Abstract
Objective:
The excessive amount of adipose tissue, mainly visceral, determines adiposopathy. With respect to oncogenesis, visceral adipose tissue (VAT) releases secretes adipokines, proinflammatory citokines and growth factors, considered mediating molecules in the development of obesity-related tumors. In this study, we quantify VAT in male patients with clear cell renal cell carcinoma (ccRCC) subgrouped according to the presence or absence of peritumoral collateral vessels.
Methods:
in this retrospective study, we enrolled 141 male caucasian patients divided into 2 groups: the ccRCC group (n = 106) composed of patients with ccRCC and control group (n = 35). The ccRCC group was further divided into two subgroups: the ccRCCa subgroup which showed absence of collateral vessels (n = 48) and ccRCCp subgroup with collateral vessels (n = 58).
Total adipose tissue (TAT) area, VAT area and subcutaneous adipose tissue (SAT) area were measured in the groups and subgroups. VAT/SAT ratio was calculated for each subject.
Results:
Statistically significant differences were obtained between ccRCC group and control group for TAT area (p < 0.005), VAT area (p < 0.005) and SAT area (p = 0.01). Between ccRCCa subgroup and control group for TAT area (p < 0.001), VAT area (p = 0.005) and SAT area (p = 0.001). Between ccRCCp subgroup and control group for TAT area (p = 0.01) and VAT area (p = 0.01).
Conclusion:
This study confirms the increase of abdominal, especially visceral, adipose tissue in ccRCC patients and demonstrates a significant VAT accumulation in both categories of patients with and without peritumoral collateral vessels.
Advances in knowledge:
Visceral adiposity is present in patients with ccRCC regardless the presence of peritumoral collateral vessels, with surprisingly stronger results in the ccRCCa subgroup.
Introduction
The relationship between obesity and carcinogenesis in various anatomic districts is well known. In particular, a correlation has been found with colorectum, pancreas, esophagus, endometrium, breast (post-menopausal) and kidney.1,2 Obesity is defined as body mass index (BMI) greater than 30 kg/m2, instead overweight as BMI higher than 25 kg/m2.3 However, BMI does not distinguish different tissues, not allowing to have any information on the distribution of adipose tissue, nor on the quantity of the two abdominal compartments separately: visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT).4 Adipose tissue is an endocrine/metabolic organ.5 Indeed, VAT has a higher hormonal and metabolic function than SAT, differing in molecular, cellular and anatomic composition.6,7 Considering the VAT activity with respect to oncogenesis, VAT secretes adipokines, proinflammatory citokines and growth factors, considered mediating molecules impacting the occurrence of obesity-related tumors.8,9
CT and MRI are essential imaging techniques for non-invasive tissue assessment and characterization.10–14
As for the different distribution of adipose tissue in males and females, it is known that males have a greater amount of VAT, while females have more SAT.14 Pre-menopausal females have a higher amount of SAT. After menopause, with the decrease of the estrogen levels, there is a shift of the adipose tissue distribution characterized by increased amount of VAT and a higher risk of obesity-related metabolic disorders.14
Patients with clear cell renal cell carcinoma (ccRCC) showed a greater amount of abdominal fat, particularly visceral, with respect to control subjects, suggesting a link between VAT and ccRCC.15
CT imaging studies demonstrated that ccRCC can be detected with or without peritumoral collateral vessels.16
To date, the abdominal adipose tissue distribution in male patients with ccRCC with and without peritumoral collateral vessels has not been investigated in detail. Given the angiogenic activity of biochemical mediators released by VAT,8,9 it is interesting to assess the possible relationship between VAT and peritumoral collateral vessels.
In this study, we used a CT imaging-based approach to confirm in a larger cohort the previous association between ccRCC and VAT and to investigate whether the increase of VAT can be found in both male ccRCC patients with and without peritumoral collateral vessels.
Methods
The study was approved by the local ethical committee and was conducted in accordance with the Declaration of Helsinki.
Controls
As the abdominal CT is normally not performed in healthy subjects, the control group was composed by male patients, without history of malignancies, who have performed a chest-abdomen CT for pre-operative cardiovascular surgery planning.
A total of 77 consecutive patients were evaluated and screened, by means of medical history and CT images, according to the exclusion criteria.
The exclusion criteria for controls were as follows: female patients, patients with non-Caucasian ethnicity, patients with congenital solitary kidney, nephrectomized and heminephrectomized patients, patients with previous renal ablation, cirrhotic patients with collateral vessel, narrow field of view (FOV) images not allowing to quantify SAT, history of malignancies and unclear or unknown medical history.
