The evaluation of the association between the metabolic syndrome and tumor grade and stage of bladder cancer in a Chinese population
The evaluation of the association between the metabolic syndrome and tumor grade and stage of bladder cancer in a chinese population
Da-wei Tian 1 2 3 4 5
Wan-qin Xie 0 3 4 5
Yu Zhang 1 2 3 4 5
0 Key l aboratory of g enetics and Birth h ealth of h unan province, Family Planning r esearch institute of h unan Province , c hangsha, h unan, People's republic of china
1 Tianjin Key laboratory of Urology, Tianjin institute of Urology , Tianjin
2 Department of Urology, The second hospital of Tianjin Medical University
3 Zhou-liang Wu
4 Zhong-hua shen
5 Xiao-teng liu
8 1 0 2 - l u J - 3 1 n o 3 7 . 7 1 1 . 7 3 . 4 5 y b / m o c . s s re .
metabolic syndrome; primary carcinoma of the bladder; diabetes mellitus
open access to scientific and medical research
O r i g i n a l r e s e a r c h
Bladder cancer is one of the most common malignant neoplasms in the world.1 It is
the sixth leading cause of new cancer cases and ninth leading cause of cancer-related
mortality worldwide. According to the data provided by the International Agency
for Research on Cancer in 2012,2 55,486 cases and 26,820 deaths were estimated for
the population in the People’s Republic of China, which accounts for a large
proportion of bladder cancer in East Asia (85,451 cases and 37,491 deaths). In developed
countries, ~360,000 men and women are diagnosed with bladder cancer; the highest
incidence rates are found in the countries of Europe and North America.3 However,
it is of note that the incidence of bladder cancer has been steadily increasing in the
People’s Republic of China over recent years.4
Several risk factors have been implicated in urinary bladder
carcinogenesis, such as chemical industrial products, smoking,
and urinary tract infection.5–7 Metabolic syndrome (MetS) is
characterized by overweight, hypertension, blood glucose, and
dyslipidemia. The age-adjusted prevalence of MetS is 9.8%
in males and 17.8% in females in the People’s Republic of
China.8 It has consistently been associated with an increased
risk of cardiovascular diseases and type 2 diabetes, also with a
risk of urinary tract diseases.9 In recent years, a large number
of epidemiological studies have shown that MetS is closely
related to the occurrence and development of a variety of
malignant tumors. Also, some researches showed that MetS
promotes tumorigenesis by a number of inflammatory
molecules including interleukin-6 and tumor necrosis factor-α.10,11
Association between MetS and prostate cancer, liver cancer,
and colorectal cancer has been reported; however, there is
a limited large-sample research to evaluate the association
between the MetS and risk of bladder cancer in a Chinese
population, for separate components and for MetS factors
combined. The aim of this study was to investigate the association
between components in the MetS (single and combination)
with a risk of bladder cancer in a Chinese population.
Patients and methods
After obtaining approval from the Institutional Review Board
of the Second Hospital of Tianjin Medical University, a total
of 323 patients at our institution from January 2012 to January
2014 were retrospectively selected for the analysis. Clinical
and pathological information were retrospectively obtained
from patient charts and electronic medical records,
including age, sex, height, weight, body mass index (BMI), blood
pressure, fasting serum glucose, tumor grade, and stage. All
patients had primary bladder urothelial carcinoma. Patients
with metastatic bladder urothelial carcinoma, carcinoma in
situ, adenocarcinoma, or squamous cell carcinoma at
diagnosis were excluded from this study.
Pathological stage was diagnosed by a single pathologist
according to the 2009 tumor–node–metastasis (TNM)
classification staging system. Ta and T1 tumors were accepted as lower
stage bladder urothelial carcinoma. T2, T3, and T4 tumors were
accepted as higher stage bladder urothelial carcinoma. Also,
tumor grading was done according to the 2004 World Health
Organization grading system. Patients who had noninvasive
papillary urothelial neoplasm of low malignant potential were
regarded as having low-grade papillary urothelial cancer.
