Introduction

Renal cell carcinoma (RCC) is one of the most common tumors in the urinary system, with its incidence increasing annually1. Clear cell renal cell carcinoma (ccRCC) accounts for approximately 80% of all RCC cases2. Typically, ccRCC is characterized by the abnormal accumulation of lipid droplets within tumor cells, which is closely related to the unique mechanism of lipid metabolism within these tumors3.

Obesity is defined by the World Health Organization (WHO) as an abnormal or excessive fat accumulation that presents a risk to an individual’s health4. It is characterized by a high body mass index (BMI), a simple weight-for-height index commonly used to classify overweight and obese adults. In recent years, the number of individuals affected by obesity has increased globally. The increase in obesity rate is a significant public health concern because of its association with numerous health complications, including heart disease, diabetes, and certain types of cancer5.

Previous studies have highlighted obesity as a risk factor for developing RCC6,7,8,9. Recent cohort studies across different ethnic groups in epidemiology have demonstrated that the hazard ratio for the obese population versus the normal-weight population was 2.16 and 1.77, respectively6,10. However, it is paradoxical that many studies have found that obesity is associated with a better prognosis in patients with RCC11,12. Several researchers suggest that the “obesity paradox” may be associated with immunity, metabolism, epigenetic alterations, and tumor microenvironment reshaping7,13,14,15. However, the mechanism of the “obesity paradox” in RCC remains unclear.

Furthermore, although transcriptomic signatures related to the “obesity paradox” in patients with ccRCC have been documented16, and some studies have reported associations between BMI and general pathological features such as tumor stage and grade17,18,19, the specific relationship between BMI and detailed pathological indices, including renal capsular invasion, sinus fat invasion, and vein embolus, remains understudied. Therefore, in this study, we performed a detailed analysis of the potential associations between BMI and the clinicopathological features of clinically localized renal masses in a large cohort.

Patients and methods

Cohort

We reviewed the records of patients who underwent partial or radical nephrectomy for renal masses between 2013 and 2023 at Changhai Hospital, the First Affiliated Hospital of Naval Medical University, Shanghai, China. The study was approved by the Institutional Review Board. Due to the retrospective nature of the study, the First Affiliated Hospital of Naval Medical University Ethics Committee waived the need of obtaining informed consent. Patients with pathological subtypes other than ccRCC, distant metastases, or incomplete data were excluded. A total of 2541 patients with pathologically confirmed ccRCC were included in the final cohort eligible for the current analysis.

The patients were divided into three groups based on the Chinese BMI classification20,21. The groups included normal-weight (BMI<24), overweight (24 ≤ BMI<28), and obese (BMI ≥ 28). The pathological variables compared among these groups included pathological tumor diameter, pathological T (pT) stage, Fuhrman, or WHO/ International Society of Urological Pathology (ISUP) grades, renal capsular invasion, perirenal or renal sinus fat invasion, and vein cancerous embolus. The pT stage was divided into eight categories, pT1a, pT1b, pT2a, pT2b, pT3a, pT3b, pT3c, and pT4. The Fuhrman and WHO/ISUP grades were merged into one variable, as almost all patients had one or the other grade to evaluate nuclear morphometry. Notably, patients in earlier years were more likely to have Fuhrman grades, while others tended to use the WHO/ISUP grades. The WHO/ISUP grade was preferred for inclusion if a patient had both grades. The variable representing vein cancerous embolus indicated the presence of either renal venous or vena cava thrombosis.

Statistical analysis

The retrieved variables included patient sex, age, height, weight, BMI, pathologic tumor size, pT stage, Fuhrman grade, WHO/ISUP grade, renal capsular invasion, perirenal or renal sinus fat invasion, and vein cancerous embolus. Normally distributed continuous variables were compared using the Student’s t-test or one-way ANOVA, while categorical variables were analyzed using the chi-square or Fisher’s test. Continuous variables were reported as the median and interquartile range (IQR), while categorical variables were denoted as absolute numbers (n) with relative percentages (%). All tests were two-tailed, with a significance level set at p < 0.05. Statistical analyses were performed using IBM SPSS Statistics version 20.

All methods of this study were performed in accordance with the relevant guidelines and regulations.

