Socioeconomic differences in incidence of cervical ...

Acta Oncologica, 2010; 49: 180–184

ORIGINAL ARTICLE

Socioeconomic differences in incidence of cervical cancer in Finland by cell type

EERO PUKKALA1,2, NEA MALILA1,2 & MATTI HAKAMA1,2 1Finnish

Cancer Registry, Institute for Statistical and Epidemiological Cancer Research, Helsinki, Finland and School of Public Health, University of Tampere, Tampere, Finland

Acta Oncol Downloaded from informahealthcare.com by 27.111.35.155 on 05/20/14 For personal use only.

2Tampere

Abstract Introduction. We studied variation in incidence of cervix cancer during 1971–1995 among Finnish women born in 1906 to 1945 by social class and cell type. Material and methods. The Finnish Cancer Registry data were linked to the 1970 Population Census, which included social class data. There were 0.8 million individuals in the cohort under follow-up, with 5 102 squamous cell cancers and 573 cases of cervical adenocarcinoma diagnosed after the census date. Results. Incidence of squamous cell cancer was more than two-fold in the lowest social class (standardized incidence ratio (SIR) 1.29, 95% CI 1.21–1.36) as compared with the highest one (SIR 0.59, 0.51–0.66), while there was no association between social class and risk on adenocarcinoma (SIR 1.07, 0.87–1.28 and 1.08, 0.79–1.45, respectively). Discussion. Oncogenic HPV is regarded as the necessary cause of all types of cervix cancer. Sexually transmitted diseases and social status are correlated. Lack of association between adenocarcinoma and social class makes the HPV-etiology of this cell type less credible than that of squamous cell cancer.

Cervical cancer is one of the few cancerous diseases with a known aetiology. Oncogenic HPV infections are considered as the necessary cause of all types of cervical cancer independently of the histological cell type [1]. Furthermore, HPV is considered to be a sexually transmitted disease (STD) [2]. Social status and sexual habits are correlated [3], which implies that cervical cancer is socially determined. For years ago low socioeconomic status (SES) was found to be a strong risk determinant of cervical cancer [4]. Our aim was to test the credibility of the hypothesis that oncogenic HPV infections are the necessary cause of both adenocarcinoma and squamous cell carcinoma of cervix uteri. This was done by observing the association between the extremes in the causal chain from SES to sexual habits and further to the STD of HPV infection and finally to cervical cancer. Our data stem from the linkage of Census Finland including data on SES with data from the Finnish Cancer Registry including cervical cancer by cell type.

Material and methods The cohort The study cohort comprised of women born in 1906–1945 and recorded in the official Population Census organized by Statistics Finland on the last day of 1970 [5]. All residents in Finland were expected to complete a comprehensive questionnaire including demographic and socio-economical questions. The response rate was 98% [6]. An indicator of the socioeconomic status with four classes was based on the social ranking of the occupation [7]. Financially dependent persons (e.g., housewives and students) were classified by the occupation of their supporter and economically inactive persons by their former occupation. The four social classes were defined as follows: I.

managers and other high administrative or clerical employees, farmers owning more than 50 hectares of land,

Correspondence: Nea Malila, Finnish Cancer Registry, Institute for Statistical and Epidemiological Cancer Research, Pieni Roobertinkatu 9, FI-00130 Helsinki, Finland. Tel: +358 9 135 33 271. E-mail: [email protected] (Received 10 June 2009; accepted 2 Ocrober 2009) ISSN 0284-186X print/ISSN 1651-226X online © 2010 Informa UK Ltd. (Informa Healthcare, Taylor & Francis AS) DOI: 10.3109/02841860903386390

Social class and cervical cancer by cell type II.

low administrative or clerical employees, small-scale entrepreneurs, farmers owning 15 to 49.9 hectares of land, III. skilled and specialized workers, farmers owning 5 to 14.9 hectares of land, and IV. laborers, farm and forestry workers, institutions’ inmates, farmers owning less than 5 hectares of land, pensioners whose former occupation was unknown.


