations and implications for follow-up.

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Re: Long-lasting increased risk of cervical cancer after treatment of CIN: explanations and implications for follow-up.

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