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Differential effect of body mass index by gender on oncological outcomes in patients with renal cell carcinoma


 Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, TN, USA

Correspondence Address:
Melih Balci,
Vanderbilt University Medical Center, A-1302, Medical Center North, Nashville, TN 37232-2765
USA
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.JCRT_546_18

 > Abstract 


Objectives: To investigate the relationship between gender, body mass index (BMI), and prognosis in renal cell carcinoma (RCC) patients.
Materials and Methods: We retrospectively reviewed 1353 patients with RCC who underwent a partial or radical nephrectomy between 1988 and 2015. The association among sex, BMI, stage, grade, overall survival (OS), and recurrence-free survival (RFS) was analyzed.
Results: The median age of the patients was 59.4 ± 11.9 years. Female patients had proportionally lower grade tumors than male patients (Grade I–II in 75.5% vs. 69.3% in women and men, respectively, P = 0.022). There was no relationship between Fuhrman grade and BMI when substratified by gender (p > 0.05). There was a nonsignificant trend toward more localized disease in female patients (p = 0.058). There was no relationship between T stage and BMI when stratified by gender (p > 0.05). Patients with higher BMI had significantly better OS (p = 0.0004 and P = 0.0003) and RFS (P = 0.0209 and P =0.0082) whether broken out by lower 33rd or 25th percentile. Male patients with higher BMI had significantly better OS and RFS rates. However, there was no relationship between BMI and OS or RFS for female patients (P > 0.05). Multivariate analysis of the entire cohort demonstrated that a BMI in the lower quartile independently predicts OS (hazard ratio 1.604 [95% confidence interval: 1.07–2.408], P = 0.022) but not RFS (P > 0.05). When stratified by gender, there was no relationship between BMI and either OS or RFS (P &> 0.05).
Conclusions: Increasing BMI was associated with RCC prognosis. However, the clinical association between BMI and oncologic outcomes may be different between men and women.

Keywords: Body mass index, gender, renal cell carcinoma, survival



How to cite this URL:
Balci M, Glaser ZA, Chang SS, Herrell S D, Barocas DA, Keegan KA, Moses KA, Resnick MJ, Smith Jr. JA, Penson DF, Scarpato K, Clark PE. Differential effect of body mass index by gender on oncological outcomes in patients with renal cell carcinoma. J Can Res Ther [Epub ahead of print] [cited 2020 Oct 28]. Available from: https://www.cancerjournal.net/preprintarticle.asp?id=275401




 > Introduction Top


In the United States, kidney and renal pelvis cancers account for 5% of new cancer cases in men and 3% in women. It is estimated that 14,240 cases of kidney cancer were diagnosed in 2016.[1] Renal cell carcinoma (RCC) represents approximately 90% of the cases. The incidence of RCC has increased in the last several decades and continues to rise in the United States, in large part due to widespread use of diagnostic imaging procedures and the resultant diagnosis of low stage disease.[2] However, this increase may not be attributed solely to rising rates of imaging but also reflects an increase in the prevalence of certain risk factors, such as obesity.

Obesity is an important risk factor for the development of RCC, as it has been noted that for every 5 kg/m2 increase in body mass index (BMI), the risk of RCC rises 24% for men and 34% for women.[3] Globally, the prevalence of being overweight (BMI >25 kg/m2) and obesity (BMI >30 kg/m2) increased by 28% in adults between 1980 and 2013.[4] Interestingly, although obesity significantly increases the risk of developing RCC, the data on the impact of BMI on survival are less clear, with some studies demonstrating improved survival with normal or lower BMI and others demonstrating higher BMI was related with better survival.[5],[6],[7],[8] Although various studies have investigated the association between BMI and prognosis of RCC,[5],[6],[7] few studies have investigated the gender-related differences for the prognostic implications of BMI. Hence, the aim of this retrospective analysis was to evaluate the influence of BMI stratified by gender on oncological outcomes in patients undergoing radical or partial nephrectomy for RCC.


