http://orcid.org/0000-0002-2368-1326
Figures
Abstract
Objective
To explore the relation between cigarette smoking intensity and bladder cancer aggressiveness at first diagnosis.
Methods
Patients diagnosed with urinary bladder cancer (BC) between 1995–2011 under the age of 75 years were retrospectively identified from the Netherlands Cancer Registry and invited for a study on genetic and lifestyle risk factors for BC. Information on patients’ self-reported smoking history was retrieved by means of a postal questionnaire. Tumors were stratified regarding the risk of progression defined by tumor stage and grade. Multinomial logistic regression was used to analyze the relation between smoking intensity and aggressiveness of the tumor.
Results
The UBC study population comprised 323 (17.4%) never smokers, 870 (46.8%) former cigarette smokers, and 630 (33.9%) current cigarette smokers. A higher smoking amount was a risk factor of getting high-risk non-muscle invasive bladder cancer (NMIBC) compared with low-risk NMIBC in ever and former cigarette smokers (OR: 1.02 per cigarette smoked, 95% CI: 1.00–1.03 and OR: 1.03, 95% CI: 1.01–1.05, respectively). A statistically significant dose-response increase in the risk of a more aggressive cancer type (high-risk NMIBC and MIBC) was observed with increasing smoking duration among former smokers (p for trend 0.035 and 0.008, respectively). No significant association of the evaluated smoking intensity variables was observed in current smokers. A longer time of smoking cessation correlated with a lower odds of a more aggressive cancer.
Conclusion
We observed a weak increase in the risk of a more aggressive tumor type with increasing smoking intensity in former smokers, but this association was absent in current smokers.
This conflicting result may suggest that there is no strong relation between smoking intensity and bladder cancer aggressiveness. Analyses of prospective studies with longitudinal smoking assessment may provide a more definitive answer to the research question.
Citation: Barbosa ALA, Vermeulen SHHM, Aben KK, Grotenhuis AJ, Vrieling A, Kiemeney LA (2018) Smoking intensity and bladder cancer aggressiveness at diagnosis. PLoS ONE 13(3): e0194039. https://doi.org/10.1371/journal.pone.0194039
Editor: Francisco X. Real, Centro Nacional de Investigaciones Oncologicas, SPAIN
Received: October 2, 2017; Accepted: February 25, 2018; Published: March 23, 2018
Copyright: © 2018 Barbosa et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: The data have been made publicly available thru the Data Archiving and Networked Services (DANS-EASY) and can be accessed via the link http://dx.doi.org/10.17026/dans-2a6-ate2.
Funding: The author(s) received no specific funding for this work.
Competing interests: The authors have declared that no competing interests exist.
Introduction
Worldwide, urinary bladder cancer (BC) is the fifth most prevalent type of cancer among men, while it ranks twelfth among women [1]. In high income countries, >90% of all BC are urothelial cell carcinomas (UCC), the remaining mainly being squamous cell, adeno or small cell carcinomas [2]. BC comprises a heterogeneous group of tumors that arise by different molecular pathways. Relatively benign, low grade papillary tumors are characterized by loss of heterozygosity of chromosome 9 and mutations in FGFR3, PIK3CA and STAG2. Muscle-invasive bladder cancer (MIBC) commonly shows TP53 mutations and RB1 defects. Carcinoma in situ (CIS) and a small part of the T1 tumors may have the same characteristics as MIBC [2]. Approximately 75% of patients with BC present with a tumor confined to the mucosa or submucosa of the bladder wall, i.e., non-muscle-invasive bladder cancer (NMIBC), characterized by a relatively good prognosis but high relapse rate. On the other hand, the 25% of patients with MIBC (including metastatic disease) are at considerable risk of cancer-specific mortality [3–5].
Tobacco smoking, occupational exposure to aromatic amines and other carcinogens, genetic factors, pelvic radiation therapy, and cyclosphosphamide chemotherapy are risk factors for UCC [6]. Schistosomiasis infection and chronic inflammation secondary to bacterial infections, indwelling catheters, bladder calculi or chronic bladder outlet obstruction are also risk factors, although more related to squamous cell carcinoma (SCC) [7,8]. Smoking is recognized as the most important risk factor for BC and is estimated to account for 50% of all tumors [9]. Tobacco contains multiple carcinogens, such as 4-aminobiphenyl, 2-naphthylamine, and aromatic amines which are associated with BC induction in smokers [10]. The risk of bladder cancer increases with the number of cigarettes and years smoked [11].