Persons with unknown social class (1.5% of the total population; mainly farmers and fishermen) were included in the social class III, because their general mortality and morbidity patterns resembled those of social class III [8]. Follow-up The follow-up started on January 1, 1971, and finished at emigration, death or on December 31, 1995, whichever came first. Person-years were counted by five-year female birth cohorts (1906–1910, 1911– 1915, 1916–1920, 1921–1925, 1926–1930, 1931– 1935, 1936–1940, and 1941–1945) for each social class and the follow-up period was divided into fiveyear groups (1971–1975, 1976–1980, 1981–1985, 1986–1990, and 1991–1995). The Finnish Cancer Registry (FCR) has collected data on incident cancer cases in Finland since 1953. Institutions with hospital beds, medical practitioners, and pathological laboratories notify the Registry about cancer cases identified. Moreover, Statistics Finland reports to the FCR whenever cancer is mentioned on the death certificate. If there are only laboratory notifications or death certificate information from a cancer case, the FCR requests clinical data from the hospitals where treatment took place. Linkages between the census, emigration, mortality, and cancer registry files were performed using

181

the personal identity codes. These unique elevendigit codes given to each resident in Finland since 1967 are used in all main personal registers in the country. The magnitude of mistakes due to incorrect personal identity codes is less than 0.01%, and has a negligible effect on cancer risk estimates [9]. Among eligible cervical cancer cases, 2.4% had to be excluded because the patients were not found in the 1970 Population Census. Risk estimates Cancer risk estimates were calculated for strata defined by social class, calendar period, and birth cohort. For each stratum, two types of indicators were calculated: Incidence rate: observed number of cases divided by the stratum-specific number of person-years (per 100 000). This analysis had to be restricted to ages 45 to 64 years at the beginning of each 5-year observation period because these are the only age categories among women born 1906–1945 who could be followed throughout the 25-year observation period of our study. The totals over the four age categories were adjusted for age with weights based on the age distribution of all person-years in the study series. Standardized incidence ratio (SIR): ratio of the observed and expected number of cases.The expected number of cases was achieved by multiplying the stratum-specific number of person-years by period and birth cohort specific incidence rates of the total Finnish female population. Confidence intervals (CI) were defined assuming that the observed number of cases followed a Poisson distribution. Results The number of women born in 1906–1945 and diagnosed with squamous cell cancers of cervix uteri in 1971–1995 was 5 102 (Table I). There was a linear

Table I. Observed and expected numbers of adenocarcinoma and squamous cell carcinoma of cervix uteri, with standardised incidence ratios (SIR) and 95% confidence intervals (CI) in Finland in women born in 1906–1945 and diagnosed in 1971–1995, by socioeconomic status (SES). Number of cases SES Squamous cell carcinoma I II III IV Total Adenocarcinoma I II III IV Total

Observed

Expected

SIR

95% CI

231 1278 2535 1058 5102

394.1 1477.8 2407.3 822.8

0.59 0.86 1.05 1.29 1.00

0.51, 0.66 0.82, 0.91 1.01, 1.09 1.21, 1.36 (reference)

46 164 258 105 573

42.4 158.5 273.8 98.2

1.08 1.03 0.94 1.07 1.00

0.79, 1.45 0.88, 1.20 0.83, 1.06 0.87, 1.28 (reference)

182

E. Pukkala et al.


gradient in risk; the SIR in social class IV was 1.29 (95% CI 1.21–1.36), more than two times the SIR in social class I (0.59, 95% CI 0.51–0.66). The trend over time in the incidence of squamous cell cancers was decreasing and it was not consistent by SES (Figure 1). In social class I the risk went down more than in the other classes in the more recent calendar periods of 1986–1990 and 1991–1995. Altogether 573 women were diagnosed with adenocarcinoma of cervix in 1971–1995. There was little variation in the SIR estimates over SES categories, and none of them was statistically significantly different from unity (Table I). The incidence of adenocarcinoma was relatively stable over time in all socioeconomic groups (Figure 1). Discussion We report here the risk of cancer of the cervix uteri by socioeconomic status (SES) in the total Finnish population over the period of a quarter of a century. Our results are in line with the well known fact of