 > Materials and Methods Top


A total of 2363 patients with RCC underwent a radical or partial nephrectomy at Vanderbilt University Medical Center, in Nashville, Tennessee, between April 1988 and December 2015. The study protocol underwent Institutional Review Board approval. The exclusion criteria included patients with known metastatic disease at the time of nephrectomy (n = 218), known history of Von Hippel–Lindau disease (n = 19), and <24 months of follow-up due to new diagnosis or lost to follow-up (n = 773). Therefore, a cohort of 1353 patients met all criteria and were included in this analysis.

Patient demographic and clinical characteristics such as age, gender, stage, Fuhrman grade, and tumor characteristics were part of a prospectively collected, IRB-approved electronic database. BMI (kg/m2) was categorized based on the current WHO definitions (http://www.who.int/bmi): <18.5 = underweight, 18.5–24.99 = normal range, >25 overweight. The exact weight and body height of each patient were assessed immediately before surgery and recorded in the medical record. In addition, for analyzing the relationship between RCC prognosis and increasing BMI, we used median, tertiles, and quartiles of BMI. Tumor stage was assigned according to the seventh edition of the American Joint Committee on Cancer tumor-node-metastasis classification.[9]

In follow-up, patients underwent a physical examination, serologic studies, and cross-sectional imaging (ultrasound or computed tomography) on a quarterly basis and then followed at intervals as dictated by pathologic stage and clinical circumstances. Follow-up generally corresponded to recommendations put forth by the American Urologic Association Guideline on follow-up after nephrectomy for RCC.[10]

Statistical analysis

The relationship between BMI, gender, and clinicopathologic variables was assessed using Chi-squared tests. Univariate survival analyses were performed using the Kaplan–Meier and log-rank methods. We incorporated additional independent variables (age, gender, tumor size, histology, tumor grade, tumor stage, lymphovascular invasion, sarcomatoid features, and necrosis) into a multivariate model to allow adjustment of their effects on survival using the Cox proportional hazards model. Analyses were done both in the entire cohort adjusted for gender and separately by gender. All analyses were conducted with STATA data analysis software (version 12, StataCorp LLC, College Station, TX, USA).


 > Results Top


The median age of the patients was 59.4 ± 11.9 years (interquartile range 51.3–69.3). Overall, 34.5% of the patients were women. The median follow-up for all patients was 67.6 months; during this period, 124 (9.2%) died of RCC and 40 (2.9%) died of other causes. Patient and tumor characteristics are summarized in [Table 1].
Table 1: Patient and tumor characteristics

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The mean BMI of all patients was 30.5 ± 7.1 with a significant difference between men (30.1 ± 6) and women (31.1 ± 8.2) (P = 0.024). At the time of presentation, weight loss was present in 18 patients and only two of these patients were underweight. Because of the small number of underweight patients (n = 10), they were grouped together with normal-weight patients for further analysis. In total, 19.1% patients presented with a BMI <25 kg/m2, while 35.2% were overweight (BMI ≥25 to <30 kg/m2) and 45.7% were obese (BMI ≥30 kg/m2) [Table 2].
Table 2: Comparison results of male and female patients

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Female patients had significantly lower grade tumors than male patients (75.5% vs. 69.3% Grade I-II tumors respectively, P = 0.022). There was no relationship between BMI and either Fuhrman grade, T stage, or N stage (P > 0.05 for each). There was a nonsignificant trend toward female patients having more localized tumors (P = 0.058). There was no relationship between T stage and BMI overall or when stratified by gender (P > 0.05). There was no relationship between N stage and either gender or BMI [Table 2] and [Table 3], P > 0.05].{Table 2}
Table 3: Comparison results of body mass index groups