Some studies suggest that a higher intensity of smoking is significantly related to a more aggressive bladder tumor at diagnosis [12–19], while other studies found no association between smoking intensity and grade or stage of the tumor [20–28]. Table 1 summarizes the current evidence on the relation between smoking intensity and tumor characteristics. If a relation between the amount and duration of smoking and tumor aggressiveness exists, it may improve the doctor’s ability to identify patients at risk of a more severe tumor type. Also, it may be one more reason to stimulate counseling for smoking cessation. This study explores the association between the intensity of smoking and the aggressiveness of UBC at first diagnosis in a large population-based BC series from the Netherlands.
Materials and methods
Study population
This study used data from the Nijmegen Bladder Cancer Study (NBCS). This study population has been described in more detail previously [29]. Briefly, BC patients diagnosed between 1995–2011 under the age of 75 years in the mid-eastern part of the Netherlands were identified through the Netherlands Cancer Registry (NCR) held by the Netherlands Comprehensive Cancer Organization (IKNL) and contacted via their treating physicians.
Patients who consented to participate in the study were asked to fill out a lifestyle questionnaire, including questions on education, occupation, medical history, physical activity, and complete history of smoking. Furthermore, blood samples were collected by Thrombosis Service centers, which hold offices in all the communities in the region. The study was approved by the institutional review board of the Radboud university medical center, Nijmegen, The Netherlands (CMO Arnhem-Nijmegen).
Smoking assessment
Information on smoking history was obtained via the lifestyle questionnaire. Patients were asked for their smoking status at recruitment, age at smoking initiation and cessation, number of cigarettes, pipes and cigars smoked per day and duration of smoking in years. The timing of smoking cessation with respect to the diagnosis was calculated as age at diagnosis minus age at cessation. Smoking status at diagnosis was classified as never smoker, former smoker (quitted >1 year before diagnosis), current smoker (continuing cigarette smoker or quitted ≤ 1 year before diagnosis). The cutoff point of 1 year before diagnosis was chosen for 2 reasons. First, because we believe that most patients with early symptoms will be diagnosed within a year, and second because a change in smoking habits in the year before diagnosis will probably not have any major effect on bladder cancer aggressiveness. Ever smokers were defined as the combination of former and current smokers. In the current smokers group, only the smoking period in years before the diagnosis was considered. Smoking amount was evaluated as cigarettes per day. Cumulative smoking exposure (in pack-years) was calculated by multiplying the cigarette smoking duration and packages per day (20 cigarettes representing one package). Pipe and/or cigar smoking (5.9% of all patients) was ignored in the main analyses, assuming that the majority of Dutch pipe and cigar smokers do not inhale the smoke [30].
Outcome assessment
Detailed clinical data concerning age at diagnosis, tumor stage, tumor grade, tumor number (single or multiple), tumor size (<3cm and ≥ 3cm), presence of concomitant CIS, and histological type were collected through a medical file survey. Tumor stage and grade were recorded according to the final conclusion in the pathology report. Tumors with WHO 1973 differentiation grade 1 or 2, WHO/ISUP 2004 low grade, or Malmström (Modified Bergkvist) grade 1 or 2a were considered low-grade tumors. We classified tumors with WHO 1973 differentiation grade 3, WHO/ISUP 2004 high grade, or Malmström (Modified Bergkvist) grade 2b or 3 as high-grade [31,32]. Tumor aggressiveness was classified according to the risk of progression as follows: low-risk NMIBC (low-grade Ta tumors), high-risk NMIBC (all stage T1 tumors, all high-grade tumors, or CIS) and MIBC (stage ≥ T2 or any stage with ≥N1 and/or M1) [33].
Statistical analysis
Patient and tumor characteristics were compared between the smoking status categories using chi-square, Fisher exact, and one-way analysis of variance (ANOVA) tests where appropriate. Because it is generally believed that there is no ‘no effect level’ in the relation between smoking and the risk of cancer, we analyzed the dose of smoking using continuous variables. The distribution of continuous smoking variables was compared between the categories of tumor multiplicity and tumor aggressiveness and tested for statistical significance using the non-parametric Kruskal-Wallis test. Multinomial logistic regression was used to analyze the relation between smoking intensity and aggressiveness of the tumor with adjustment for gender and age at diagnosis. Low-risk NMIBC was considered as the reference group. We repeated similar analyses for tumor multiplicity as the dependent variable using solitary tumors as the reference group. The association of each smoking intensity variable (smoking amount, smoking duration and cumulative smoking exposure), age at smoking initiation, and time since smoking cessation was assessed separately in ever, former and current smokers. Statistical analysis was performed using IBM SPSS Statistics for Windows 20 (IBCM Corp., Armonk, NY, USA) with a p value < 0.05 indicating statistical significance. The data have been made publicly available thru the Data Archiving and Networked Services (DANS-EASY) and can be accessed via the link http://dx.doi.org/10.17026/dans-2a6-ate2.