MetS was defined according to the Chinese Diabetes
Society definition.12 MetS was diagnosed when complying
with three or more of the following abnormalities: patients
were diagnosed with MetS when they had three or more
of the following indications: 1) BMI $25.0 kg/m2,
2) fasting plasma glucose $6.1 mmol/L or 2-hour plasma
glucose $7.8 mmol/L, 3) systolic blood pressure $140 mmHg
or diastolic blood pressure $90 mmHg, 4) triglyceride
(TG) $1.70 mmol/L or high-density lipoprotein cholesterol
(HDL-C) ,0.9 mmol/L in males and ,1.0 mmol/L in
females. Participants met the criteria for high blood
pressure or high fasting glucose concentration if they underwent
hypertension or hyperglycemia treatment. BMI was
calculated as weight in kilograms divided by the square of height in
meters. Because our database does not include the HDL-C and
TG, in order to study, we used a modified Chinese Diabetes
Society definition. MetS was diagnosed when complying with
the first three conditions of the aforementioned criteria.
Statistical analysis was performed using statistical
software (SPSS, version 17.0; SPSS Inc., Chicago, IL, USA).
Analyses were completed using chi-square tests and logistic
regression analysis. All tests were two-sided with P,0.05
considered to be significant.
As given in Table 1, among the 323 patients analyzed in
our study, there were 255 males and 68 females, with an
average age of 69.81±5.821 years. MetS was found in
64 (19.8%) patients. Some components of MetS such as
hypertension, diabetes mellitus (DM), and BMI $25 kg/m2
were determined in 50.8%, 46.7%, and 65.9% of patients,
no of patients
age (mean ± sD) (years)
respectively. The clinicopathological demographics of
characteristics between patients with or without MetS were
demonstrated in Table 2. Sixty-four (19.8%) patients were
diagnosed with MetS. The mean age of the patients in the
MetS group was 65.05±1.618 years and non-MetS group was
70.98±5.885 years. Lower (Ta, T1) and higher (T2, T3, T4)
tumor pathologic stages were found in 70.3% and 29.7% of
patients with MetS, respectively, and histopathologic low
grade and high grade were found in 26.6% and 73.4% of
patients, respectively. According to our data, statistically
significant differences were observed in tumor pathologic stage
(P=0.006) and tumor histologic grade (P,0.001) between
patients with and without MetS. In age-adjusted binary
logistic regression analysis, the presence of MetS predicts
the risk of higher T stage (odds ratio =4.029, P,0.001)
and grade (odds ratio =3.870, P,0.001) of bladder cancer.
Also, some MetS parameters (except serum TGs and serum
HDL-C) were depicted in Table 3.
In recent years, a large number of epidemiological studies13
have shown that MetS is closely associated with the
occurrence and development of urinary tract diseases, and the vast
majority of research confirmed that MetS was related to the
pathogenesis and prognosis of prostate cancer.14 However,
limited information was available on the association between
MetS, as well as the components of MetS, and bladder cancer.
So, we explored the association between MetS, as well as
the components of MetS, and grading and staging of bladder
In this study, we retrospectively reviewed 323 patients at
our institution, comparing those with MetS with those with
non-MetS to assess its potential association with histologic
stage and grade of bladder cancer. At the same time, we also
assessed the relationship between the three components of
the MetS (obesity, DM, hypertension) and bladder cancer
histologic grade and stage.