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Increasing BMI was significantly associated with better overall survival (OS) on univariate analysis [Figure 1]. This remained true regardless of whether OS was analyzed when BMI was broken down by median, tertiles, or quartiles (separated by median value: P =0.0091, separated into tertiles: P =0.0017, separated into quartiles: P =0.0039, lower 33rd percentile compared to the rest: P =0.0004, lower 25th percentile compared to the rest: P =0.0003). However, differences for recurrence-free survival (RFS) were only significant for the lowest BMI cohort (33rd or 25th percent) compared to the rest (P = 0.0209 and P = 0.0082, respectively).
Figure 1: Study population Kaplan–Meier overall survival and recurrence-free survival estimates

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Overall, female patients had better OS and RFS than male patients [P = 0.0131 and P = 0.03, [Figure 2]. When we analyzed BMI stratified by gender, we found that in male patients, increasing BMI was associated with better OS [Figure 3]. Regarding the BMI analysis, the OS on univariate analysis separating groups of men by median, tertiles, and quartiles were statistically significant (Median: P =0.0077, tertiles: P =0.0008, quartiles: P =0.0036, lower 33rd P = 0.0003, lower 25th: P =0.0010). For RFS in men, only the comparison of lower 33rd percentile to the rest was statistically significant (P = 0.0188). Interestingly, when stratified by gender, there was no longer a relationship between BMI and either OS or RFS rates in female patients (P > 0.05) [Figure 4].
Figure 2: Male versus female Kaplan–Meier overall survival and recurrence-free survival estimates

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Figure 3: Male Kaplan–Meier overall survival and recurrence-free survival estimates

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Figure 4: Female Kaplan–Meier overall survival and recurrence-free survival estimates

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On multivariate analysis, the lowest quartile BMI was independently associated with OS (hazard ratio [HR] 1.604 (95% confidence interval [CI]: 1.07–2.408), P = 0.022) after correcting for age, gender, stage, Fuhrman grade, lymphovascular invasion, sarcomatoid features, and tumor necrosis. This remained true when we restricted the analysis to male patients (HR 1.568 [95% CI: 0.949–2.59], P = 0.079) but, when restricted to female patients, OS was not independently associated with BMI (HR 1.56 [95% CI: 0.72–3.40] P = 0.259) [Table 4].
Table 4: Multivariate analysis using Cox proportional hazards for overall survival

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 > Discussion Top


Obesity is generally associated with an increased risk of developing RCC. Obesity might be associated with increased risk of kidney cancer through several hormonal mechanisms. Increasing BMI is associated with elevated levels of free insulin growth factor 1 and free endogenous estrogen, both of which contribute to the stimulation of renal cell proliferation.[11] In addition, obese patients have been reported to have higher glomerular filtration rate and renal plasma flow, which may increase the risk of kidney damage and thereby render the kidney more susceptible to carcinogens.[11] However, controversy remains regarding the association between BMI and prognosis in RCC. Calle et al.[12] prospectively studied a population of >900,000 United States adults and found that BMI was significantly associated with a higher rate of cancer-related mortality in obese men (relative risk 1.7) and women (relative risk 4.75). Nevertheless, most studies, including ours, have shown that obesity is associated with improved survival in patient with localized RCC.[5],[13],[14],[15] Schips et al.[13] found that patients with higher BMI had a significantly better overall and disease-free survival compared to patients with normal weight. Similarly, a study by Kamat et al.[14] found that higher BMI is an independent predictor of better disease progression and both disease-specific and OS in patients undergoing nephrectomy for nonmetastatic RCC. Awakura et al.[15] found a significant advantage regarding overall and cancer-specific, but not recurrence-free, survival for patients with a BMI of 23 kg/m2 or greater compared with those with a BMI of <23 kg/m2. In the same study, BMI was an independent predictor of overall and cancer-specific, but not recurrence-free, survival. Parker et al.[5] reported reduced cancer-specific mortality and prolonged OS in patients with a BMI >25 kg/m2 in univariate but not in multivariate analysis.

