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American Journal of Epidemiology Advance Access originally published online on June 24, 2007
American Journal of Epidemiology 2007 166(5):582-591; doi:10.1093/aje/kwm108
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American Journal of Epidemiology © The Author 2007. Published by the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org.

ORIGINAL CONTRIBUTIONS

Renal Cell Cancer and Body Size at Different Ages: An Italian Multicenter Case-Control Study

Luigino Dal Maso1, Antonella Zucchetto1, Alessandra Tavani2, Maurizio Montella3, Valerio Ramazzotti4, Renato Talamini1, Vincenzo Canzonieri5, Antonio Garbeglio6, Eva Negri2, Annamaria Tonini7, Carlo La Vecchia2,8 and Silvia Franceschi9

1 S.O.C. Epidemiologia e Biostatistica, Centro di Riferimento Oncologico, Aviano (PN), Italy
2 Istituto di Ricerche Farmacologiche "Mario Negri," Milano, Italy
3 Servizio di Epidemiologia, Istituto Tumori "Fondazione Pascale," Napoli, Italy
4 Servizio Integrato di Epidemiologia e Sistemi Informativi, Istituto Nazionale Tumori "Regina Elena," Roma, Italy
5 S.O.C. Anatomia Patologica, Centro di Riferimento Oncologico, Aviano (PN), Italy
6 Unità Operativa di Urologia, Azienda Ospedaliera "Santa Maria degli Angeli," Pordenone, Italy
7 Consiglio Nazionale delle Ricerche, Istituto di Fisiologia Clinica, Milano, Italy
8 Istituto di Statistica Medica e Biometria, Università degli Studi di Milano, Milano, Italy
9 International Agency for Research on Cancer, Lyon, France

Correspondence to Dr. Luigino Dal Maso, Epidemiology and Biostatistics Unit, Aviano Cancer Institute, Aviano Via Franco Gallini 2, 33081 Aviano (PN), Italy (e-mail: epidemiology{at}cro.it).

Received for publication November 2, 2006. Accepted for publication March 7, 2007.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
An increased risk of renal cell cancer (RCC) has been reported in overweight persons. The authors aimed to clarify which anthropometric measures are associated with risk of RCC and whether risk may vary according to selected variables. Between 1992 and 2004, they carried out an Italian multicenter case-control study including 767 (494 men, 273 women) incident cases of RCC and 1,534 hospital controls, frequency-matched to cases. To estimate odds ratios and 95% confidence intervals, they used conditional logistic regression matched on study center, sex, and age and adjusted for period of interview, years of education, smoking habits, and family history of kidney cancer. Using body-size measurements taken 1 year prior to diagnosis/interview, the authors found an odds ratio of 1.3 (95% confidence interval (CI): 1.0, 1.7) among obese persons (body mass index (BMI; weight (kg)/height (m)2) ≥30) versus normal-weight persons (BMI <25) and an odds ratio of 1.5 (95% CI: 1.1, 2.0) among persons in the highest tertile of waist-to-hip ratio. Direct associations emerged for BMI ≥30 (vs. <25) at ages 30 years (odds ratio = 1.5, 95% CI: 1.0, 2.3) and 50 years (odds ratio = 1.5, 95% CI: 1.1, 2.0). The direct association with waist-to-hip ratio was stronger among women than among men. RCC risks among overweight and obese persons were apparently higher in never smokers, persons with the clear-cell histologic type, and persons with a Fuhrman nuclear grade of G3–G4.

body mass index; body size; carcinoma, renal cell; case-control studies; waist-hip ratio

Abbreviations: BMI, body mass index; CI, confidence interval; OR, odds ratio; RCC, renal cell carcinoma; WHR, waist-to-hip ratio


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Renal cell carcinoma (RCC) accounts for approximately 2 percent of all cancers in adults in many Western countries, and its incidence has been rising over the last few decades (1). Although several potential risk factors have been recognized, including tobacco smoking (2, 3), hypertension (4), and family history of kidney cancer (5, 6), the etiology of RCC is still largely undefined.

