Several case-control and prospective observational studies have established obesity as a risk factor for RCC, but little is known about its specific association with the different histological subtypes of RCC [3
]. In a group of patients with a renal mass treated with surgery, we found increasing BMI to be independently associated with the clear-cell variant. While controlling for all measured covariates, we found that for every 1 kg/m2
increase in BMI there was a 4% increase in the odds of having conventional clear-cell RCC histology. This statistically and clinically significant association remained even when BMI was treated as a dichotomous variable within our models. Obese patients (with a BMI of ≥30 kg/m2
) had a 48% greater odds of having clear cell histology than non-obese patients.
Our results confirm and extend the findings of two other studies. Donat et al.
] reported that a BMI of ≥ 30 kg/m2
was associated with an increased proportion of clear-cell renal cancers. Survival was the primary endpoint of their study, and therefore their multivariate analyses did not specifically explore predictors of clear-cell histology in patients with RCC. Although they found no association between BMI and survival in the patients studied, the univariate association of obesity with clear-cell tumours remained intriguing, as this histology is generally considered more virulent than are the papillary and chromophobe variants. In an Italian case-control study, RCC was associated with obesity, with the association strongest among patients with the clear-cell subtype (odds ratio 1.84, 95% CI 1.09–3.11) [6
]. Combining our findings from a contemporary cohort of patients with these two cited studies provides more evidence of a link between obesity and clear cell histology.
Based on the work many investigators, obesity is widely considered to increase the risk of RCC [3
]. In a meta-analysis examining 17 different datasets, Renehan et al.
] confirmed a strong association between obesity and RCC for both men and women. Chow et al.
] studied a large Swedish cohort and found that higher BMI independently increased the risk of RCC. Interestingly, there was a direct relationship; even with small increases in BMI there were increases in cancer risk. Similarly, we showed an increasing risk of clear cell histology with incremental increases in BMI.
The exact biological mechanisms linking obesity to increased risk of RCC and of clear cell histology are unknown, but there are several theories. An increased incidence of hypertension and diabetes, and increased levels of IGF and oestrogen in obese patients might contribute to tumorigenesis [5
]. Interestingly, obesity is also associated with impaired immune function, and recent studies of T cell co-stimulation suggest that negative regulators of T cell activation are present on clear-cell RCC cells and are associated with adverse pathological features and poor survival [16
]. Our refined understanding of the association of BMI with clear-cell RCC will hopefully help to elucidate the mechanism behind the effect of obesity on RCC risk.
Clear-cell RCC is the most common and probably the best understood variant of RCC. It accounts for 70–80% of RCC cases; the next most common histological variants are papillary, chromophobe and collecting-duct carcinoma. Clear-cell RCC typically results from a somatic mutation within the von Hippel-Lindau tumour-suppressor gene found on the short arm of chromosome 3 (3p25) [18
]. Activation of the von Hippel-Lindau gene results in up-regulation of hypoxia-inducible factor, leading to the increased transcription of genes like vascular endothelial growth factor, that play a key role in renal cell tumorigenesis [20
]. This new understanding of the molecular pathogenesis of clear-cell RCC has led to rapid advances in targeted therapy. Drugs like sunitinib, sorafenib, temsirolimus and bevacizumab block specific molecular targets and impede tumour angiogenesis. These drugs are effective in the clear-cell variants of RCC, but the same may not be true for the other histological subtypes. Early identification of patients with or at risk of clear-cell RCC is needed as the role of targeted agents expands.
Our findings could have an influence on the management of small renal masses. Although the prognostic significance of RCC histological subtypes has been disputed [21
], clear-cell tumours are generally considered to be more aggressive than are papillary or chromophobe cancers [22
]. Although the diagnostic capabilities of percutaneous renal biopsy are improving, they are not perfect. If obese patients are definitively shown to be at an increased risk for clear-cell RCC, providers might be more aggressive in treating these patients and less inclined to actively survey them.
Our study has some limitations; it is a retrospective case series, and as such lacks a control group. Our results could be explained by a lower prevalence of non-clear-cell histological subtypes in obese patients rather than higher prevalence of the clear-cell variant. However, we consider this explanation to be unlikely, given the well documented association between obesity and increased risk of RCC in general. As the Memorial Sloan-Kettering Cancer Center is a tertiary-care centre, this study is subject to referral/selection bias. BMI was calculated by height and weight at one point in time (just before surgery); weights can certainly fluctuate over time. Our findings need to be corroborated by others before strong conclusions are made about the importance of this association with clear-cell RCC and obesity.
In conclusion, BMI appears to be an independent predictor of conventional clear-cell histology in patients undergoing removal of a renal cortical tumour. As BMI increased, the odds of having a clear-cell RCC also increased. Although the mechanism of pathogenesis requires further study, this finding might have implications in determining a patient's risk of harbouring a clear-cell RCC and in subsequent treatment recommendations.