Importantly, none of the studies examining BMI and RCC outcomes sought to determine if the relationship between BMI and outcomes was modulated by patient gender. Our study demonstrated that RFS and OS rates were better for patients with a higher BMI. However, when stratified by gender, the BMI was only independently associated with OS in male patients with RCC. This finding is despite that fact that in our study, female patients had significantly lower Fuhrman grade tumors than male patients and female patients had significantly higher RFS and OS rates than male patients.

The biologic reasons underpinning the association between obesity and oncologic outcomes in RCC patients are still not known. Yu et al.[16] speculated that the increased amount of fat, located between the kidney and Gerota's fascia, may function as a barrier for further invasion of cancer outside Gerota's fascia. Rasmuson et al.[17] reported that serum insulin-like growth factor-1 was positively correlated with BMI, and the increased insulin-like growth factor-1 in obese patients might be associated with increased survival. Schrader et al.[6] suggest that multiple hormonal/endocrine and maybe nutritional factors, possibly from adipose tissue, could contribute to the protective association between being overweight and RCC progression. Clearly then, more biological research is needed to investigate these and other mechanisms further.

The relationship between prognosis and gender in patients with RCC is equivocal. Aron et al.[18] reported OS is better in women, whereas cancer-specific survival is not significantly different. Woldrich et al.[19] found that a trend toward increased survival was noted in women relative to men although the difference was not statistically significant. It may be that women have a better prognosis than men related to differences in tumor characteristics. In our study, lower grade lesions accounted for 76.7% and 69.3% of tumors in women and men, respectively (P = 0.022). Localized disease was seen in 78.3% and 73.6% of women and men, respectively (P = 0.080). This trend was similar in the Aron et al.'s[18] study and suggests that women present at a slightly older age than men with tumors that are smaller, lower stage, and lower grade. Further investigation is needed to determine why women with RCC tend to have lower stage and grade disease. In the present study, the OS and RFS stratified by gender suggest a more favorable prognosis for women (P = 0.0131 and P = 0.03). It might be related to the differences in estrogen (E) and androgen axis signaling in men and women. Yu et al.[20] showed that estrogen stimulation activated estrogen receptor (ER) β and inhibited proliferation in RCC cells, reducing migration and invasion, and enhancing apoptosis. Similarly, Chen et al.[21] showed that E2 resulted in RCC growth inhibition through an ER-dependent pathway that involved both ERα and ERβ.

We demonstrate here that increased BMI is associated with better OS. Importantly, however, we show that this is largely confined to male patients, and that in women, there is little discernible independent association between BMI and survival. Limitations of our study include its retrospective nature, single-center patient recruitment, and the fact that the study population was primarily Caucasian patients in an academic referral practice. Further prospective studies will help to confirm the present findings.


 > Conclusions Top


Our results showed that increased BMI is an independent favorable prognostic factor in male patients with RCC, but not in female patients. While female patients in general had lower grade tumors and better survival, the clinical prognostic value of BMI appears to differ between men and women with RCC.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

1.
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin 2016;66:7-30.  Back to cited text no. 1
    
2.
Knox M, Colli JL. Characterizing changes in kidney and renal pelvis cancer incidence from 1998 to 2006 in the United States. Int Urol Nephrol 2011;43:359-63.  Back to cited text no. 2
    
3.
Renehan AG, Tyson M, Egger M, Heller RF, Zwahlen M. Body-mass index and incidence of cancer: A systematic review and meta-analysis of prospective observational studies. Lancet 2008;371:569-78.  Back to cited text no. 3
    
4.
Smith KB, Smith MS. Obesity statistics. Prim Care 2016;43:121-35, ix.  Back to cited text no. 4
    
5.
Parker AS, Lohse CM, Cheville JC, Thiel DD, Leibovich BC, Blute ML, et al. Greater body mass index is associated with better pathologic features and improved outcome among patients treated surgically for clear cell renal cell carcinoma. Urology 2006;68:741-6.  Back to cited text no. 5
    