It has been suggested that obesity, generally measured as body mass index (BMI; weight (kg)/height (m)2), is related to RCC (7), and obesity may be responsible, at least in part, for the rising incidence rates (8). Anthropometric measures other than BMI, including waist-to-hip ratio (WHR) and variation in BMI throughout the life course, have been less frequently considered (9–12). Only scanty information is available on the variation of RCC risk in obese patients according to tumor histologic type, stage or grade, and other potential risk factors.

To obtain further information on the link between RCC and lifetime anthropometric measures and whether such a potential relation may vary according to smoking habits, histologic type, and clinical presentation, we carried out a large case-control study in Italy.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 References
 
Between 1992 and 2004, we conducted a hospital-based case-control study on RCC in four areas of Italy: the provinces of Pordenone and Gorizia (northeastern Italy), the greater Milan area (northwestern Italy), the province of Latina (central Italy), and the urban area of Naples (southern Italy). Cases were 767 subjects (494 men and 273 women; median age, 62 years (range, 24–79 years)) admitted to major teaching or general hospitals in one of the above areas with incident cancer of the renal parenchyma (International Classification of Diseases, Ninth Revision, code 189.0). Histologic information included cancer cell type, according to the 2004 World Health Organization classification (13, 14), tumor extension, according to the tumor-node-metastasis classification (15), and Fuhrman nuclear grade (16). Patients reporting transplantation or chronic renal failure were excluded.

Control subjects were 1,534 patients (988 men and 546 women; median age, 62 years (range, 22–79 years)) admitted to the same network of hospitals as cases. Causes of admission included acute nonneoplastic conditions not associated with hormone-related disorders and urinary or genital tract diseases (32 percent had nontraumatic orthopedic disorders, 26 percent had traumatic injuries, 14 percent had surgical conditions, and 28 percent had miscellaneous other illnesses, such as eye, ear, nose, throat, dental, or skin disorders). Controls were frequency-matched to cases (2:1) according to study center, sex, and quinquennium of age.

Centrally trained staff interviewed the eligible subjects during their hospital stay. Fewer than 5 percent of the approached cases and controls refused the interview. The response rates were similar across hospitals and geographic areas.

All interviews were conducted using a structured questionnaire that collected information on age, education and other socioeconomic factors, physical activity, smoking habits, alcohol intake, diet, and history of cancer in first-degree relatives; the questionnaire also included a problem-oriented medical history. In a detailed section of the questionnaire, study subjects were asked to report their height, weight 1 year before cancer diagnosis or interview (in controls), weight at different ages, lifelong highest and lowest weights, and perceived body size at age 12 years (i.e., thinner than, the same as, or heavier than one's peers). BMI was computed as weight (kg) divided by height squared (m2). The interviewer measured the circumference of the participant's waist (2 cm above the umbilicus) and hips (maximal protrusion); hence, waist-to-hip ratio (WHR) was also computed. In 38 percent of RCC patients and 34 percent of control subjects, the waist or hips could not be measured for technical reasons. However, median BMI in subjects with a measured WHR was not significantly different from that in subjects with missing WHR—26.2 and 25.9, respectively. Corresponding values were 26.4 and 26.2 among cases and 26.1 and 25.8 among controls.

Standard BMI categories (<25, 25–<30, and ≥30) were used to allow comparison with most previous studies. Conditional logistic regression was applied to calculate odds ratios and the corresponding 95 percent confidence intervals. In all analyses, controls were matched to cases on study center, sex, and age, and results were adjusted for calendar period of interview, years of education, smoking habits, and family history of kidney cancer in first-degree relatives (17). Additional adjustment for energy or alcohol intake, physical activity, or history of treated hypertension did not materially modify the risk estimates. Selected analyses were repeated separately according to strata of sex, age at diagnosis/interview, smoking habits, histologic type, tumor extension, and Furman nuclear grade. Data on histologic type, extension, and grade were not systematically collected at all participating centers; consequently, the proportion of missing values was high. Stratified analyses were conducted on BMI at age 30 years to avoid exclusion of subjects (16 percent) below age 50 years. Use of BMI at age 30 years permitted evaluation of the impact of "long-duration" overweight on RCC risk.

