The present study examined associations between cigarette smoking and bladder cancer subtypes at diagnosis. Regardless of the exposure index under examination (smoking status, number of cigarettes per day, or number of years of smoking), risks associated with cigarette smoking were higher for invasive tumors.
Some11-13, 18, 19
, but not all20-23
, studies have found that bladder cancer among smokers is often more invasive than it is among nonsmokers. In some studies12
, age appeared to modify this association with the association limited to or more pronounced among younger individuals (<60 years old). Among the studies that did not observe an impact of smoking on tumor invasiveness, two studies found that smokers had poorer prognosis20, 23
. Most of these studies were based on simple comparisons of a small number of subjects and none of these studies formally tested for the heterogeneous effect of smoking. By far, the largest study was that of Sturgeon et al18
, which found that risks of each stage of bladder cancer (invasive, noninvasive) increased with number of cigarettes smoked per day, but the more advanced the stage the higher the relative risk. Similarly, in this study we found that smokers were proportionally more likely than nonsmokers to be diagnosed with invasive disease and this difference was statistically significant.
The exact mechanism of bladder carcinogenesis in smokers remains unknown. Allelic loss on chromosome 9 has been reported as an early lesion in the development of bladder cancer and does not distinguish between different subtypes of tumors24
. Other events may occur during independent evolution of different tumor sub-clones. Experimental studies have observed distinctive genetic defects in subtypes of bladder cancer: the low-grade non-invasive papillary tumors are characterized by activating mutations in the FGFR3 gene, while the high-grade invasive tumors are characterized by structural and functional defects in the p53 and RB protein tumor-suppressor pathways2
. Tumor invasion is promoted by over-expression of COX-2, a downstream target of p53 that regulates cell growth, angiogenesis, immune surveillance and apoptosis. Zhang et al.25
found that chromosome 9 alterations were more common in smokers compared to those in nonsmokers. Chromosome 9p21 has been found to be a molecular target for damages induced by benzopyrene diolepoxide (BPDE), the metabolic product of benzopyrene, a constituent of tobacco smoke26
. Smoking seems to affect the pattern of Tp53 mutations, but have no effect on the incidence and pattern of FGFR3 mutation27
. Consistently, occupational exposure to polycyclic aromatic hydrocarbons, which are also commonly found in cigarette smoke, did not influence the frequency or spectrum of FGFR3 mutations28
. These observations support our findings that even though cigarette smoking was associated with an increased risk of all subtypes of bladder cancer, possibly by inducing alterations in chromosome 9, a stronger effect was observed for invasive tumors which are characterized by p53 mutations.
The above hypothesis is strengthened by the observation that the heterogeneity of smoking’s effect was attenuated among regular users of NSAIDs, which function to inhibit COX-2. The presence of a wild-type p53 is known to suppress COX-2 transcription, and the loss or mutation of p53 up-regulates the expression of COX-2 29
. If the heterogeneous effect of smoking functions by deactivating the p53 pathway therefore leading to over-expression of COX-2, use of NSAIDs may counteract, at least partially, this heterogeneous effect by blocking COX-2 activity. Consistent with this notion, we found that the gender-smoking interaction was limited to invasive diseases. In rabbit studies, estrogen deficiency induces a significant decrease in prostaglandin E2
, one of COX-2’s enzymatic products, in the urinary bladder mucosa and estrogen treatment restored the level of prostaglandin E230
. It has been reported that estrogen stimulates prostaglandin synthesis by activating COX-231, 32
. Therefore, it is possible that through COX-2, estrogen may promote the progression of bladder tumor.
Alternatively, the heterogeneous effect of smoking can be due to different surveillance for smokers. Compared with nonsmokers, cigarette smokers might be less likely to seek medical care, thus more likely to be diagnosed with higher grade and/or more invasive bladder cancer. One Japanese study19
found that, at the time of diagnosis, current smoker were more likely to be diagnosed at a higher stage and have larger tumor size than nonsmokers; however, there were no differences between smokers and nonsmokers in initial symptoms, indicating that the difference in diagnosis was not likely due to delayed presentation of smokers to medical attentions.
While the present study has several strengths including population-based design, relatively large sample size, and well characterized risk/protective factors, a potential weakness is the fact that the bladder cancer histology was recorded by trained personnel from pathology reports and was not determined by a single reference laboratory. The various grading schemes used by pathologists who produced the original pathology reports can be a source for misclassification. Since it is unlikely the pathologist would know the status of the exposures we measured, the variations in grading schemes is most likely to bias results to the null and lead to false negative findings. This misclassification is unlikely to result in differential effects of exposures such as cigarettes by stage at diagnosis as we observed here. In addition, by reviewing individual pathology reports, we were able to separate Ta from CIS, which is not possible if relying on SEER registry data alone. Another potential limitation of our study is the confinement in case selection to relatively younger cases of bladder cancer, making our findings not directly applicable or generalizable to patients diagnosed at older ages. Finally, some of our subgroup analyses, especially those conducted among women and regular users of NSAIDs, were based on very small numbers; so interpretation must be cautious.
In summary, this study reported a higher risk associated with cigarette smoking for invasive bladder tumors than for superficial tumors. Studies with bigger sample sizes are needed to confirm these findings and to understand the molecular pathways that might explain the observed heterogeneity by cancer subtypes.