Lung Cancer
Volume 67, Issue 2 , Pages 144-150, February 2010

Characteristics of never smoker lung cancer including environmental and occupational risk factors

  • Christelle Clément-Duchêne

      Affiliations

    • Respiratory Diseases Department, University Hospital, Vandoeuvre-Les-Nancy, France
    • Corresponding Author InformationCorresponding author at: Service de Pneumologie, Hôpital de Brabois, CHU de Nancy, 54511 Vandoeuvre-lès-Nancy, France. Tel.: +33 3 83 15 33 93; fax: +33 3 83 15 34 06.
    • ,
  • Jean-Michel Vignaud

      Affiliations

    • Pathology Department, University Hospital, Nancy, France
    • ,
  • Audrey Stoufflet

      Affiliations

    • Inserm U954, Vandoeuvre-Les-Nancy, France
    • ,
  • Odile Bertrand

      Affiliations

    • Occupational Diseases Department, University Hospital, Nancy, France
    • ,
  • Antoine Gislard

      Affiliations

    • Occupational Diseases Department, University Hospital, Rouen, France
    • ,
  • Luc Thiberville

      Affiliations

    • Pneumology Clinic, University Hospital, EA 4108 LITIS-QUANTIF Laboratory, Rouen, France
    • ,
  • Gilles Grosdidier

      Affiliations

    • Thoracic Surgery Department, University Hospital, Nancy, France
    • ,
  • Yves Martinet

      Affiliations

    • Respiratory Diseases Department, University Hospital, Vandoeuvre-Les-Nancy, France
    • ,
  • Jacques Benichou

      Affiliations

    • Biostatistics Department, University Hospital, Rouen, France
    • ,
  • Pierre Hainaut

      Affiliations

    • Cluster of Molecular Carcinogenesis Department, International Agency for Research on Cancer, Lyon, France
    • ,
  • Christophe Paris

      Affiliations

    • Inserm U954, Vandoeuvre-Les-Nancy, France
    • Occupational Diseases Department, University Hospital, Nancy, France

Received 14 November 2008; received in revised form 25 January 2009; accepted 15 April 2009. published online 22 May 2009.

Article Outline

Abstract 

Introduction

Clinical characteristics and risk factors of nonsmoker patients with lung cancer are still debated.

Aim and methods

The aim of this work is to describe the characteristics of never smoker patients with lung cancer, focusing on occupational and environmental exposures, Data collected were: age, gender, histological types, methods of diagnosis, TNM staging, smoking, and occupational data. Statistical analysis included descriptive analyses, Pearson's chi-square or nonparametric tests, and logistic regressions.

Results

All lung cancers diagnosed between January 1, 1997 and December 31, 2006, representing 1493 cases were included. Lung adenocarcinoma (ADC) [Odds Ratio (OR)=2.5 (1.5–4.3), p<0.0001] as well as clinical stage I cases at diagnosis [OR=2.4 (1.3–4.3)] were most frequent in nonsmokers relative to ever smokers. Comparison of clinical features among male and female nonsmoker patients did not reveal significant differences. Conversely, strong differences appeared when comparing environmental tobacco smoke (ETS) and occupational exposures in nonsmoker women vs men: ETS exposure (78.6% nonsmoker women vs 21.4% nonsmoker men, p<0.0001), occupational exposure (9.4% vs 48.6%, p<0.0005). Noteworthy, a sizeable number of nonsmoker male (40.0%), and nonsmoker female (31.2%) patients had no known exposure to major lung carcinogens.

Conclusions

Main risk factors (ETS and occupational exposure) may only explain some cases.

Keywords: Lung cancer, Nonsmokers, Environmental tobacco smoke (ETS), Smoking exposure, Occupational exposure, Adenocarcinoma

 

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1. Introduction 

Lung cancer is the leading cause of death by cancer in developed countries, with an estimated 5-year survival rate of 15% [1], [2], [3], [4]. In France, lung cancer is responsible for approximately 28,000 deaths per year, and its incidence is still increasing, particularly in women [5].