To avoid potentially arbitrary categorizations, we also investigated the "dose-response" relation between BMI and risk of RCC using logistic regression splines (18, 19) with the appropriate calculation of pointwise confidence intervals. We selected the optimal number of segments by minimizing Akaike's Information Criterion (20).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 References
 
Table 1 shows the distribution of cases and controls according to sex, age, and other selected covariates, including histologic type, extension, and Fuhrman nuclear grade. Compared with controls, cases had a higher level of education, were more frequently heavy current smokers, and more frequently reported a family history of kidney cancer in first-degree relatives.


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  		TABLE 1. Distribution of 767 cases of renal cell carcinoma and 1,534 frequency-matched controls according to sex, age, and selected covariates, Italy, 1992–2004

 
Median BMIs 1 year before diagnosis/interview were 26.4 (range, 15.4–56.0) for cases and 26.1 (range, 15.6–49.0) for controls; corresponding figures for WHR were 0.95 (range, 0.66–1.13) for cases and 0.94 (range, 0.63–1.19) for controls.

Table 2 shows the distribution of RCC cases and controls and the corresponding odds ratios, according to various body size measures 1 year before diagnosis/interview. No association emerged between height and RCC. An increased risk of RCC emerged for persons in the highest tertile of body weight (odds ratio (OR) = 1.18, 95 percent confidence interval (CI): 0.95, 1.46) as compared with the lowest and for obese (BMI ≥30) persons (OR = 1.29, 95 percent CI: 0.99, 1.69) as compared with persons with a BMI <25. The association between BMI 1 year before diagnosis/interview and RCC risk was approximately linear, with an odds ratio of 1.19 (95 percent CI: 1.06, 1.33) for a five-unit increase in BMI (table 2). WHR was also directly associated with RCC risk (for the highest tertile vs. the lowest, OR = 1.50, 95 percent CI: 1.12, 2.00) (table 2).


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  		TABLE 2. Distribution of 767 cases of renal cell cancer and 1,534 frequency-matched controls according to body-size measurements taken 1 year before diagnosis/interview and corresponding odds ratios, Italy, 1992–2004

 
A consistent and significant association emerged between BMI during adulthood and RCC (table 3). The odds ratios were 1.46 (95 percent CI: 0.95, 2.25) among persons who were obese (BMI ≥30) at age 30 years and 1.48 (95 percent CI: 1.07, 2.03) among persons who were obese at age 50 years, as compared with a BMI <25. The odds ratio was 1.75 (95 percent CI: 1.24, 2.46) when the lowest BMI during adult life was ≥25, as compared with <20, whereas an increase in BMI from the lowest level or from age 30 years was not associated with RCC risk (table 3).


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  		TABLE 3. Distribution of 767 cases of renal cell carcinoma and 1,534 frequency-matched controls according to lifetime body-size measurements and corresponding odds ratios, Italy, 1992–2004

 
The pattern of risk for BMI at different ages and WHR was not modified using other categorizations (i.e., quartiles or quintiles; data not shown in tables).

The shape of the best-fitting regression splines (dose-response curve) for selected body mass measures is shown in figure 1. The risk of RCC increased monotonically for BMI at all ages considered and for WHR. These direct relations were approximately linear, and no threshold effect emerged.


Figure 1
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  		FIGURE 1. Odds ratios for renal cell carcinoma according to body mass index (BMI; weight (kg)/height (m)2) at different times and waist-to-hip ratio (WHR), as estimated by regression spline models, Italy, 1992–2004. Curves are shown for the spline models that were the best-fitting according to Akaike's Information Criterion. The regression equations included terms for study center, sex, age, calendar period of interview, years of education, smoking habits, and family history of kidney cancer (first-degree relatives). The filled circle in part C shows the location of a knot. Dashed lines represent 95% confidence intervals. A) BMI 1 year before diagnosis/interview (2.4% of subjects were out of displayed range; p for linear trend = 0.18); B) WHR (4.4% of subjects were out of displayed range; p for linear trend < 0.01); C) BMI at age 30 years (4.4% of subjects were out of displayed range; p for linear trend < 0.01); D) BMI at age 50 years (2.1% of subjects were out of displayed range; p for linear trend < 0.01).