Obesity is one of the characteristics of MetS, according
to the population-based longitudinal study in the People’s
Republic of China; standardized prevalences have reached
up to 9.1% for obese population.15 Obviously, it has already
accounted for a significant proportion. Therefore, as clinical
doctors, we should pay close attention to the disease,
especially malignant tumor caused by obesity. A number of
studies have shown that obesity is associated with many
malignant tumors, and some studies have shown an increased
risk.16,17 As we know, the relationship between obesity and
diabetes, especially type 2 diabetes, is definite. Obesity and
DM represent two important components of MetS;
epidemiological studies have shown that obesity and type 2 diabetes
are associated with an increased risk of several cancers, such
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as kidney, colon, and liver.18,19 The link between obesity and
cancer seems to be related to insulin resistance and high
serum level of insulin-like growth factor (IGF)-1.20 IGF-1
could stimulate proliferation and inhibit apoptosis, which
could ultimately result in cancer. Previous reports showed
that IGF-1 played an important role in the development of
prostate, lung, and liver cancers. Association with bladder
cancer has also been presented.21,22 A BMI $25 kg/m2 was
2108 used as measurement for obesity in our study. Our results
l--Ju showed that the value of the BMI (obesity) is associated
31 with the pathological grade and stage of bladder cancer in a
no3 Chinese population. So far, there are many studies exploring
.717 the association between obesity and risk of bladder cancer.
.137 Several epidemiological studies have also confirmed that
.54 obesity was positively associated with bladder cancer
/yb risk.16,17,23 Two reasons may be used to explain these results.
.com Biochemically, excess energy in hosts can contribute to
rsse . risks of carcinogenesis.24 Excessive fat is also associated
.vdoepw lsyeonu important role in cancer.25
with systemic inflammatory response, which may play an
/:/ww loan Additionally, a number of large cohort studies have made
tsp rse efforts to indicate that there is a higher risk of cancer in
rom oF populations with DM. Zhan et al26 performed the first study
fd to investigate the characteristics of glucose metabolism in
dea different kinds of cancer in a Chinese population; the results
lonw revealed that high level of fasting plasma glucose had a
ydo relationship with bladder cancer, and the incidence of
hyperrepa glycemia is higher than that of hypoglycemia in the same
hT kind or different kinds of cancer. According to our study, we
dan found that DM was associated with pathological grading and
trseg staging of bladder cancer. Possible reasons may be 1) reduced
aoT insulin sensitivity and elevated levels of IGF-1, which may
cnO in turn stimulate cell proliferation and play an important role
in the processes of cancer development and metastasis.27,28
2) In addition, hyperglycemia causes dysfunction of the
vital cellular signal system regulated by the protein kinase
C family, which induces the processes of tumor growth and
metastasizing in carcinogenesis.
The impact of hypertension and antihypertensive drugs
on malignant tumor is still a controversial issue. In the
literature, several research evidence has indicated that
hypertension in itself represents a significant risk for malignancies,
even in a long-term prospective study.29 One prospective
study demonstrated that systolic blood pressure and risk of
cancer mortality were positively correlated only after 5 years
of follow-up.30 However, little is known about possible
pathways between hypertension and cancer.31 Dal Moro
et al32 performed retrospective analyses of 343 patients, and
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reported that only hypertension was significantly associated
with risk in men among single MetS components. Grove
et al,33 who conducted a retrospective review of 63 patients,
reported no association. There was a nonsignificant
correlation between bladder cancer and various kinds of
antihypertensive drugs. A study with a total of 1,585 cases conducted
in Los Angeles has shown a reduced risk of bladder cancer
among hypertensive patients who did not use
antihypertensive drugs regularly.34 However, there are little data about
the association between hypertension and bladder cancer in
a Chinese population. Our study showed that there was no
correlation between hypertension and histopathologic stage
and grade of bladder cancer, but we did not analyze the
relationship between antihypertensive treatment and grading,
staging, and prognosis of bladder cancer.
According to our data, in the three parameters of MetS,
when assessed individually, it has been found a negative or
no statistically significant association with histopathologic
stage and grade of bladder cancer. However, when they are
considered MetSs, patients were found to have statistically
significant higher T stage and grade of bladder cancer.
Our study is not devoid of limitations. First and foremost is
its retrospective characteristic and the limited study sample,
although all data were extracted from our medical
institution, the possibility of selection bias cannot be excluded.