Incidence / 100 000 50 40

Squamous cell carcinoma

30 Social class

20

IV III II 10 8 6

4

I

Adenocarcinoma

3 IV II III I

2

1 1971–75

1976–80

1981–85

1986–90

1991–95

Figure 1. Age adjusted incidence of adenocarcinoma and squamous cell carcinoma of cervix uteri by socioeconomic status (SES) among Finnish women aged 45–64 at the beginning of each 5-year period between 1971 and 1995.

high risk of cervix cancer in women of low SES [4]. The risk in the occupation of highest socio-economic position was less than one third of the risk in the occupation of lowest socio-economic position in a recent study based on almost 50 000 cervical cancer cases diagnosed in the five Nordic countries [10]. However, these observations were due to the dominant role of squamous cell cancers; adenocarcinoma was not studied as a separate entity. The incidence of adenocarcinoma did not vary between the SES categories in our study. The incidence rates of squamous cell cervical cancer were decreasing in Finland but there was practically no trend in risk of adenocarcinoma by calendar time. We hypothesized a causal chain first from SES to sexual habits and secondly from the sexual habits to infection with oncogenic HPV types and thirdly from the HPV infection to cervical cancer. While the evidence between individual steps is well established [2,4,11] direct observations on the association between SES and HPV infection are few [3] and mainly based on developing countries [12]. The completeness of the Finnish Cancer Registry is over 99% for all malignant solid tumours diagnosed in Finland [13], and accuracy is high. False positive diagnoses are not registered as cancers. The coverage and accuracy of the death and emigration files in Finland are also very high. Screening affects the incidence of invasive cervical cancer. It is more effective in preventing squamous cell tumours than adenocarcinomas [1]. Because the attendance to screening in general varies by SES [1], the estimates of risk by SES may be affected by screening. The organized screening programme covered all the population in 1971–1995 [14]. In Finland differences in attendance by SES are small. In the region of lowest known attendance, Punavuori district in the city of Helsinki, the attendance rate was 53% among the highest social class (professionals) and 51% in the lowest (labourers) [15]. Time trends indicate that screening reduced only the incidence of squamous cell cancers while the incidence of adenocarcinoma was not affected [16]. Hence, it is not credible that the lack of association between SES and adenocarcinoma was due to effects from screening. Our cohorts by SES were closed ones. The social status was measured in 1970 and there has been social diffusion mainly towards higher social positions since then. This drift is most likely in young women who had not completed their education in 1970. We therefore repeated the analyses excluding the youngest five-year birth cohort. The results were virtually identical with the ones shown in Table I, just with slightly smaller numbers of cases and wider confidence intervals. The range in cancer risk by SES


Social class and cervical cancer by cell type should have been reduced if there still was a residual social diffusion that in general results in regression towards the mean. This was true in the early years until the 1980s. However, the reason was probably due to the effect of screening. The organized screening programme in Finland reduced inequality by providing the service also in remote areas with low income and education, and in women with low SES and not routinely using gynaecological services in well to do areas. By 1980s the programme had operated for a sufficiently long period with full coverage. However, in recent decades the range in cancer risk by SES rather increased than decreased (Figure 1). This observation contradicts the credibility that changes in SES by calendar time would have diluted the effect of SES on the incidence of adenocarcinoma. Oncogenic types of human papilloma viruses are currently considered as the necessary cause both of squamous cell cancer and of adenocarcinoma of cervix uteri [1]. There are numerous materials with relative risks more than 100.The more common squamous cell cancers dominate these studies. Studies on adenocarcinoma are few and the relative risks are not as high as those of squamous cell cancer, but still between 50 and 100. It is likely that even these estimates are contaminated by adenosquamous lesions. Co-factors of HPV and the risk of cervix cancer include infections (Chlamydia trachomatis, HIV) and smoking [1,17]. They were associated with squamous cell cancers but not with adenocarcinomas [18,19]. The lack of association makes it unlikely that these co-factors would account for the lack of any association observed between SES and adenocarcinomas in our study. The results of other studies on the association between cervical adenocarcinoma and SES have been contradictory. A meta-analysis on social inequality and the risk of cervical cancer found an increase in risk of adenocarcinoma in women with low SES independently whether measured by education (RR⫽2.2, based on 3 studies) or income (RR⫽1.6, based on 2 studies) [11]. We found six additional studies. In the reanalysis of 12 epidemiological studies [20] the adenosquamous cancers were combined with adenocarcinomas as in the original reports. Adenosquamous types have been shown to have a risk factor pattern close to the pattern of squamous cell cancers [21]. Thus it is likely that adenosquamous cancers resemble more squamous cell cancers than adenocarcinomas. Also in the re-analysis of 12 epidemiological studies the adenosquamous cancers were combined with the adenocarcinomas [20]. Therefore, the inverse association between SES and adenocarcinoma reported in the individual studies of the international collaboration were likely to be due to the definition of adenocarcinoma [22].