Patients included in the control group underwent the following cardiac surgery: 8 aortic valve replacement, 1 aortic valve and ascending aorta replacement, 1 combined coronary artery bypass and aortic valve replacement, 18 mitral valve replacement, 3 combined coronary artery bypass and mitral valve replacement, 1 mitral and tricuspid valve replacement, 1 combined coronary artery bypass with mitral and tricuspid valve replacement, 2 left atrial myxoma resection.
CcRCC patients
CT images of ccRCC group were taken from The Cancer Imaging Archive (TCIA).17–19
A total of 267 consecutive patients were evaluated and screened, by means of medical history and CT images, according to the exclusion criteria.
The exclusion criteria for ccRCC patients were as follows: female patients, patients with non-Caucasian ethnicity, patients who had undergone CT without administration of contrast medium, patients who had undergone magnetic resonance examination only, patients with congenital solitary kidney, nephrectomized and heminephrectomized patients, patients with previous renal ablation, cirrhotic patients with collateral vessel, narrow FOV images not allowing to quantify SAT, patients who had undergone chest CT only and patients who had undergone upper abdomen CT in which collateral vessels were not entirely visible.
Final cohort enrolled
Finally, a cohort of 141 male caucasian patients divided into two groups were enrolled: the ccRCC group (n = 106) composed of patients with ccRCC and control group (n = 35). The ccRCC group was further divided into two subgroups: the ccRCC group which showed the absence of collateral vessels (ccRCCa; n = 48), the ccRCC group with collateral vessels (ccRCCp; n = 58). ccRCC group was composed by 106 patients (mean age: 58.5, range: 26–84).
ccRCCa subgroup was composed by 48 patients (mean age: 57.1, range: 26–78), ccRCCp subgroup was composed by 58 patients (mean age: 59.7, range: 34–84); and control group was composed by 35 patients (mean age: 61.1, range: 40–82). The descriptive data of the two subgroups are summarized in Tables 1 and 2.
Table 1.
| Sex | Male (48) |
|---|---|
| Mean age | 57.1; 26–78 (48) |
| Ethnicity | Caucasian (48) |
| Histology | ccRCC (48) |
| History of other malignancy | No (34) Yes (14) |
| History of neoadjuvant treatment | No (43) Yes (5) |
| Staging | T1aN0M0 (9) T1aNXM0 (19) T1bN0M0 (5) T1bNXM0 (6) T2N0M0 (3) T2NXM0 (1) T3aN0M0 (2) T3aN0M1 (2) T3bNXM0 (1) |
ccRCC, clear cell renal cell carcinoma.
Descriptive data of ccRCCa subgroup.
Table 2.
| Sex | Male (58) |
|---|---|
| Mean age | 59.7; 34–84 (58) |
| Ethnicity | Caucasian (58) |
| Histology | ccRCC (58) |
| History of other malignancy | No (49) Yes (9) |
| History of neoadjuvant treatment | No (54) Yes (4) |
| Staging | T1aNXM0 (10) T1bN0M0 (2) T1bNXM0 (7) T2N0M0 (5) T2N0M1 (1) T2NXM0 (2) T2aNXM0 (2) T3aN0M0 (9) T3aNXM0 (4) T3aNXM1 (5) T3aN1M1 (1) T3bN0M0 (3) T3bNXM0 (4) T3bNXM1 (1) T4N1M1 (1) T4NXM0 (1) |
ccRCC, clear cell renal cell carcinoma.
Descriptive data of ccRCCp subgroup.
CT analysis
All patients underwent CT examination. Total adipose tissue (TAT), VAT and SAT areas were calculated using Horos v. 4.0.0 RC2. Particularly, all cross-sectional CT images were analyzed with a semi-automatic function able to recognize the typical attenuation values of adipose tissue (i.e. about −100 Hounsfield unit).The measurements were acquired as areas (cm2), on the axial plane 3 cm above the lower margin of L3 as described elsewhere.20 Region of interest (ROI) of TAT area were segmented and calculated. Subsequently, ROI of SAT area were obtained by subtracting ROI of VAT area from those of TAT area. Values of VAT area were then calculated by subtracting values of SAT area from those of TAT area.
All the ROIs were performed by consensus of two radiologists (Federico Greco, 5 years of experience; Carlo Augusto Mallio, 9 years of experience), who were blinded to clinical data.
Statistical analysis
The TAT, VAT and SAT areas and the VAT/SAT ratio were compared between ccRCC group and control group, between ccRCCa subgroup and control group, and between ccRCCp subgroup and control group using the Student’s t‐test. The level of statistical significance was considered as p < 0.05.