Results

Baseline characteristics of the study cohort

Of the 3856 available records, 2541 met the inclusion criteria and were reviewed after obtaining Institutional Review Board approval. The baseline characteristics of the entire cohort are presented in Table 1. The median age and BMI were 58 (50–67) years and 24.9 (22.7–27.0) kg/m2, respectively. The male-to-female ratio was 2.5:1. Moreover, 424 (16.7%) patients were smokers, 1119 (44.0%) had a diagnosis of hypertension, and 381 (15.0%) had a diagnosis of diabetes. Based on the Chinese BMI classification, 1000 (39.4%), 1096 (43.1%), and 445 (17.5%) patients were divided into normal-weight, overweight, and obese groups, respectively. Notably, the male-to-female ratio (p < 0.001) and smoking rate (p < 0.01) were higher, and comorbidities such as hypertension (p < 0.001) and diabetes (p < 0.01) were more prevalent in the overweight and obese groups than in the normal-weight group. The American Society of Anesthesiologists (ASA) score, used to assess preoperative fitness, showed no significant differences between the groups.

Table 1 The baseline characteristics of the entire cohort.
Full size table

Correlation between BMI and pathological diagnosis in patients with ccRCC

Pathological parameters were compared among the three BMI groups, and the results are shown in Table 2. No significant association was found between pathological tumor diameter and BMI among the normal-weight, overweight, and obese groups (normal-weight vs. overweight, p = 0.31; normal-weight vs. obese, p = 0.21). No statistical difference was observed in the pT stage (normal-weight vs. overweight, p = 0.28; normal-weight vs. obese, p = 0.23). However, there were significant differences in the distribution of Fuhrman/ISUP grade, proportion of patients with renal capsular invasion, perirenal fat or renal sinus fat invasion, and vein cancerous embolus confirmed by pathology between the normal-weight and obese groups. However, there was no statistical difference in the distribution of Fuhrman/ISUP grade (p = 0.12), the proportion of patients with renal capsular invasion (p = 0.49), perirenal or renal sinus fat invasion (p = 1.00), or vein cancerous embolus (p = 0.11) between the normal-weight and overweight groups. Furthermore, patients in the obese group tended to have low Fuhrman or WHO/ISUP grades (p < 0.001), and decreased rates of renal capsular invasion (p < 0.05), perirenal fat or renal sinus fat invasion (p < 0.05), and vein cancerous embolus (p < 0.05).

Table 2 Comparison of pathological parameters among the three BMI groups.
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Discussion

The incidence of RCC has increased in recent years, and obesity, a known risk factor for RCC, is becoming increasingly common. An intriguing paradox exists wherein obesity not only increases the risk of developing RCC but is also associated with a better prognosis in patients with RCC. The mechanism of this “obesity paradox” in RCC is poorly understood. However, the correlation between BMI and the characteristics of RCC remains controversial. Considering the confounding factors caused by different subtypes that usually correspond to varying degrees of malignancy22,23, we aimed to investigate the association between BMI and the clinicopathological characteristics of ccRCC, the most common RCC subtype. We compared pathological characteristics—including pathological tumor diameter, pT stage, Fuhrman or WHO/ISUP grade, renal capsular invasion, perirenal fat or renal sinus fat invasion, and vein cancerous embolus which are closely associated with the prognosis in patients with RCC treated with surgery, among the patients classified into normal-weight, overweight, and obese groups based on the Chinese BMI classification.

Notably, in our cohort, the mean age of the obese group was 55 years, which was lower compared to other groups. The overweight and obese groups also exhibited higher male-to-female ratios. Peired et al.24 revealed that males are twice as likely to develop kidney cancer as females. In our study, males accounted for over three times the number of females in both the overweight and obese groups and roughly twice the number in the normal-weight group. This suggests that RCC susceptibility to sex may be amplified by a high BMI. Sun et al.25 suggested that estrogen plays an important role in the etiology of RCC and may modify the association between obesity and RCC risk in women. Moreover, we found that the overweight and obese groups had a higher proportion of smokers than the normal-weight group. This trend extended to comorbidities such as hypertension and diabetes, with overweight and obese patients being more prone to smoking and these health conditions. However, no significant difference was observed in the ASA score, which was used to evaluate the preoperative fitness of patients.