183

Three of the additional studies [23–25] used squamous cell cancers as controls for adenocarcinomas. One study [25] suggested an identical risk factor pattern for these two histologies while the other two [23,24] indicated a difference in the effects of known risk factors of cervix cancer. In the study by Peters et al. [26] young women residing in an upper and middle income neighbourhood had a high risk of adenocarcinoma. We have previously shown [27] that the neighbourhood does not predict the risk in the individual. In fact, women with low SES living in a well-to-do environment had a high risk of cervix cancer. Our present study was based on SES data at individual level. Therefore, our result of no association is more plausible than those with an ecological design. Worldwide the incidence of adenocarcinoma of the cervix has been increasing while the overall incidence of cervical cancer is going down even in populations without effective screening for the disease [1,28,29]. Some of the increase in the incidence of adenocarcinoma is due to improvement in the coverage and quality of diagnostics (microscopic diagnosis). It is unlikely that misclassification in the histological type would account for the lack of correlation with SES in Finland. The SES is not known at diagnosis and the histology was coded at the Finnish Cancer Registry by a pathologist. Therefore, time trends (in misclassification or otherwise) are not likely to account for our result. Our result of no association between SES and incidence of adenocarcinoma of cervix uteri seems to be credible. It is in contradiction with that of the squamous cell type, and with several other reports on adenocarcinoma. Because SES is a marker or indicator of a multitude of specific life habits, the result implies that adenocarcinoma and squamous cell carcinoma have at least partly different aetiologies. Because the unique role of oncogenic HPV infections in the aetiology of squamous cell cervix cancer is widely accepted, other HPV types and other exposures are likely to be of more importance in the aetiology of adenocarcinoma. Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper. References [1] IARC Handbook of cancer prevention. Lyon: IARC Press; 2005. [2] Dillner J, Kallings I, Brihmer C, Sikstrom B, Koskela P, Lehtinen M, et al. Seropositivities to human papillomavirus types 16, 18, or 33 capsids and to Chlamydia trachomatis are markers of sexual behavior. J Infect Dis 1996;173:1394–8.


184

E. Pukkala et al.

[3] Social inequalities and cancer. Lyon: International Agency for Research on Cancer; 1997. [4] Clemmesen J. Statistical studies in the aetiology of malignant neoplasms. I. Review and results. Supplement 174. I. Acta Pathol Microbiol Scand Suppl 1965;174:1–543. [5] Population census 1970: Occupation and social position. Helsinki: Central Statistical Office of Finland; 1974. [6] Sauli H. Occupational mortality in 1971–75. Helsinki: Central Statistical Office of Finland; 1979. [7] Rauhala U. Social structures of the Finnish society. Helsinki: Ministry of Social Affairs and Health; 1966. [8] Pukkala E. Cancer risk by social class and occupation. A survey of 109,000 cancer cases among Finns of working age. Basel: Karger; 1995. [9] Pukkala E. Use of record linkage in small-area studies. In: Elliott P, Cuzick J, English D, Stern R, editors. Geographical & environmental epidemiology: Methods for small-area studies. Oxford: Oxford University Press; 1992. p 125–31. [10] Pukkala E, Martinsen J, Lynge E, Gunnarsdottir H, Sparen P, Tryggvadottir L, et al. Occupation and cancer -- follow-up of 15 million people in five Nordic countries. Acta Oncol 2009;48:646–790. [11] Parikh S, Brennan P, Boffetta P. Meta-analysis of social inequality and the risk of cervical cancer. Int J Cancer 2003;105:687–91. [12] Varghese C. Prevalence and determinants of Human Papillomavirus (HPV) infection in Kerala, India. Tampere: University of Tampere; 2000. [13] Teppo L, Pukkala E, Lehtonen M. Data quality and quality control of a population-based cancer registry. Experience in Finland. Acta Oncol 1994;33:365–9. [14] Anttila A, Pukkala E, Soderman B, Kallio M, Nieminen P, Hakama M. Effect of organised screening on cervical cancer incidence and mortality in Finland, 1963–1995: Recent increase in cervical cancer incidence. Int J Cancer 1999;83: 59–65. [15] Kallio M, Kauraniemi T, Nousiainen AR, Hansten S, Rytsola J, Heikkila M, et al. [Participation of women in cervical cancer screening]. Duodecim 1994;110:1061–7. [16] Nieminen P, Kallio M, Hakama M. The effect of mass screening on incidence and mortality of squamous and adenocarcinoma of cervix uteri. Obstet Gynecol 1995;85: 1017–21. [17] Hakama M, Luostarinen T, Hallmans G, Jellum E, Koskela P, Lehtinen M, et al. Joint effect of HPV16 with Chlamydia trachomatis and smoking on risk of cervical cancer: Antagonism

