## 3 Discussion  
This cross-sectional observational study shows a significant decrease of SAT in ccRCCp patients compared to ccRCCa patients (Figures 3 and 4). In the regulation of the body composition molecular crosstalk between adipose tissue, liver, muscles, heart and brain play a fundamental role [2]. Adipose tissue secretes a series of hormones such as adipokines and chemokines which can regulate tumor behavior, tumor microenvironment and inflammation [2]. Lipotoxicity in cancer cachexia is determined by several factors such as adipokine and myokine secretion, increased lipolytic activity and chronic inflammation [19]. The systemic inflammation present in advanced cancer patients is based on the excessive release of cytokines which seem to modulate cancer cachexia, comprising interleukin-1\(\upbeta\) (IL-1\(\upbeta\)), interleukin-6 (IL-6), tumor necrosis factor-\(\upalpha\) (TNF-\(\upalpha\)) and interferon-\(\upgamma\) (IFN-\(\upgamma\)) [5; 20; 21; 22]. IL-6 inhibits synthesis and increases lipid and protein catabolism in adipocytes and myocytes respectively, causing loss of body mass with reduction of the amount of adipose tissue contributing to muscle atrophy [5; 23]. In fact, high concentrations of IL-6 have been correlated with high tumor growth rate [5]. This explains the lipolytic action of IL-6 in adipose tissue [2]. TNF-\(\upalpha\) released from both adipose tissue and muscle plays an important role in cancer cachexia acting on the reduction of glucose transporter 4 (GLUT4) levels and on the inhibition of glucose transport, thereby reducing substrates for lipogenesis [19; 24]. In cancer cachexia TNF-\(\upalpha\) recalls monocytes in adipose tissue and consequently the infiltrating macrophages cause an increase of IL-6 and IL-1\(\upbeta\) levels [25; 26]. Similar to TNF-\(\upalpha\), IFN-\(\upgamma\)  
Figure 4: Axial CT images showing the orange ROIs of SAT areas in ccRCCa patients (**a**–**c**) and ccRCCp patients (**d**–**f**), the tumors in ccRCCa patients (yellow arrows in **a**–**c**) and ccRCCp patients (yellow arrows in **d**–**f**) and peritumoral collateral vessels in ccRCCp patients (red arrows in **d**–**f**). Note that there is a clear reduction of SAT in ccRCCp patients (**d**–**f**). acts on the metabolism of adipose tissue in cancer cachexia; in fact, in rodent tumor models, a relationship with weight loss and anorexia has been demonstrated [27]. Leptin increases energy expenditure and suppresses food intake [28]. Physiologically it is believed that lipogenesis inhibition and an increase of fatty acids oxidation protects the adipocytes from lipotoxicity [28]. In cancer cachexia, the adipose tissue produces leptin which, acting on the hypothalamus, regulates the amount of energy stored in the adipose tissue by influencing the appetite [29]. It also upregulates inflammatory cytokines production [30]. The presence of collateral vessels showed a specificity of 94% and a positive predictive value of 88% in predicting locally advance disease in RCC patients, considered as final histopathological staging [12]. However, there is not always overlap between histopathology and radiology, mostly due to well-known CT pitfalls which can produce disagreements between radiological locoregional staging and final histopathological staging [31; 32; 33; 34]. According to the results of the present study, the significant decrease in the amount of SAT in ccRCCp patients compared to ccRCCa patients could be considered a clue to cancer cachexia associated with advanced ccRCC. It is known that adipose tissue exhibits several functions in the pathogenesis and development of RCC, as well as a relationship with VHL and KDM3C ccRCC genetic mutations [35; 36; 37]. SAT might be a primary source of energy used by the tumor, which would explain the decrease observed in ccRCCp patients (therefore with locally advanced disease) compared to ccRCCa patients.