Results
Statistically significant differences between ccRCC group and control group were obtained for TAT area (p < 0.005), VAT area (p < 0.005) and SAT area (p = 0.01).
Statistically significant differences between ccRCCa subgroup and control group were obtained for TAT area (p < 0.001), VAT area (p = 0.005) and SAT area (p = 0.001).
Statistically significant differences between ccRCCp subgroup and control group were obtained for TAT area (p = 0.01) and VAT area (p = 0.01).
No statistically significant difference was obtained between ccRCC group and control group for VAT/SAT ratio, between ccRCCa subgroup and control group for VAT/SAT ratio, and between ccRCCp subgroup and control group for SAT area and VAT/SAT ratio.
The results are listed in Tables 3–5 and are represented in Figure 1.
Table 3.
Mean, standard deviation and range of the ccRCC group and control group and Student’s t‐test results
| TAT area (cm2) | VAT area (cm2) | SAT area (cm2) | VAT/SAT ratio | |
|---|---|---|---|---|
| ccRCCgroup | 435,38 (±184,63) (97,3 – 914,7) |
231,22 (±105,57) (18 – 505,1) |
204,15 (±108,11) (64,6 – 632,1) |
1,27 (±0.7) (0,22–5,3) |
| Control group | 328,82 (±137,3) (148 – 704) |
172,53 (±95,48) (35,7 – 408,2) |
155,6 (±64,28) (55 – 349,3) |
1,19 (±0,71) (0,3–3,7) |
| p | 0,002 | 0,004 | 0,01 | 0,55 |
TAT, total adipose tissue; VAT, visceral adipose tissue; SAT, subcutaneous adipose tissue; ccRCC, clear cell renal cell carcinoma.
Table 4.
Mean, standard deviation and range of the ccRCCa subgroup and control group and Student’s t‐test results
| TAT area (cm2) | VAT area (cm2) | SAT area (cm2) | VAT/SAT ratio | |
|---|---|---|---|---|
| ccRCCa group | 468,09 (±205,06) (97,3 – 914,7) |
239,63 (±112,07) (18 – 434,3) |
228,45 (±121,23) (64,6 – 632,1) |
1,16 (±0,61) (0,22–2,91) |
| Control group | 328,82 (±137,3) (148 – 704) |
172,53 (±95,48) (35,7 – 408,2) |
155,6 (±64,28) (55 – 349,3) |
1,19 (±0,71) (0,3–3,7) |
| p | 0,00007 | 0,005 | 0,001 | 0,86 |
TAT, total adipose tissue; VAT, visceral adipose tissue; SAT, subcutaneous adipose tissue; ccRCC, clear cell renal cell carcinoma.
Table 5.
Mean, standard deviation and range of the ccRCCp subgroup and control group and Student’s t‐test results
| TAT area (cm2) | VAT area (cm2) | SAT area (cm2) | VAT/SAT ratio | |
|---|---|---|---|---|
| ccRCCp group | 408,31 (±162,72) (108,2 – 903,8) |
224,27 (±100,33) (39,2 – 505,1) |
184,03 (±92,21) (69 – 596,8) |
1,36 (±0,76) (0,32–5,3) |
| Control group | 328,82 (±137,3) (148 – 704) |
172,53 (±95,48) (35,7 – 408,2) |
155,6 (±64,28) (55 – 349,3) |
1,19 (±0,71) (0,3–3,7) |
| p | 0,01 | 0,01 | 0,1 | 0,28 |
TAT, total adipose tissue; VAT, visceral adipose tissue; SAT, subcutaneous adipose tissue; ccRCC, clear cell renal cell carcinoma.
Figure 1.
Mean value and error bars of TAT, VAT, SAT areas in ccRCC group and control group (a), in ccRCCa subgroup and control group (b), and in ccRCCp subgroup and control group (c). ccRCC, clear cell renal cell carcinoma; SAT, subcutaneous adipose tissue; TAT, totaladipose tissue; VAT, visceral adipose tissue.
Discussion
This study shows a significantly greater amount of TAT, VAT and SAT between ccRCC group and control group, with a predominant increase of VAT (Figure 2). These data confirm in a larger sample size (i.e. 106 male patients with ccRCC) the result of a previous study on a small number of patients (i.e. 10 male patients with ccRCC) in which a significant increase of VAT in ccRCC patients compared to control group was shown.15
Figure 2.
Six examples of axial CT images showing greater area of abdominal fat, especially VAT segmented in orange, in ccRCC patients (a, b and c) with respect to control subjects (d, e and f). VAT, visceral adipose tissue; ccRCC, clear cell renal cell carcinoma.