Results
A total of 1859 BC patients were included in the study. The majority of the patients were men (81.1%). The mean age at diagnosis (SD) was 62.4 (±9.7). Never cigarette smokers represented 323 (17.4%) of all patients, former cigarette smokers 870 (46.8%), and current cigarette smokers, 630 (33.9%). Of all patients, only 40 had a non-UCC histology. Because their smoking distribution was quite similar (Never 25%, Former 40% and Current 30%) to that of the UCC patients, we decided not to exclude these 40 patients. A comparison of patient and tumor characteristics by smoking status is shown in Table 2. The groups differ from each other in age at diagnosis, gender, history of cigar or pipe smoking and tumor stage.
Table 3 shows the distribution of smoking variables in different tumor aggressiveness groups and different tumor multiplicity groups, by smoking group. In former cigarette smokers, there is a significant difference in the smoking amount, smoking duration and cumulative smoking in the subgroups of aggressiveness. The median of smoking amount is higher in the high-risk NMIBC compared with low-aggressive NMIBC, but lower in MIBC. In former smokers, smoking duration is highest in patients with MIBC and lowest in patients with low risk NMIBC. The median time since smoking cessation was highest in patients with low-risk NMIBC and lowest in patients with MIBC. In ever and current cigarette smokers, there was no difference in the distribution of smoking variables between the subgroups of aggressiveness. There doesn’t seem to be a strong correlation between smoking and tumor multiplicity. If anything, only current smokers may have more frequently solitary tumors.
In multinomial regression analyses with adjustment for age at diagnosis and gender (Table 4), smoking amount was a risk factor of getting high-risk NMIBC compared with low-risk NMIBC in ever and former cigarette smokers (OR: 1.02 per cigarette smoked a day, 95% CI: 1.00–1.03 and OR: 1.03, 95% CI: 1.01–1.05, respectively). Smoking duration was a risk factor for MIBC compared with low-risk NMIBC in ever and former cigarette smokers (OR per year smoked: 1.01, 95% CI: 1.00–1.03 and OR: 1.02, 95% CI: 1.00–1.04, respectively). Time since smoking cessation was a protective factor in both comparisons, i.e., a longer time of smoking cessation leads to a lower odds of a more aggressive cancer. Smoking intensity variables were not significantly related to tumor aggressiveness in current cigarette smokers. By contrast, only in current smokers there seems to be an association between smoking duration and tumor multiplicity suggesting that a longer smoking history leads to a higher risk of solitary tumors.
Table 5 presents the results from multinomial logistic regression after including smoking duration as a categorical instead of continuous variable. A longer smoking duration is associated with higher risks of MIBC compared with low-risk NMIBC mostly in ever and former cigarette smokers (p value for trend: 0.004 and 0.008, respectively). Comparing high-risk NMIBC with low-risk NMIBC, there is a higher odds ratio with increasing smoking duration until 30 years. Thereafter, the risk remains the same or even decreases. In former smokers, there is a significantly increasing trend (p value: 0.035).
Discussion
The present study was performed with the goal of examining the association between smoking intensity and tumor aggressiveness. Different aspects of smoking intensity were evaluated such as smoking amount in cigarettes per day, smoking duration and cumulative smoking in pack-years. Significant but weak positive associations were found in ever cigarette smokers concerning smoking amount and smoking duration. When the ever cigarette smokers were separated in former and current cigarette smokers, inconsistent results were found. In the subgroup of former cigarette smokers, the same relations were found as in ever cigarette smokers, but in the subgroup of current cigarette smokers no clear relation was found. Apparently, the results in ever smokers were driven by those in former smokers only. In the analyses of tumor multiplicity the reverse was seen. Only in current smokers, there was a significantly lower risk of multiple tumors with a longer smoking history.
Among ever smokers, smoking amount was a significant risk factor for high-risk NMIBC compared with low-risk NMIBC, but not for MIBC compared with low-risk NMIBC. The same holds true with smoking duration among ever and former smokers and cumulative smoking in former smokers. These conflicting results suggest that the relation between smoking intensity and tumor aggressiveness is probably weak or even just a chance finding. Previous studies [20–28] showed no dose-response relations between tumor characteristics and smoking intensity, supporting our findings.