For several decades, numerous epidemiological studies have identified smoking and occupational exposure to carcinogens such as asbestos as main causes of lung cancer [6]. Smoking is without doubt the major risk factor of lung cancer in both sexes. Overall Odds Ratios (OR) of lung cancer are estimated at 23.9 (19.7–29) for male current smokers vs never smokers, and at 7.5 (6.2–9.1) for male former smokers vs never smokers [7]. Excess risk of lung cancer is lower in women, with an estimated OR of 8.7 (7.4–10.3) for female current smokers vs nonsmokers and 2.0 (1.6–2.4) for female former smokers vs never smokers [8]. Consequently, attributable fractions of 90% for men and 60% for women are generally reported for smoking habits [9]. In a recent meta-analysis [10], all histological types were found to be associated with tobacco smoking, the relationship being stronger for squamous cell carcinoma (OR: 25.4 [18.4–35.1]) and small cell carcinoma (OR: 42.0 [21.7–81.2]) than for adenocarcinoma (OR: 6.18 [4.59–8.32]). Similar patterns were observed in women [11].

Several occupational carcinogens, including asbestos, chromium, arsenic, cadmium, silica, nickel, and polycyclic aromatic hydrocarbons have also been proven to cause lung cancer [12]. Not surprisingly, gender differences in the distribution of occupational exposure to carcinogens in lung cancer patients have been reported. Lee et al. observed, according to tobacco status (smokers, ex-smokers, and nonsmokers), that the frequency of occupational exposure in industries was higher in male patients with squamous cell carcinoma than in female patients [13]. Most other studies documenting such exposures have been based on male smokers, as data in female patients remain relatively sparse [14].

It is important to note that, although relatively uncommon, particularly in male patients, lung cancer can also occur in patients without known risk factors. In a European meta-analysis on lung cancer risk factors, Simonato reported that only 2% of male lung cancer patients are never smokers [7], [8]. This percentage is significantly higher in females, ranging between 30% and 50%, depending on the study [15], [16], [17]. Actually, in never smokers, the main causes are unknown as environmental tobacco exposure (ETS) is considered to explain only approximately 10% of never smoker males and 20% of never smoker females [9], [18], [19], regardless of exposure site (home, work or social environment). Interestingly, other risk factors of never smokers patient presenting with lung cancer are rarely reported. As a result, even if some gender differences are likely to exist for occupational or ETS exposures, to date, the description of lung cancer risk factors in never smokers remains largely incomplete [9]. Moreover, recent papers have reported apparent clinical, histological, and survival differences between smoker and never smoker lung cancer patients [18], [20]. Thus, at present, identification of risk factors in never smoker patients may be of importance in the management, diagnosis, and treatment of lung cancer [18].

The aim of this work is to describe the characteristics of never smoker patients with lung cancer, focusing on occupational and environmental exposures, and to compare the distribution of these parameters between genders.

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2. Material and methods 

2.1. Patients 

This study included all incident cases of lung cancer consecutively diagnosed in the Respiratory Diseases Department of Rouen University Hospital from January 1, 1997, through December 31, 2000, and in the Thoracic Surgery and Respiratory Diseases Departments of Nancy University Hospital from January 1, 2001, through December 31, 2006.

Inclusion required histologically confirmed primary lung cancer, regardless of the provenance of the tumor tissue, for example, bronchoscopy, CT-guided puncture, surgical lung biopsy, biopsy of metastatic sites, or other surgical removal. No autopsy samples were available. No age, sex or tumor stage limits were set. However, the patient's ability to effectively respond to an interview was required; hence, the presence of mental deterioration was an exclusion criterion.

2.2. Histological diagnosis 

We used all available pathologic samples as described above. For each University Hospital, samples were analysed by a single physician with extensive experience in the pathologic diagnosis of lung cancer. Histological types were classified according to the International Classification of Lung Tumors [21] using the following five categories: squamous cell carcinoma (SCC), adenocarcinoma (ADC), small cell carcinoma (SCLC), undifferentiated large cell carcinoma (LCC), and other cancer types (OC).

2.3. Medical data 

Age, gender, histological types, methods of diagnosis, and TNM staging [22] were collected by medical staff and from patient records.

2.4. Smoking and occupational data 

Data were collected through a medical interview, based on a standardized questionnaire. All subjects were systematically interviewed about their current and lifetime smoking status. Detailed data were obtained about tobacco consumption including: smoking start age, current smoking status, duration, intensity, cumulative dose (pack-years) of smoking, and time since quitting, where applicable. Patients who had quit smoking for more than 1 year were considered former smokers. Patients who had smoked less than 100 cigarettes in their lifetime were defined as never smokers. ETS exposure was also collected for never smokers and classified as follows: not exposed to ETS, exposed to ETS at home, exposed to ETS at work, or exposed to ETS at both home and work.