In addition, factors that are definitely proved to be
associated with bladder cancer risk (such as smoking, urinary
tract infection) are not included in the study, which can be
related to the MetS. Furthermore, unlike prior studies, our
database does not include the HDL-C and TG; it is possible
to exclude the patients with MetS actually. Finally, although
the BMI can replace central obesity, it cannot accurately
explain abdominal obesity, percentage of fat, and body fat
Patients with MetS were found to have statistically
significant higher T stage and grade of bladder cancer, while the
parameters of MetS, BMI, DM, and high blood pressure,
cannot individually predict higher T stage and grade of bladder
cancer. Further researches are needed to confirm our study
and to study all urinary tract infections.
This study was funded by the Natural Science Foundation
of Tianjin (Nos 12ZCDZSY16600, 14JCYBJC26300, and
15JCYBJC24600) and the National Key Specialty
Construction of Clinical Projects.
The authors report no conflicts of interest in this work.
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1. Jemal A , Bray F , Center MM , Ferlay J , Ward E , Forman D . Global cancer statistics. CA Cancer J Clin . 2011 ; 61 ( 2 ): 69 - 90 .
2. Ferlay J , Soerjomataram I , Dikshit R , et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012 . Int J Cancer . 2015 ; 136 ( 5 ): E359 - E386 .
3. Parkin DM , Bray F , Ferlay J , Pisani P . Global cancer statistics, 2002 . CA Cancer J Clin. 2005 ; 55 ( 2 ): 74 - 108 .
4. Yang L , Parkin DM , Li LD , Chen YD , Bray F . Estimation and projection of the national profile of cancer mortality in China: 1991-2005 . Br J Cancer. 2004 ; 90 ( 11 ): 2157 - 2166 .
5. Zaridze DG , Karpov RS , Kiseleva SM , et al. [ Smoking: the main cause of high mortality rate among Russian population] . Vestn Ross Akad Med Nauk . 2002 ; 9 : 40 - 45 . Russian.
6. Bosetti C , Pira E , La Vecchia C. Bladder cancer risk in painters: a review of the epidemiological evidence, 1989 - 2004 . Cancer Causes Control. 2005 ; 16 ( 9 ): 997 - 1008 .
7. Kantor AF , Hartge P , Hoover RN , Narayana AS , Sullivan JW , Fraumeni JF Jr. Urinary tract infection and risk of bladder cancer . Am J Epidemiol . 1984 ; 119 ( 4 ): 510 - 515 .
8. Gu D , Reynolds K , Wu X , et al. Prevalence of the metabolic syndrome and overweight among adults in China . Lancet . 2005 ; 365 ( 9468 ): 1398 - 1405 .
9. Kurella M , Lo JC , Chertow GM . Metabolic syndrome and the risk for chronic kidney disease among nondiabetic adults . J Am Soc Nephrol . 2005 ; 16 ( 7 ): 2134 - 2140 .
10. Gallagher EJ , LeRoith D. Epidemiology and molecular mechanisms tying obesity, diabetes, and the metabolic syndrome with cancer . Diabetes Care . 2013 ; 36 ( suppl 2 ): S233 - S239 .
11. Hammarsten J , Peeker R . Urological aspects of the metabolic syndrome . Nat Rev Urol . 2011 ; 8 ( 9 ): 483 - 494 .
12. Chinese Metabolic Syndrome Study Cooperation . Suggestions about metabolic syndrome of Chinese diabetes society . Chin J Diab . 2004 ; 12 : 156 - 161 .
13. Zhang JQ , Geng H , Ma M , Nan XY , Sheng BW . Metabolic syndrome components are associated with increased prostate cancer risk . Med Sci Monit . 2015 ; 21 : 2387 - 2396 .
14. De Nunzio C , Aronson W , Freedland SJ , Giovannucci E , Parsons JK . The correlation between metabolic syndrome and prostatic diseases . Eur Urol . 2012 ; 61 ( 3 ): 560 - 570 .
15. Hou X , Jia W , Bao Y , et al. Risk factors for overweight and obesity, and changes in body mass index of Chinese adults in Shanghai . BMC Public Health. 2008 ; 8 : 389 .
16. Koebnick C , Michaud D , Moore SC , et al. Body mass index, physical activity, and bladder cancer in a large prospective study . Cancer Epidemiol Biomarkers Prev . 2008 ; 17 ( 5 ): 1214 - 1221 .
