Etiologic heterogeneity of clear‐cell and papillary renal cell carcinoma in the Netherlands Cohort Study

At present, mostly case‐control and retrospective studies have investigated the association between etiologic risk factors and the development of histologic subtypes of renal cell carcinoma (RCC). Therefore, we assessed the heterogeneity between body mass index (BMI), cigarette smoking, alcohol consumption and hypertension across clear‐cell RCC (ccRCC) and papillary RCC (pRCC) risk in the prospective Netherlands Cohort Study on diet and cancer. In 1986, 120 852 participants aged 55 to 69 completed a self‐administered questionnaire on diet and other risk factors for cancer. Participants were followed up for cancer through record linkage. Tumor histology was assessed through centralized revision by two experienced uropathologists. After 20.3 years of follow‐up, 384 histologically verified RCC cases, including 315 ccRCC and 46 pRCC cases and 4144 subcohort members were eligible for case‐cohort analysis. Hazard ratios and 95% confidence intervals were estimated by multivariable‐adjusted proportional hazards models. Overall, BMI was associated positively with ccRCC risk, but inversely with pRCC risk. Cigarette smoking was associated with an increased ccRCC, but a decreased pRCC risk. Alcohol consumption was inversely associated with both ccRCC and pRCC risk. Hypertension was associated with an increased risk of both ccRCC and pRCC. Statistically significant etiologic heterogeneity was observed for BMI, BMI change since age 20, and smoking duration in current smokers across ccRCC and pRCC risk. In conclusion, we observed potential heterogeneity for BMI, BMI change and smoking duration across ccRCC and pRCC risk. What's new? Etiologic risk factors for clear cell renal cell carcinoma (ccRCC) and papillary renal cell carcinoma (pRCC) include alcohol consumption, body mass index (BMI), cigarette smoking, and hypertension. Little is known, however, about variability in how these factors affect the development of RCC histologic subtypes. In this population‐based prospective cohort study, examination of variability in associations between established etiologic factors and RCC histologic subtypes revealed significant heterogeneity between BMI and ccRCC and pRCC risk and between risk of these subtypes and smoking duration in current smokers. The findings provide novel insight into relationships between etiologic heterogeneity and mechanisms of RCC development.