Occupational exposures to lung carcinogens were then assessed by an occupational physician. This assessment was performed by the same physician, who was blinded to the clinical and histological data from the two hospital centers. Patients also completed a standard questionnaire about occupational exposures. All jobs (duration at least 6 months) were screened; careers were listed and briefly described. Specific questions were asked in order to assess main carcinogen exposures, mainly, asbestos, chromium, arsenic, cadmium, silica, nickel, and polycyclic aromatic hydrocarbons. Only subjects with documented exposure to a lung carcinogen for at least 1 year were considered as occupationally exposed.

2.5. Design of the study 

The present study is prospective and descriptive, with inclusion of all consecutive patients of two hospitals during the defined period.

2.6. Statistical analysis 

The statistical analysis aimed to describe risk factors for lung cancer, particularly occupational and environmental exposures among never smokers and to compare frequency of these factors between male and female never smokers.

First, we described overall characteristics, namely, gender, age, histological types, TNM staging, and methods of diagnosis, in relation to tobacco consumption (never smokers, current smokers, ex-smokers).

A restricted analysis was then conducted among never smokers in order to compare main variable frequencies between sexes.

Finally, multiple analyses were also conducted to identify significant differences between ever smokers and never smokers, taking into account age, sex and histological types, depending on the analysis.

Categorical comparisons were based on Pearson's chi-square or other nonparametric tests, depending on the number of subjects (Fisher's exact test). Multiple analyses were based on unconditional logistic regression. A p value less than 5% was deemed statistically significant. All analyses were performed with SAS (SAS Institute Inc., Cary NC, release 9.0) software.

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3. Results 

Overall, 1493 subjects were consecutively included in this study, with a men/women ratio of 6.85 (1303/190) (Table 1). Only 67 of them (4.5%) were never smokers, but this percentage was higher (16.8%) in female patients. ADC and SCC were the most frequent histological types overall, with 32.7%, and 33.3% of cases, respectively.

Table 1. Main characteristics across smoking status of the 1493 patients.
Nonsmokers (n=67)Ex-smokers (n=635)Current smokers (n=791)p
Age (mean in years)64.766.358.5<0.0001a
Range(33.0–84.0)(39.0–91.0)(34.0–89.0)

Sex n (%)
Men35 (52.2)585 (92.1)683 (86.4)p<0.0001b
Women32 (47.7)50 (7.9)108 (13.6)

Histological typing n (%)
Adenocarcinoma36 (53.7)205 (32.3)248 (31.4)p<0.0001b
Squamous cell carcinoma12 (17.9)228 (35.9)257 (32.5)
Small cell carcinoma2 (3.0)96 (15.1)153 (19.3)
Large cell carcinoma3 (4.5)66 (10.4)89 (11.2)
Others14 (20.9)40 (6.3)44 (5.6)

OR nonsmokers/ex-smokers2.2 (1.3–3.6)

OR nonsmokers/current smokers 2.7 (1.6–4.7)p<0.0001b

OR nonsmokers/ex-smokers and current smokersc2.5 (1.5–4.3) p<0.0001b

TNM staging n (%)
I20 (29.8)97 (15.3)82 (10.4)p<0.0001b
IIA1 (1.5)10 (1.6)14 (1.8)
IIB1 (1.5)30 (4.7)33 (4.2)
IIIA9 (13.4)74 (11.6)75 (9.5)
IIIB4 (6.0)104 (16.4)124 (15.7)
IV30 (44.8)289 (45.5)426 (53.8)
Missing2 (3.0)31 (4.9)37 (4.6)

OR nonsmokers/ex-smokers and current smokers (stage I)d2.4 (1.3–4.3) p=0.0037b

Diagnosis n (%)
Bronchial biopsy28 (41.8)364 (57.3)460 (58.1)p=0.0169b
CT-guided puncture4 (6.0)59 (9.3)52 (6.6)
Others organ biopsies (liver, bone, …)11 (16.4)60 (9.4)67 (8.5)
Surgery23 (34.3)127 (20.0)172 (21.7)
Others0 (0.0)20 (3.1)23 (2.9)
Missing1 (1.5)5 (0.9)17 (2.2)

For 4 patients, there were 2 methods of diagnosis.

aFisher's exact test.

bKhi2.

cAdjustment for age and sex.

dAdjustment for histological types, age, and sex.