Jiang et al. [15] combined tumor grade and stage to classify tumor aggressiveness and found that the risk of more advanced tumors was positively associated with smoking duration and smoking intensity. Unfortunately, the authors did not make a distinction between former and current cigarette smokers like we did.
In our study, a longer time of smoking cessation was associated with a lower risk of an aggressive bladder cancer. In contrast, Jiang et al. [15] showed that an increasing number of years since quitting leads to a decreased risk of UBC, but there was no difference among subgroups of tumor aggressiveness.
FGFR3 mutations are associated with low-grade and low-stage tumors while TP53 mutations are associated with high-grade and high-stage tumors [2,34]. If smoking leads to different mutations in these or other stage-related genes, then it would be logical to find an association between smoking and disease aggressiveness. It has been shown in lung cancer, based on data from The Cancer Genome Atlas (TCGA), that smoking induces specific gene mutations [35]. However, this does not seem to be the case in bladder cancer. In The Cancer Genome Atlas there was no statistically significant association between smoking status and the mutational spectrum, frequency of mutation in any significantly mutated gene, occurrence of focal somatic CNAs or expression subtype in 131 muscle invasive bladder cancers (although it is not clear from the paper how ‘smoking’ was phenotyped). However, a major subtype of MIBC (‘CIMP’) was identified by unsupervised cluster analysis that has high-level promoter hypermethylation associated with the number of pack-years smoking [36]. In a follow-up paper describing a larger number of tumors (N = 409) somewhat more ERCC2 signature mutations are found among smokers [37]. A small study from Canada showed that TP53 mutations are more common with increasing years of smoking, although not more common with increasing numbers of cigarettes smoked [38].
McConkey et al. [39] and other groups have recently suggested a new molecular subclassification of bladder cancer related with distinct patterns of progression and response to conventional chemotherapy. It is possible that this new classification is stronger related to the intensity of smoking. Indeed, in a recent study, again based on TCGA, it was shown that patients with the more aggressive basal-like subtypes, started smoking earlier than patients with a luminal subtype [40]. Unfortunately, we were unable to examine this in our study.
A strength of the present paper is its large sample size. A weakness is that the NBCS had a retrospective design which means that prevalent cases were recruited for the study. Especially patients with more severe disease may have deceased prior to recruitment. The time lag between diagnosis and study enrollment was up to 12 years. The absence of prevalent patients that failed to survive until the sampling date has resulted in a study population biased towards favorable tumor aggressiveness. In theory, this may have biased the effect size estimates and thereby the ability of our study to identify any relation between smoking and tumor aggressiveness. For that reason, we repeated our analyses using only the subset of our patient cohort with a maximum time between diagnosis and study enrollment of 3 years (approximately 50% of the series). This analysis showed only marginal differences with the results using the whole series.
If there is a shorter diagnostic delay among smokers, it might cause a bias towards an association between smoking and a more favorable disease stage. In The Netherlands, there is no screening or active case finding for bladder cancer. In the case of unexplained macroscopic hematuria, the guidelines dictate that bladder cancer should be ruled out. We believe that the adherence to this guideline is very good in men, irrespective of their smoking status. It is generally known that the diagnostic delay is somewhat longer in women. We cannot rule out that smoking habits may have influenced this diagnostic delay in some women.
In theory, our study may have suffered from differential misclassification if patients with a more aggressive tumor reported their smoking habits in a different way than patients with a less aggressive tumor. Unfortunately, there is no way to check this. Of course, there will have been a certain degree of non-differential misclassification of smoking habits. Also, we did not collect information on, e.g., the use of filter cigarettes, depth of inhaling, brand of the cigarette, and passive smoking. It is impossible to capture all of these differences but a prospective design with serial measurements may lead to less misclassification compared to the single retrospective measurement in our study.
For a large percentage of patients, tumor size was missing due to a lack of information in the medical records. This prohibited us to evaluate an association between smoking intensity and this characteristic.
Among former cigarette smokers, larger smoking amount and longer smoking duration are weakly related with a more aggressive cancer but no relation was found among current smokers.
This inconsistency may suggest that there is no strong relation between smoking intensity and aggressiveness of the tumor. However, the retrospective design of the study may have influenced the results to some extent. Analyses of prospective studies with longitudinal smoking assessment might answer the research question in a more definitive way.
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