 
When the association between WHR (highest tertile vs. lowest) and RCC risk was examined in strata of selected variables, higher odds ratios emerged in women (OR = 2.66, 95 percent CI: 1.52, 4.65), in never smokers (OR = 1.83, 95 percent CI: 1.10, 3.04), and in subjects with a tumor extension of T2–T4 (OR = 2.62, 95 percent CI: 1.63, 4.22), while no difference emerged by histologic type (table 4).


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  		TABLE 4. Odds ratio for renal cell carcinoma according to tertile of waist-to-hip ratio in strata of selected variables, Italy, 1992–2004*

 
The direct association between BMI (≥30 vs. <25) at age 30 years and RCC risk was apparently stronger in women (OR = 1.57, 95 percent CI: 0.78, 3.18) and, more notably, in never smokers (OR = 1.82, 95 percent CI: 0.94, 3.51) (table 5). Additional adjustment for reproductive factors in women did not modify risk estimates. Moreover, an association between BMI and RCC emerged only in subjects with the clear-cell subtype of RCC (OR = 1.84, 95 percent CI: 1.09, 3.11) and the highest Fuhrman grades (OR = 1.82, 95 percent CI: 0.90, 3.68), whereas no difference emerged by tumor extension (table 5).


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  		TABLE 5. Odds ratio for renal cell carcinoma according to body mass index at age 30 years in strata of selected variables, Italy, 1992–2004*

 
The combined effect of WHR and BMI at age 30 years on RCC risk is shown in table 6. An apparently independent (additive) effect emerged for the two factors, with an odds ratio of 1.69 (95 percent CI: 1.14, 2.52) for overweight persons in the highest tertile of WHR. In overweight women in the highest tertile of WHR, the odds ratio was 2.83 (95 percent CI: 1.31, 6.14).


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  		TABLE 6. Odds ratio for renal cell carcinoma according to tertile of waist-to-hip ratio and body mass index at age 30 years, Italy, 1992–2004*

 
Mutual adjustment for BMI and WHR did not substantially change any of the above results.

After adjustment for potential confounders, the fraction of RCC cases attributable (21) to overweight in young adulthood (BMI ≥25) in this Italian population was 6 percent (95 percent CI: 0, 12).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
References
 
In this study, we observed direct associations between several measures of body weight and RCC risk. The association with BMI was approximately linear, with no evidence of a threshold effect. Our findings on BMI are consistent with the overall epidemiologic evidence from case-control and prospective studies (10, 12, 22–29). Some investigators have reported that the association between BMI and RCC incidence or mortality was stronger in women (26, 30). However, in our study, this association did not vary substantially between men and women, a finding that is in agreement with larger cohort studies (24, 25), case-control studies (11, 31), and a recent pooled analysis (22).

The relation of WHR with RCC has less frequently been explored (26, 27, 32), but consistent, direct associations that are stronger in women have been reported. WHR differed substantially in the two sexes, and this difference should largely explain the weaker association that emerged between WHR and RCC in men.

The association between obesity and RCC risk may be mediated by several hormonal mechanisms (22). Overweight and obesity are accompanied by elevated levels of fasting serum and free insulin-like growth factor I (33), which contributes to cell growth and proliferation (34). Obesity also increases levels of free endogenous estrogens (35), which may, in turn, increase renal cell proliferation. Moreover, since obese persons have been reported to have a higher glomerular filtration rate and renal plasma flow, independently of hypertension, these conditions may increase the risk of kidney damage (36, 37) and therefore make the kidney more susceptible to carcinogens. In addition, overweight is correlated with hypertension and could share a causal pathway with hypertension, a consistently reported risk factor for RCC (4, 38), and diabetes mellitus, a more controversial risk factor for RCC (38–41). Physical activity is another factor potentially related to overweight and RCC. However, in this same population, we previously found a moderate inverse association between occupational physical activity and risk of RCC, while we found no association for leisure-time physical activity, which has a low prevalence and is engaged in at only moderate levels in Italy (42).