The comparison of clinical features showed significant differences between never smokers and former or current smokers. At time of diagnosis, current smokers were younger (mean age 58.5 years, SD 34.0–98.0), compared to never and former smokers (p<0.0001). Adenocarcinoma was the most common histological type in never smokers (53.7%), while SCC was the most common histological type in current smokers (32.5%) and former smokers (35.6%, p<0.0001). The Odds Ratio associated with the presence of ADC (vs all other histological types) in never smokers was 2.2 [1.3–3.6] relative to former smokers, and 2.7 [1.6–4.7] relative to current smokers. After adjustment for age and sex, this association persisted (OR 2.5 [1.5–4.3]) relative to ever smokers. According to TNM staging, stage I was found to be more frequent in never smokers (29.8%) than in former (15.3%) or current smokers (10.4%) (p<0.0001). Adjustment for histological types, age, and sex did not modify this result when compared to ever smokers (OR 2.4 [1.3–4.3]).

Table 2 describes the main clinical differences among male and female never smokers. No significant gender differences were observed for age, histological types, TNM staging, and methods of diagnosis. However, we observed that adenocarcinoma frequency (62.5% vs 45.7%) was higher in female never smokers than in male patients, albeit these differences were not significant, even after adjustment for age (OR 2.1 [0.8–5.7]). The same observation can be made for stage I distribution, as the associated OR in female never smokers vs male never smokers is 1.9 [0.6–5.8] after adjustment for age and histology.

Table 2. Main characteristics of the 67 nonsmokers included in this study.
CharacteristicsMen n=35 (%)Women n=32 (%)p
Age (years)64.0 (33.0–80.0)65.6 (44.0–84.0)0.5534a

Histological typing
Adenocarcinoma16 (45.7)20 (62.5)0.5215b
Squamous cell carcinoma6 (17.1)6 (18.8)
Small cell carcinoma1 (2.9)1 (3.1)
Large cell carcinoma2 (5.7)1 (3.1)
Others10 (28.6)4 (12.5)

TNM staging
I8 (22.8)12 (37.5)0.6317b
IIA1 (2.9)0 (0.0)
IIB1 (2.9)0 (0.0)
IIIA5 (14.3)4 (12.5)
IIIB3 (8.6)1 (3.1)
IV15 (42.8)15 (46.9)
Missing2 (5.7)

Diagnosis
Bronchial biopsy16 (45.7)12 (37.5)0.8289b
CT scan ponction2 (5.7)2 (6.3)
Others organ biopsies (liver, bone, …)6 (17.1)5 (15.6)
Surgery10 (28.6)13 (40.6)
Missing1 (2.9)

After adjustment for age, for adenocarcinoma, the OR of women/men is 2.1 (0.8–5.7).

After adjustment for age and histology, for stage I, the OR of women/men is 1.9 (0.6–5.8)

aKhi2.

bFisher's exact test.

Table 3 describes frequencies of ETS and occupational exposures among never smokers. Female patients were significantly more exposed to ETS than male patients (OR=11.0 [3.4–35.4]). Conversely, exposure to occupational lung carcinogens occurred more frequently in male patients than in female patients (48.6% vs 9.4%, p<0.0005), mainly due to asbestos exposure. Other exposures were mainly polycyclic aromatic hydrocarbons (5 subjects, average exposure duration: 10.2 years), welding fumes (4 subjects, average exposure duration: 13.2 years), diesel exhaust (3 subjects, average duration exposure: 28.3 years) and silica (1 subject, more than 40 years of exposure).

