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Introduction

Although there is some progress in the knowledge of function of von Hippel-Lindau disease gene and molecular genetic mapping of other hereditary tumors, the pathogenesis of different types of renal cell carcinoma (RCC) remains unclear. Incidence of RCC is low in primitive animals, it was described in rats, cats, guinea-pigs, rabbits, sheep, cows, pigs, dogs, horses, and a variety of birds and fishes [1]. Some chemical agents, such as aromatic hydrocarbons or aflatoxin, produce cortical tumor in rats [2,3]. Diethylstilbestrol caused RCC in high percentage of male and castrated female Syrian hamsters [1,4]. Agents, which were potentially cancerogenic in experiment, were also studied in humans. Professional exposure to asbestos, fossil fuel burning products, gasoline, herbicides and polyvinyl chloride is considered higher risk, although we do not have any proof of their specific cancerogenic effects, nor of effects of other professional factors [5,6]. Application of experimental data to pathogenesis of human RCC is troublesome, because the genesis in experimental models and humans is different.

Epidemiological studies show, that smoking and obesity are major risk factors for RCC. The effect of hypertension and its treatment remains unclear. Diet goes hand in hand with incidence of RCC.

The aim of the study

Evaluation of risk factors incidence, especially smoking, obesity and hypertension, in our group of long-term observed patients with renal cell carcinoma (RCC) in comparison to group of hypothetic population frequency-matched on age and sex.

Materials and methods

In the years 1982 ? 1998, 316 patients were operated for renal cell carcinoma at our department. In this patients? group we evaluated the incidence of risk factors, especially smoking, obesity and hypertension. We created hypothetic population frequency-matched on age and sex as in the group of patients. Population data were derived from the data of Institute of Health Information and Statistics of the Czech Republic [7]. As heavy smokers were identified people smoking over 20 or more cigarettes per day and as obese people with BMI ł35 kg/m2. Incidence of risk factors was analysed in both groups by log-rank test.

Results

There were 12.7% (40/316) obese patients, 20,6% (65/316) heavy smokers and 36.1% (114/316) hypertensives in the patients? group. There were 4.3% obese people, 5.9% smokers and 33.3% hypertensives in the population group. In comparison to selected population there was significantly higher incidence of heavy smokers (p <0.01) and obese patients (p <0.01) in the patients? group. There was no significant difference (p = 0.22) in the occurrence of hypertension (Fig. 1).

Six patients (1,9%) had alcohol abuse problems, four (1.3%) had radiotherapy of retroperitonaeum for other malignancies in their history, four (1.3%) had polycystic kidney disease and three (0.9%) had end-stage renal disease. Seven percent had a malignant duplicity which was diagnosed prior to RCC and 15,8% (50/316) had malignant tumor in their family history.

Discussion

Cigarette smoking is one of acknowledged risk factors for renal cell carcinoma [5,8], although the enhancement is relatively small (1,4 ? 2,3 x) [9,10]. Risk is higher for smokers, who also chew tobacco [11]. There is a probably higher risk for pipe-smokers as well [12]. The relative risk in smoking women is comparable to nonsmokers in selected population [10]. Muscat et al. (1995) described higher risk for male smokers 1.4 and 1,1 for female smokers in group of 788 patients with RCC in comparison to 779 respondents in control group. Higher risk was proven in smokers who have smoked filtertip free cigarettes for over 30 years. No risk was proven in smoking filter-tipped cigarettes and in women [13]. There is a linear dependence in the risk of RCC between the length of smoking and the number of ?pack-years?. Systematic review of the literature data showed that only consumption over 20 ?pack-years? leads to significant association [5]. Quitting smoking lowers the risk relatively slowly. Parker et al. (2003) compared group of 387 patients to group of 2 333 controls randomly selected from the general population, frequency-matched on age and sex. Regression analysis provided evidence of a consistent inverse linear trend between years of smoking cessation and risk of RCC development. Concerning age, sex, body mass index (BMI), hypertension and ?pack-years?: those quitting smoking more than 30 years ago experienced a 50% reduction in risk of RCC in comparison to current smokers. In contrast, cessation of <10 years, 10 to 19 years and 20 to 29 years all resulted in a less pronounced reduction in RCC risk (approximately 20% to 30%). While cessation of smoking is indeed associated with a linear decrease in renal cancer risk, this benefit may not be sizeable until more than 20 years following cessation [14]. Smoking has no effect on the course of RCC [15].