Adipocyte- and adipose tissue-related disorder are determined by an excessive accumulation of adipose tissue, mostly visceral. This metabolic disorder is expressed by the concept of “adiposopathy.”21,22
The increase in BMI has been linked to increased risk of renal cell carcinoma (RCC).22
Specific adipokines secreted by visceral adipocytes, and associated with metabolic syndrome such as leptin, adiponectin, resistin and visfatin, are considered a possible bridge between obesity and carcinogenesis of RCC.23,24
This study confirms VAT area as a quantitative imaging parameter related to oncological risk of ccRCC development. A significant increase in the amount of VAT was also recently found in male patients with non-ccRCC.25
Obese patients with localized ccRCC treated by nephrectomy have a higher survival rate than localized ccRCC patients with normal weight in WHO's categorization (BMI 18 · 5–24 · 9 kg/m2); this phenomenon is called obesity paradox.26–28 It has also been observed in patients with metastatic ccRCC treated with target therapy.29 Sanchez et al compared the angiogenic and immunological transcriptomic fingerprints of tumor and peritumoral adipose tissue in ccRCC obese patients and ccRCC normal weight patients.30
Transcriptomic analyses demonstrated significant upregulation of genes associated with hypoxia and angiogenesis in obese ccRCC patients compared to ccRCC patients with normal weight.30
Based on these results, the researchers suggested that angiogenesis and alterations of the tumor microenvironment are promoted by regions of hypoxia created by visceral adipose tissue, which controls the growth of ccRCC. Hence, the hypothesis that the increased angiogenesis in obese patients determines higher susceptibility to tyrosine kinase inhibitors probably due to the greater local concentration of tyrosine kinase inhibitors.30,31
A significantly increased markers of hypoxia, inflammation and immune infiltration in the peritumoral adipose tissue of the obese ccRCC patients compared to the normal weight ccRCC patients was found, suggesting that the peritumoral adipose tissue could represent an active reservoir of immune cells stimulating antitumour immune response with immune checkpoint inhibitors.30,31
In our study, we found a significant increase of TAT area, VAT area and SAT area in the ccRCCa subgroup compared to the control group and a significant increase of TAT area and VAT area in the ccRCCp subgroup compared to the control group; the angiogenic and immunological transcriptomic patterns of peritumoral adipose tissue described by Sanchez et al might explain the increase of VAT in the ccRCCp subgroup compared to control group.
The hypertrophy of the adipocytes present in the visceral adipose tissue of obese patients creates regions of hypoxia that determine angiogenesis.32 Moreover, leptin secreted by adipocytes determines proliferation, and migration of endothelial cells by means VEGF and VEGF receptor-2 upregulation.33
The result of the VAT area in the ccRCC group confirms the data of the previous study.15 VAT area can be considered as a quantitative imaging parameter associated to the oncological risk of ccRCC development.
The increase of the VAT area in the ccRCCp subgroup is the macroscopic expression of a direct link between the quantity of VAT and the presence of collateral vessels in the ccRCC patients.
The limitations of this study, due to the retrospective design, are the possible selection bias and the lack of some clinical information such as BMI and hormonal status. Interestingly, the results of the present study were found to be stronger for the ccRCCa subgroup, despite expected to be as such in the ccRCCp subgroup. This finding, that deserves to be further explored, will stimulate additional research on the subject. Indeed, future studies, including a multivariate analysis taking into account clinical, laboratory, genetic and quantitative CT data, will be essential in order to provide a multiparametric and comprehensive risk-threshold or cut-off level of abdominal fat (including VAT), to better identify the metabolic process possibly resulting in tumor formation.
Conclusions
This study confirms the increase of abdominal, especially visceral, adipose tissue in ccRCC patients and demonstrates a significant VAT accumulation in both categories of patients with and without peritumoral collateral vessels.
Footnotes
Ethical approval:Institutional Review Board was not required because this is an observational retrospective study, and only existing information collected from human participants are used and there are not any identifiers linking individual to the data. This article does not contain any studies with animals performed by any of the authors. The study was performed in accordance with the Declaration of Helsinki. The Institutional Ethical Committee approved the study. All subjects enrolled provided a written informed consent to use their anonymized data for research purposes.
Contributor Information
Federico Greco, Email: federicogreco@outlook.com.
Luigi Giuseppe Quarta, Email: luigigquarta@libero.it.
Rosario Francesco Grasso, Email: r.grasso@unicampus.it.
Bruno Beomonte Zobel, Email: b.zobel@unicampus.it.
Carlo Augusto Mallio, Email: c.mallio@unicampus.it.
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