Tobacco smoking is a well recognizedmodifiable risk factor for renal cell carcinoma (RCC), but not for all RCC histologicsubtypes, according to researchers. 

In a study of 816 patients undergoingnephrectomy, a team led by EricC. Kauffman, MD, of the RoswellPark Cancer Institute in Buffalo, discoveredthat smoking is a risk factorfor clear cell and papillary RCC(ccRCC and pRCC, respectively), butnot chromophobe RCC (chRCC).Using propensity analyses adjustingfor multiple variables, active smokingwas independently associated with asignificant 2.2 and 2.4-fold increasedodds of ccRCC and pRCC, respectively,Dr. Kauffman’s group reported in TheJournal of Urology (2015;194:640-646). 

According the investigators, their studyprovides the first demonstration thatsmoking, the most important modifiablerisk factor for RCC, increases the riskof certain common RCC subtypes butnot others. “These findings underscorethe distinct carcinogenic mechanismsunderlying RCC subtypes, including adifferential effect of tobacco carcinogens,”they concluded. “Important inthis regard may be tobacco induced oxidativestress injury to the renal proximaltubule, the presumed origin of ccRCCand pRCC but not chRCC.” 

Dr. Kauffman and his colleagues saidthe new findings may be clinically usefulin predicting renal tumor histologicsubtype. Given the lower metastaticpotential of chRCC compared withpRCC and ccRCC, knowledge of thehistologic subtype “can aid in clinicalrisk stratification, including amongolder or sicker patients with early stagerenal tumors who are debating surgicalresection vs active surveillance.” 

The authors noted that the mechanismsby which tobacco might promotedevelopment of RCC are unclear.“Oxidative stress injury with smokingmediated by increases in local hypoxiaand reactive oxygen species couldexplain the risk of ccRCC and pRCCand not chRCC,” they wrote. 

They pointed out that the associationof smoking with angiogenesis mightalso contribute to ccRCC tumorigenesis.“Nicotine is known to increase endothelialcell number, capillary networkformation, and angiogenic response inneoplasia, mediated in part by the vascularendothelial growth factor proteincommonly up-regulated in ccRCC.” 

Dr. Kauffman’s team acknowledgedstudy limitations, including the retrospectivestudy design and restriction to asingle institution and geographic region.Additionally, they noted, smoking maybe associated with confounding variablesthat affect RCC risk but were not measured,including a history of hypertension. 

Of the 816 patients in the study, 705had nonfamilial RCC and 111 hadbenign pathology and 51% reportedsmoking (21% active smokers and 30%former smokers). 

The new study adds to a growingnumber of recent investigations characterizingthe different RCC histologicsubtypes and their associated riskfactors. For example, researchers atVanderbilt University Medical Centerin Nashville, Tenn., studied RCCtumors from 1,532 patients who underwentnephrectomy and found a substantiallyhigher proportion of patientswith pRCC among black patients thanwhite patients, according to a paperpublished online ahead of print in BJUInternational. Additionally, patientswith chRCC were significantly morelikely to be female. In a separate studyof 487 RCC patients, also publishedin BJU International (2014;114:496-502), researchers demonstrated thatincreased visceral fat was associatedwith ccRCC, and visceral fat areaoutweighed the effects of body massindex (BMI) and type 2 diabetes forpredicting RCC pathology in multivariateanalyses.

Additionally, a SouthKorean study of 2,769 patients withnon-metastatic RCC demonstratedthat higher BMI was associated withgreater recurrence-free survival (RFS)and cancer-specific survival (CSS) ratesamong patients with ccRCC and lowerRFS and CSS rates among those withchRCC, according to a findings publishedin Clinical Genitourinary Cancer(2015;13:461-468). The study found noassociation between BMI and RFS orCSS in patients with pRCC.