[18]

[19]

[20]

[21]

[22]

[23]

[24]

[25]

[26]

[27]

[28]

[29]

or misclassification (Nordic countries). Cancer Causes Control 2000;11:783–90. Koskela P, Anttila T, Bjorge T, Brunsvig A, Dillner J, Hakama M, et al. Chlamydia trachomatis infection as a risk factor for invasive cervical cancer. Int J Cancer 2000;85:35–9. Kapeu AS, Luostarinen T, Jellum E, Dillner J, Hakama M, Koskela P, et al. Is smoking an independent risk factor for invasive cervical cancer? A nested case-control study within Nordic biobanks. Am J Epidemiol 2009;169:480–8. Comparison of risk factors for invasive squamous cell carcinoma and adenocarcinoma of the cervix: Collaborative reanalysis of individual data on 8,097 women with squamous cell carcinoma and 1,374 women with adenocarcinoma from 12 epidemiological studies. Int J Cancer 2007; 120:885–91. Brinton LA, Tashima KT, Lehman HF, Levine RS, Mallin K, Savitz DA, et al. Epidemiology of cervical cancer by cell type. Cancer Res 1987;47:1706–11. Cervical carcinoma and reproductive factors: Collaborative reanalysis of individual data on 16,563 women with cervical carcinoma and 33,542 women without cervical carcinoma from 25 epidemiological studies. Int J Cancer 2006;119:1108–24. Horowitz IR, Jacobson LP, Zucker PK, Currie JL, Rosenshein NB. Epidemiology of adenocarcinoma of the cervix. Gynecol Oncol 1988;31:25–31. Korhonen MO. Epidemiological differences between adenocarcinoma and squamous cell carcinoma of the uterine cervix. Gynecol Oncol 1980;10:312–7. Silcocks PB, Thornton-Jones H, Murphy M. Squamous and adenocarcinoma of the uterine cervix: A comparison using routine data. Br J Cancer 1987;55:321–5. Peters RK, Chao A, Mack TM, Thomas D, Bernstein L, Henderson BE. Increased frequency of adenocarcinoma of the uterine cervix in young women in Los Angeles County. J Natl Cancer Inst 1986;76:423–8. Hakama M, Hakulinen T, Pukkala E, Saxen E, Teppo L. Risk indicators of breast and cervical cancer on ecologic and individual levels. Am J Epidemiol 1982;116:990–1000. Bray F, Carstensen B, Moller H, Zappa M, Zakelj MP, Lawrence G, et al. Incidence trends of adenocarcinoma of the cervix in 13 European countries. Cancer Epidemiol Biomarkers Prev 2005;14:2191–9. Bray F, Loos AH, McCarron P, Weiderpass E, Arbyn M, Moller H, et al. Trends in cervical squamous cell carcinoma incidence in 13 European countries: Changing risk and the effects of screening. Cancer Epidemiol Biomarkers Prev 2005;14:677–86.