Regarding pathological diagnosis, our study did not reveal significant differences in pathological tumor diameter or pT stages among the normal-weight, overweight, and obese groups, which is consistent with the findings of Tsivian et al.18 However, Choi et al.26 revealed that overweight and obese patients had smaller tumors in a clinical cohort of 1543 patients with RCC. Jeon et al.19 reported that these patients had a lower pT stage than normal-weight patients. In addition, we demonstrated a significant difference in the distribution of tumor nuclear grades, as evaluated by the Fuhrman or WHO/ISUP grades. Specifically, high BMI was associated with low nuclear grade in patients with ccRCC. The obese group had a significantly higher rate of low nuclear grade than the normal-weight group, whereas the overweight group exhibited a higher rate of low nuclear grade, though this difference was not statistically significant. This finding is consistent with Tsivian et al.’s study, that included all kidney cancer subtypes18. They revealed that a higher BMI was associated with a lower Fuhrman grade of RCC in clinically localized renal masses, and partly explained the better survival rates in patients with higher BMI. Although Seon et al.27 did not find any significant association between nuclear grade and BMI in a cohort of 2329 patients who underwent curative surgery for RCC, they reported that 55.6% of patients with Fuhrman grade 1–2 were in the normal-weight group, 58.8% in the overweight group, and 61.6% in the obese group (p = 0.062). Furthermore, we found that the rates of renal capsular invasion, perirenal fat or renal sinus fat invasion, and vein cancerous embolus were significantly lower in the obese group than in the normal-weight group. No significant difference was observed between the overweight and normal-weight groups. According to available research28,29,30,31,32,33, the presence of renal capsular invasion, perirenal fat or renal sinus fat invasion, or vein cancerous embolus is strongly associated with RCC prognosis after surgery, especially in terms of overall survival and postoperative local recurrence or distal metastasis.

To the best of our knowledge, this is the first study to report an association between BMI and renal capsular invasion, sinus fat invasion, and vein embolus, which are key pathological indices influencing the prognosis of patients with RCC. Many studies have shown that obese patients with RCC have longer overall survival and cancer-specific survival6,11,27,34, including those with metastatic RCC35,36. A prospective trial conducted by Donin et al.37 revealed that obese patients had significantly improved overall survival compared with normal-weight patients in a cohort of high-risk patients with RCC from 14 countries. Nevertheless, the mechanism of the “obesity paradox,” where obesity increases the risk of developing RCC while being associated with a better prognosis, remains unclear. Our findings may partly explain the better prognosis in patients with higher BMI and “obesity paradox” in RCC. Obese patients showed less aggressive pathological features, such as low tumor nuclear grade and low rates of renal capsular invasion, perirenal fat or renal sinus fat invasion, and vein cancerous embolus, and therefore presented better overall survival and cancer-specific survival outcomes.

The results of our study should be carefully interpreted and prospectively validated because of some limitations. First, the retrospective nature of the study could have introduced an inherent selection bias. For instance, 3856 records of patients with ccRCC were available; however, 1315 records were excluded because of incomplete data. In addition, the BMI data was preoperative, and we did not consider BMI changes in the early years of surgery or postoperative BMI changes. Second, our cohort spanned over ten years, which could have introduced unintended errors in data collection and inconsistencies in recording indices. For example, the Fuhrman grade was preferred to evaluate tumor nuclear grade in early years, while the WHO/ISUP grade was preferred in recent years. Third, the differences in background characteristics such as age, sex, smoking status, and comorbidities between the groups may confound the causal relationship between obesity and pathological features to some extent. Last, some noteworthy pathological variables, such as sarcomatoid differentiation, tumor necrosis, and pathological nodal stage, were not included in our analysis for various reasons, potentially limiting our conclusions.

Conclusions

Our study found that obesity was associated with less aggressive pathological features in a large cohort of patients with ccRCC, such as low tumor nuclear grade, low rate of renal capsular invasion, perirenal fat or renal sinus fat invasion, and vein cancerous embolus. This finding may provide clinicopathological evidence and explanations for the “obesity paradox” of RCC.