A ‘pandemic’ of adenocarcinomas in the new millennium: a common causal pathway?

1. A ‘pandemic’ of adenocarcinomas in the new millennium: a common causal pathway? Zubair Kabir MD MSc University of Dublin (Trinity College) CResT Directorate St. James’s Hospital, Dublin-8, Ireland Email: kabirz@tcd.ie

2. Introduction • Recent studies on cancers of lung, 1 oesophagus, 2 stomach, 3 kidney, 4 prostate, 5 breast, 6 colon, 7 uterine cervix 8 and endometrium 9 show an increasing trend in a particular histologic sub-type, namely, adenocarcinoma, especially among the relatively young cohorts. • The biological implication of this distinct epidemiologic and potentially etiologic entity is poorly understood.

3. Importance of cancer trends by histologic sub-types • Long-term trends in cancer incidence provide significant leads to an underlying causal pathway of cancers. • More importantly, cancer trends by histologic sub-types identify the possible role of any putative risk factors, which may not be apparent in studies looking at cancer trends in general.

4. Examples of cancer trends by histologic sub-types • Lung cancer is one of the commonest cancers worldwide, especially among male populations. • Younger females are experiencing a relatively sharp increase in the development of lung adenocarcinoma worldwide,while the remaining histologic sub-types of lung cancer have stabilised across both sexes, particularly in the West.1

5. Diagnostic technologies or histopathologic critieria as contributing factors? • The reasons for this emerging pattern in adenocarcinomas are unclear. • Variations in the coding, classification and diagnostic technology may contribute partially to the observed trends. • The consistent upward trends observed worldwide argue against any of these, as they may be expected to demonstrate distinct regional variations.

6. The increasing trends in regions of relatively low socio-economic development suggest that better or improved medical imaging and diagnostic technologies are unlikely to have resulted in these global trends. • The survival rates of the majority of these adenocarcinomas have not improved significantly over this period worldwide, suggesting the less likely effect of treatment changes on the observed variations. • These observations also suggest that genetic or early life environmental factors may contribute to the recent trends.

7. Potential risk factors? • The contribution of some of the potential risk factors to the development of these specific cancers may be an alternative explanation. • In general, changes in smoking prevalence, alcohol use, drug intake, dietary habits (fats, fruits, vegetables, salted pickles, vitamins, etc) and infections, such as Human papillomavirus (HPV) and Helicobacter pylori, may contribute to such observed patterns across these cancers.

8. Observed trends in the potential risk factors • A declining trend in smoking prevalence may partly explain the decreasing trend in the development of lung squamous-cell carcinoma, 10 as well as squamous-cell carcinoma of oesophagus. • Introduction of filter cigarettes, including the so-called ‘low-yield’ cigarettes, may contribute to the rising incidence of lung adenocarcinoma, especially among female smokers, 10 consistent with a recent finding.11

9. The common sub-types of HPV infection are frequently associated with squamous-cell carcinoma of cervix. • An observed declining trend in the seroprevalence of H. pylori13 that is more commonly associated with non-cardia gastric adenocarcinoma, 12 as opposed to a recent increase in gastric cardia adenocarcinoma3. • Alcohol use has the strongest association, particularly with oesophageal carcinoma.

10. Possible role of dietary factors and obesity? • Regarding dietary factors, a common food hypothesis shows inconsistent findings for the majority of these cancers. • Total energy intake, as assessed by obesity, seems more biologically plausible. • Obesity being differentially associated with the development of histologic sub-types of lung cancer in females may be a possibility.14

11. Influence of hormones or any underlying interactions? • The historic findings of linking in-utero diethylstilboesterol (DES) exposure to vaginal adenocarcinoma, as well as hormone replacement therapy (HRT) have long been issues of debate. • There is speculation that females are more likely to develop lung adenocarcinoma, possibly due to interactions between genetic factors and endocrine status, 15 suggesting additional investigation in gene-environment interactions.

12. Global obesity trend: a likely factor? • Taken together, the only consistent observation in any of these known risk factors is a simultaneous rising prevalence in obesity worldwide since 1980, not only in the older cohorts13 but also among the adolescents.18 • Recently, WHO termed this phenomenon ‘globesity’, which may be a ticking time bomb.

13. Observed conclusion • These apparent observations raise the possibility of linking the development of these adenocarcinomas to body weight, which may be modified by endogenous hormone metabolism, such as sex steroids, insulin and insulin-like growth factors, throughout the life course. • This hypothesis thus generated provides a unique opportunity for further investigations.