In our study, the relation between BMI and RCC was stronger among never smokers than among ever smokers. This finding is consistent with a recent prospective study (24), while another study showed a less clear modification effect (25). A possible explanation is the direct association between RCC and smoking, which is negatively related to BMI (43). However, in our control patients, the association between smoking habits and BMI was not significant.

Our study suggests, for the first time, that the direct association between BMI and RCC risk is stronger for persons with the clear-cell histologic subtype. This can be related to recent findings showing that aberrant influx and storage of glucose are associated with an increased RCC risk (44). The relative excess of intracellular glycogen gives the cells their "clear" appearance and reflects impairments of glucose metabolism, including the up-regulation of the GLUT1 gene in the neoplastic cells (44).

The direct association between measures of body size appeared stronger in subjects with high (G3–G4) Fuhrman nuclear grades, particularly for patients with G4-grade RCC, whose odds ratios were 3.2 (95 percent CI: 1.1, 9.4) for BMI ≥30 at age 30 years versus BMI <25 and 1.9 (95 percent CI: 0.7, 5.6) for the highest tertile of WHR versus the lowest. G4 tumors are the result of de-differentiation of more differentiated tumors. It may be hypothesized that overweight persons have metabolic alterations that facilitate the neoplastic de-differentiation. The stronger association between RCC and WHR or, to a lesser extent, BMI in subjects with an advanced tumor extension (T2–T4) at diagnosis reflects possible diagnosis difficulties in obese persons.

The fraction of RCC cases attributable to overweight/obesity in this population (6 percent, 95 percent CI: 0, 12) was lower than the corresponding figure (21 percent, 95 percent CI: 11, 31) reported in a previous case-control study conducted in Canada (21, 25), based on 1,345 cases and an odds ratio of 2.7. However, the lower proportion of overweight/obesity in Italy (45) as compared with Canada also explains the difference.

Problems of reliability in anthropometric measures cannot be excluded. However, there was no evidence that weight was differentially reported by cases and controls (46). Although it is known that study subjects tend to underestimate weight and overestimate height (47–49), there was no reason for differential recall bias in subjects reporting current weight and height. In our study, cases and controls were interviewed in similar hospital settings, and the general population was unaware of the possible link between anthropometric measures and cancer. In addition, Klipstein-Grobusch et al. (50) have shown that past body measures are generally well correlated with corresponding measures, even in older people.

Hospital-based case-control studies may be more susceptible to selection and information bias than cohort studies (17). Subjects with diseases potentially linked to diet and dietary modifications were excluded from the control group, and major confounding factors for RCC were considered in the multivariate analysis. In particular, careful allowance was made for education and smoking habits, and additional allowance for potentially confounding factors did not alter the risk estimates. Possible sources of selection bias should also have been limited, since cases and controls were drawn from the same catchment areas and participation was almost complete.

In conclusion, this Italian case-control study provides further evidence of a direct association between different measures of body weight and risk of RCC. Consistency of the results at different ages supports the hypothesis of a causal role of overweight in renal carcinogenesis. Moreover, excess weight (BMI) at various ages predicts RCC risk in both sexes, while in women, abdominal obesity, as indicated by a high WHR, represents a stronger risk indicator. Further studies should confirm the differential effects of overweight by smoking habits, histologic type, and tumor grade.


   ACKNOWLEDGMENTS
 
This work was supported by the Italian Association for Cancer Research and the Italian League Against Cancer, Milan, Italy.

The authors thank L. Mei for editorial assistance, O. Volpato and Dr. M. Cozzi for study coordination, and G. Bessega, L. Zaina, Dr. M. Grimaldi, and Dr. O. Manganelli for their help in data collection. The authors are deeply thankful to Dr. D. Maruzzi for his support in identifying cancer cases and to Drs. P. Ascierto, G. Chiara, R. Di Lauro, L. Forner, A. Grandi, R. Magri, A. Mele, G. Tosolini, and E. Trevisanutto for providing hospital control patients.

Conflict of interest: none declared.


   References
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 

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