17. Holick CN , Giovannucci EL , Stampfer MJ , Michaud DS . Prospective study of body mass index, height, physical activity and incidence of bladder cancer in US men and women . Int J Cancer . 2007 ; 120 ( 1 ): 140 - 146 .
18. 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 ( 9612 ): 569 - 578 .
19. Renehan A , Smith U , Kirkman MS . Linking diabetes and cancer: a consensus on complexity . Lancet . 2010 ; 375 ( 9733 ): 2201 - 2202 .
20. Hursting SD , Hursting MJ . Growth signals, inflammation, and vascular perturbations: mechanistic links between obesity, metabolic syndrome, and cancer . Arterioscler Thromb Vasc Biol . 2012 ; 32 ( 8 ): 1766 - 1770 .
21. Yang XQ , Xu C , Sun Y , Han RF . Diabetes mellitus increases the risk of bladder cancer: an updated meta-analysis . Asian Pac J Cancer Prev . 2013 ; 14 ( 4 ): 2583 - 2589 .
22. Qin Q , Xu X , Wang X , Zheng XY . Obesity and risk of bladder cancer: a meta-analysis of cohort studies . Asian Pac J Cancer Prev . 2013 ; 14 ( 5 ): 3117 - 3121 .
23. Larsson SC , Andersson SO , Johansson JE , Wolk A . Diabetes mellitus, body size and bladder cancer risk in a prospective study of Swedish men . Eur J Cancer . 2008 ; 44 ( 17 ): 2655 - 2660 .
24. Bianchini F , Kaaks R , Vainio H. Overweight , obesity, and cancer risk . Lancet Oncol . 2002 ; 3 ( 9 ): 565 - 574 .
25. Kluth LA , Xylinas E , Crivelli JJ , et al. Obesity is associated with worse outcomes in patients with T1 high grade urothelial carcinoma of the bladder . J Urol . 2013 ; 190 ( 2 ): 480 - 486 .
26. Zhan YS , Feng L , Tang SH , et al. Glucose metabolism disorders in cancer patients in a Chinese population . Med Oncol . 2010 ; 27 ( 2 ): 177 - 184 .
27. Wolf I , Sadetzki S , Catane R , Karasik A , Kaufman B . Diabetes mellitus and breast cancer . Lancet Oncol . 2005 ; 6 ( 2 ): 103 - 111 .
28. Stoeltzing O , Liu W , Reinmuth N , et al. Regulation of hypoxia-inducible factor-1alpha, vascular endothelial growth factor, and angiogenesis by an insulin-like growth factor-I receptor autocrine loop in human pancreatic cancer . Am J Pathol . 2003 ; 163 ( 3 ): 1001 - 1011 .
29. Schmieder RE , Delles C , Messerli FH . Diuretic therapy and the risk for renal cell carcinoma . J Nephrol . 2000 ; 13 ( 5 ): 343 - 346 .
30. Wannamethee G , Shaper AG . Blood pressure and cancer in middle-aged British men . Int J Epidemiol . 1996 ; 25 ( 1 ): 22 - 31 .
31. Stumpe KO . Hypertension and the risk of cancer: is there new evidence? J Hypertens. 2002 ; 20 ( 4 ): 565 - 567 .
32. Dal Moro F , Bovo A , Crestani A , Vettor R , Gardiman MP , Zattoni F . Effect of hypertension on outcomes of high-risk patients after BCGtreated bladder cancer: a single-institution long follow-up cohort study . Medicine (Baltimore) . 2015 ; 949 : e589 .
33. Grove JS , Nomura A , Severson RK , Stemmermann GN . The association of blood pressure with cancer incidence in a prospective study . Am J Epidemiol . 1991 ; 134 ( 9 ): 942 - 947 .
34. Jiang X , Castelao JE , Yuan JM , et al. Hypertension, diuretics and antihypertensives in relation to bladder cancer . Carcinogenesis . 2010 ; 31 ( 11 ): 1964 - 1971 .