## 6 Discussion  
This is a large series study showing a novel association between collateral vessels in ccRCC male patients and high Fuhrman grades. The Fuhrman grade is the most widely used histological grading system for ccRCC [3]. Several studies investigated signs that could predict Fuhrman grades in ccRCC using a non-invasive imaging-based approach [9; 10; 11; 12; 13; 14; 15; 16; 17; 18; 19]. [PERSON] et al., measured the portion of the lesion that exhibited greater contrast enhancement and found that low contrast enhancement during the corticomedullary phase correlated with a high Fuhrman grade [14]. [PERSON] et al., reported that the correlation between the Fuhrman grade and contrast enhancement was significant only when measured in the entire lesion, compared with the portion with greater contrast enhancement on a single slice [15]. A further radiomics study showed that data obtained in the corticomedullary and nephrographic phases, separate or combined, could predict the Fuhrman grade in ccRCC [16]. Regarding small ccRCCs (<4 cm), no correlation was found between lesion contrast enhancement and the histological grade [17]. [PERSON] et al., reported that the majority of low-grade RCCs showed sharp or slightly irregular margins [18]. Furthermore, a study conducted by [PERSON] et al., showed that defined margins are associated with less aggressive RCCs due to less infiltrative behavior [19]. On the other hand, no significant correlations were found between the morphological characteristics of the lesion and the Fuhrman grades in the small RCCs, probably due to the sample being comprised by tumors smaller than 4 cm [17]. Unenhanced CT found that low lesion attenuation was a predictor of a low Fuhrman grade. This low attenuation probably reflects the intracellular lipids content [17]. In fact, histological ccRCC can be rich in intracytoplasmic lipids and glycogen; the presence of intracytoplasmic lipids gives the characteristic \"clear\" appearance of ccRCC [15]. It has been shown that there is an inverse relationship between the histological grade and intra-cellular lipid droplets [20; 21]. Additionally, [PERSON] et al., showed that low-grade ccRCCs exhibited greater expression of adipose differentiation-related protein (ADFP), a protein involved in the uptake of fatty acids and the formation of intracellular lipid droplets, compared with high-grade ccRCCs. Increased ADFP expression correlates with increased intracytoplasmic lipid accumulation in low-grade ccRCC compared with high-grade ccRCC [22; 23]. The non-invasive imaging approach with CT allows a correct qualitative and quantitative assessment of the tissues [24]. An interesting paradigm is based on the analysis of peritumal tissues, such as local composition changes of perinephric fat with collateral vessels, or the assessment of whole-body imaging composition [25; 26; 27; 28; 29; 30; 31]. Here, we confirm the known association between greater ccRCC tumor size and a high Fuhrman grade [13]. Moreover, in the present study, we demonstrated for the first time a link between peritumal collateral vessels and high Fuhrman grades in patients with ccRCC. The presence of collateral vessels can be explained as inability of the renal vein to drain venous blood also due to a tumor-related unbalance caused by an increase total size, cellularity and blood demand. These findings might cause dilation of the renal capsular veins, becoming macroscopically evident as collateral vessels in CT or MRI studies. Furthermore, the abnormal cellular architecture of the tumor due to hypercellularity diverts the blood flow toward \"alternative routes\" (e.g., dilated and macroscopically visible renal capsular veins). Taken together, these mechanisms might explain the presence of collateral vessels in RCCs with high Fuhrman grades. CcRCC can harbor inactivating mutations (or less commonly by ipermethylation) of the maternal or paternal copies of the Von Hippel Lindau (VHL) gene.