6.
Schrader AJ, Rustemeier J, Rustemeier JC, Timmesfeld N, Varga Z, Hegele A, et al. Overweight is associated with improved cancer-specific survival in patients with organ-confined renal cell carcinoma. J Cancer Res Clin Oncol 2009;135:1693-9.  Back to cited text no. 6
    
7.
Waalkes S, Merseburger AS, Kramer MW, Herrmann TR, Wegener G, Rustemeier J, et al. Obesity is associated with improved survival in patients with organ-confined clear-cell kidney cancer. Cancer Causes Control 2010;21:1905-10.  Back to cited text no. 7
    
8.
Park YH, Lee JK, Kim KM, Kook HR, Lee H, Kim KB, et al. Visceral obesity in predicting oncologic outcomes of localized renal cell carcinoma. J Urol 2014;192:1043-9.  Back to cited text no. 8
    
9.
Edge SB, Compton CC. The American Joint Committee on Cancer: The 7th edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol 2010;17:1471-4.  Back to cited text no. 9
    
10.
Donat SM, Diaz M, Bishoff JT, Coleman JA, Dahm P, Derweesh IH, et al. Follow-up for clinically localized renal neoplasms: AUA guideline. J Urol 2013;190:407-16.  Back to cited text no. 10
    
11.
Wang F, Xu Y. Body mass index and risk of renal cell cancer: A dose-response meta-analysis of published cohort studies. Int J Cancer 2014;135:1673-86.  Back to cited text no. 11
    
12.
Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med 2003;348:1625-38.  Back to cited text no. 12
    
13.
Schips L, Lipsky K, Zigeuner R, Gidaro S, Salfellner M, Rehak P, et al. Does overweight impact on the prognosis of patients with renal cell carcinoma? A single center experience of 683 patients. J Surg Oncol 2004;88:57-61.  Back to cited text no. 13
    
14.
Kamat AM, Shock RP, Naya Y, Rosser CJ, Slaton JW, Pisters LL, et al. Prognostic value of body mass index in patients undergoing nephrectomy for localized renal tumors. Urology 2004;63:46-50.  Back to cited text no. 14
    
15.
Awakura Y, Nakamura E, Ito N, Yamasaki T, Kamba T, Kamoto T, et al. Influence of body mass index on prognosis of japanese patients with renal cell carcinoma. Urology 2007;70:50-4.  Back to cited text no. 15
    
16.
Yu ML, Asal NR, Geyer JR. Later recurrence and longer survival among obese patients with renal cell carcinoma. Cancer 1991;68:1648-55.  Back to cited text no. 16
    
17.
Rasmuson T, Grankvist K, Jacobsen J, Olsson T, Ljungberg B. Serum insulin-like growth factor-1 is an independent predictor of prognosis in patients with renal cell carcinoma. Acta Oncol 2004;43:744-8.  Back to cited text no. 17
    
18.
Aron M, Nguyen MM, Stein RJ, Gill IS. Impact of gender in renal cell carcinoma: An analysis of the SEER database. Eur Urol 2008;54:133-40.  Back to cited text no. 18
    
19.
Woldrich JM, Mallin K, Ritchey J, Carroll PR, Kane CJ. Sex differences in renal cell cancer presentation and survival: An analysis of the National Cancer Database, 1993-2004. J Urol 2008;179:1709-13.  Back to cited text no. 19
    
20.
Yu CP, Ho JY, Huang YT, Cha TL, Sun GH, Yu DS, et al. Estrogen inhibits renal cell carcinoma cell progression through estrogen receptor-β activation. PLoS One 2013;8:e56667.  Back to cited text no. 20
    
21.
Chen KC, Lin CM, Huang CJ, Chen SK, Wu ST, Chiang HS, et al. Dual roles of 17-β estradiol in estrogen receptor-dependent growth inhibition in renal cell carcinoma. Cancer Genomics Proteomics 2016;13:219-30.  Back to cited text no. 21
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

 
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