Obesity was indentified as another risk factor of renal cell carcinoma in almost all studies, especially in women [5,8]. Obesity can increase estrogen levels, which in experiment can induce the development of RCC in hamsters [16]. Increase of insulin-like growth factor levels can also play a part in cancerogenesis [17]. Yuan et al. (1998) mentioned four times higher risk of RCC in people with BMI ł30 vs. 22 kg/m2 [18]. Yu et al. (1991) found out, that obese patients (ł120 % standard BMI) had higher risk of RCC development, but their prognosis was better. Both, the disease-free interval and the overall survival were longer in patients who were obese at diagnosis. The adjusted-hazard ratio for disease recurrence between obese and nonobese patients was 0.43. The obese patients had an adjusted death hazard rate 0.68 times that of the nonobese patients [19]. Kamat et al. (2004) grouped 400 patients with localized RCC after nephrectomy, according to BMI as normal (<25 kg/m2), overweight (25 ? 30 kg/m2) and obese (>30 kg/m2). Overweight and obese patients had a more favorable prognosis. According to multivariate regression analysis, the most significant predictor of tumor specific death was the time to metastasis (p <0.0001) followed by BMI (normal vs. overweight or obese; p = 0.006) and pathologic tumor stage (p = 0.007) [20]. However, some studies did not confirm these results [15].

There is 1,4 ? 2 times higher risk of renal cell carcinoma associated with hypertension or its treatment (antihypertensives, diuretics), mechanism of carcinoma development in this relationship remains unclear [21]. Multivariate analyses show, that real risk factor is probably not antihypertonic medication, but hypertension itself [18,21]. Hypertension could have been classified as a tumor marker, rather as a risk factor, because there was no dependence on hypertension severity [5]. There is also a discrepancy between the increasing incidence of RCC (since 1980) and decreasing hypertension prevalence [22]. Some authors have found that history of hypertension was predictor of better survival [15]. On the other hand, others have noticed that the hypertension was associated with an increased risk of mortality from renal cell carcinoma [23]. Discrepancy of study results evaluating dependence of hypertension and mortality risk discredit primary thesis about the hypertension risk for renal cell carcinoma.

Radiotherapy is probably a rare cause of RCC. Risk of renal cell carcinoma should be evaluated in long-term observation of people who are exposed to radiation [24].

End-stage renal disease is a major risk factor for renal cell carcinoma development. Prospective study showed that incidence as well as prevalence of RCC in end-stage renal disease is high. Overall 50% of patients with long-term dialysis develop polycystic kidney disease, sometimes complicated by renal adenomas or carcinomas which are often small, bilateral and multiple [25]. The probability of five-year tumor free survival among patients without end-stage renal disease is significantly higher (p = 0,01) than in patients with end-stage renal disease [26].

Diet habits are very important in renal cell carcinoma pathogenesis and are probably the reason for differences in incidence RCC among population. Incidence in Western Europe and the US is 5 ? 8 times higher in comparison to Asia [17]. The mortality rate for RCC and other malignancies in the first generation of immigrants from Asia remains in the middle of mortality numbers in Asia and in immigrants from Western countries [27]. Diet rich in fried, smoked and grilled meat and poultry is considered to be a main risk factor [28]. Diet rich in red meat also enhances the risk [8]. There is no secure evidence of the effect of alcoholic drinks, coffee or other beverages on RCC [17]. On the contrary, eating carotenes in fruit and vegetables has a protective effect [8]. Protective effect of fruit and vegetables has been described in multiple studies and remains one of the few consistent findings in diet [29].

Conclusions

Retrospective analysis of the patients? group proved significantly higher percentage of obese people and heavy smokers in the group of patients in comparison to the rest of population. It confirms the literature data about pathogenesis and risk factors for renal cell carcinoma. On the contrary, the meaning of hypertension as a risk factor has not been acknowledged. Association of retroperitoneal radiotherapy in patient?s history, polycystic and end-stage renal disease with RCC has also been mentioned in the literature. The results give evidence of higher susceptibility to tumors in patients with other tumor in their history or in nearest relatives.

The prevention of RCC should consist of non-smoking and ideal BMI. It is difficult to specify a protective diet. It should be rich in fruit, vegetables and fibre and low in calories, especially in animal fats. More physical activity may also reduce the risk of RCC. Therefore, it is possible that the increases in renal cell carcinoma may also be due, in part, to unhealthy lifestyle factors that have been on the increase over the past several decades.

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Ivan Kawaciuk
Department of Urology, Charles University in Prague
2nd Faculty of Medicine and Faculty Hospital in Motol
V Uvalu 84,
150 06 Praha 5, Czech Republic
Phone +420-22443 4800; Fax 22443 4820
ivan.kawaciuk@lfmotol.cuni.cz