14. Early life experiences on cancer risk development? • Until the cause-effect relation of obesity on cancer is clear, it would seem reasonable to consider whether environmental changes in later life modify the effects of early life experiences. • Foetal experience may influence adult obesity with potential consequences for risk of several major cancers.20

15. Burden of obesity • In addition to total health-care costs,23 the overall impact of obesity on population health is becoming clear across the globe, such as diabetes, coronary artery diseases, etc. (http://cdc.gov/nccdphp/dnpa/obesity/index.htm) • An estimated 72,000 new cases of obesity and overweight-related cancer occurring each year in the European Union alone is no less worrisome.24

16. Implications of this epidemiologic review • These observations may provide a new framework for large controlled trials in cancer chemoprevention. • If true, these observations also have the potential for primary prevention of an underlying adenocarcinoma pandemic in the new millennium.

17. Future directions • Governmental and non-governmental organisations, the food industry, media, worksites, schools, health professionals, educators, as well as families should have a common responsibility to produce an environment less conducive to weight gain, particularly for young people, recently recognised as the ‘common sense’ approach. 25

18. References 1.  Kabir Z, Manning PJ, Clancy L. Epidemiologic patterns of lung cancer incidence in the Republic of Ireland by major histologic types: 1994-1997. Am J Epidemiol 2002; 155 (Suppl): 19. 2.   Powell J, McConkey CC, Gillison EW, Spychal RT. Continuing rising trend in oesophageal adeonocarcinoma. Int J Cancer 2002; 102: 422-7.

19. 6.  Prehn A, Clarke C, Topol B, Glaser S, West D. Increase in breast cancer incidence in middle-aged women during the 1990s. Ann Epidemiol 2002; 12: 476-81. 7. Kim DW, Bang YJ, Heo DS, Kim NK. Colorectal cancer in Korea: characteristics and trends. Tumori 2002; 88: 262-5. 8. Krishnamurthy S, Yecole BB, Jussawalla DJ. Uterine cervical adenocarcinomas and squamous carcinomas in Bombay: 1965-1990. J Obstet Gynaecol Res 1997; 23: 521-7.

20. 11. Yang P, Cerhan JR, Vierkant RA et al. Adenocarcinoma of the lung is strongly associated with cigarette smoking: further evidence from a prospective study of women. Am J Epidemiol 2002; 156: 1114-22. 12. Schottenfeld D, Fraumeni JF Jr (Ed). In: Cancer Epidemiology and Prevention (Second Edition). New York: Oxford University Press, 1996. 13.  Swerdlow A, Silva I, Doll R (ed). In: Cancer incidence and mortality in England and Wales: trends and risk factors. New York: OUP, 2001.

21. 16. Nelson R. Steroidal oestrogens added to list of known human carcinogens. Lancet 2002; 360: 2053. 17. Batty D, Thune I. Does physical activity prevent cancer? BMJ 2000; 321: 1424-5. 18. Wang Y, Monteiro C, Popkin BM. Trends of obesity and underweight in older children and adolescents in the United States, Brazil, China and Russia. Am J Clin Nutr 2002; 75: 971-7. 19. Okasha M, McCarron P, McEwen J, Smith GD. Body mass index in young adulthood and cancer mortality: retrospective cohort study. J Epidemiol Community Health 2002; 56: 780-4.

22. 21.Dietz WH. ‘Adiposity rebound’: reality or epiphenomenon? Lancet 2000; 356: 2027. 22. Youssef AA, Valdez R, Elkasabany A, Srinivasan SR, Berenson GS. Time-course of adiposity and fasting insulin from childhood to young adulthood in offspring of parents with coronary artery disease. Ann Epidemiol 2002; 12: 553-9. 23.Thompson D, Brown JB, Nichols GA, Elmer PJ, Oster G. Body mass index and future healthcare costs: a retrospective cohort study. Obes Res 2001; 9: 210-18.

23. Acknowledgements • Dr Zubair Kabir is a Research Fellow in Cancer Epidemiology at the University of Dublin (Ireland) funded by the Royal City of Dublin Hospital Trust. • Professor Luke Clancy is supervising Dr Kabir based at St. James’s University Teaching Hospital (Dublin) in the Department of Respiratory Medicine.

24. Useful resources • Globocan 2000- Cancer Incidence, Mortality, and Prevalence worldwide. (http://www-dep.iarc.fr/globocan/globocan.html) • Surgeon’s General Report. ( ttp://www.surgeongeneral.gov/topics/obesity) • International Obesity Task Force. (http://www.iotf.org).