Table 3. Distribution of ETS, and occupational exposure in the 67 nonsmokers.
Men n=35 (%)Women n=32 (%)Total n=67p
No ETS and no occupational exposure14 (40.00)10 (31.20)24<0.0001a

Environmental tobacco smoke
No ETS29 (82.9)10 (31.2)39
ETS at home only0 (0.0)11 (50.0)11
ETS at work only6 (100.0)11 (50.0)17
Both6 (17.1)22 (68.8)28

OR ETS/no ETSc1.0011.0 (3.4–35.4) <0.0001a

Occupational exposure
Asbestos exposure
Yes14 (40.0)3 (9.4)170.0040a
No21 (60.0)29 (90.6)50

Exposure to other lung carcinogens
Yes4 (11.4)0 (0.0)40.1152b
No31 (88.6)32 (100.0)63

Occupational exposure
Any occupational exposure18 (51.4)29 (90.6)47<0.0005a
One or more occupational exposure17 (48.6)3 (9.4)20

ORc1.000.1 (0.03–0.4) 0.0012a

aKhi2.

bFisher's exact test.

cAdjusted for age.

It is important to note that 35.8% of never smokers (14 men and 10 women,) reported no known exposure to either occupational carcinogens or ETS.

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4. Discussion 

Our findings demonstrate clear clinical differences among lung cancer patients in never smokers relative to ever smokers. Differences among male and female never smokers appear slight, except for the existence of occupational carcinogens or ETS exposures—the most original finding of our study.

4.1. Differences between nonsmokers, ex-smokers, and current smokers 

There is now strong evidence that lung cancer in never smokers shows different patterns than those observed in ever smokers [9], [20], [23], [24], [25]. Our study data are consistent with these findings. The prevalence of never smokers with lung cancer is higher in women than in men, with a reported rate ranging from 10% to 30% in European or American studies [18], [23], [26], [27], [28], but reaching as high as 40% in South Asian reports [23]. With values of 29.6% of women and only 5.1% of men, our findings do not differ from literature data and are particularly harmonious with results from other French studies [26], [29]. Additional support for nonsmoker vs ever smoker differences come from differences in histological type distribution. The over-representation of ADC in never smokers is a common fact reported by numerous studies [10], [18], [30], [31]. Our results are consistent with this data, with an overall OR associated with ADC of 2.5 [1.5–4.3] in never smokers relative to ever smokers, after adjustment for sex.

Less is known about other characteristics of lung cancer in never smokers, namely, age and stage of disease. Age at diagnosis of lung cancer in never smokers is thought to be higher than in ever smokers [9], [32], [33], [34], as in our study. However, some authors do not report such differences among never and ever smokers. For instance, Wakelee et al. reported in an analysis of 6 cohorts that age at diagnosis in never smokers may be equal to that of ever smokers [30]. Moreover, in a study including 168 never smokers and 562 smokers with lung cancer, Bryant reported that never smokers were younger at diagnosis than other patients (53.6 vs 66.2 years, p=0.04) [18]. To date, various factors have been proposed to explain such discrepancies across studies, including age at smoking initiation or detection bias [9]; nevertheless, these findings remain unclear.

Discussions related to the association between disease stage at diagnosis and smoking status have been also reported. Several studies [9], [18], [23], [32], [35] described higher advanced stages in never smokers than in ever smokers, whereas others reported no differences [34], [36]. It is important to note, however, that most of these studies do not present adjusted results. Such discrepancies are not well understood. Some authors support the hypothesis that the frequency of advanced stage disease in never smokers is related to a delay in diagnosis, due to the absence of known risk factors of lung cancer or to the association with ADC observed in never smokers. Conversely, excess diagnosis of stage I in never smokers may be associated with earlier examinations in symptomatic never smokers, as in smokers with chronic symptoms related to smoking, such as cough, for example. Given that we found clear differences in clinical stage distribution associated with smoking status (p<0.0001), yielding a significant excess of stage I in never smokers, even after adjustment for histological types, age, and gender (OR=2.4 [1.3–4.3]), our results support the second hypothesis. However, these findings must be confirmed by future studies.

4.2. Gender differences in never smokers 

Though numerous studies describe separately characteristics of male or female never smokers with lung cancer [30], [33], [37], [38], [39], [40], [41], to date, few publications have aimed to study gender effect on clinical features. Obviously, the low percentage of never smokers among male lung cancer patients limits the possibility and the value of statistical analysis for such comparisons. Accordingly, we did not find any differences among men and women never smokers for our selected variables. More specifically, we found the same high frequency of ADC in both men and women (45.7 vs 62.5, p=0.5215) as some other authors before us [10], [39], [42]. Interestingly, Toyooka et al. [43] reported recently no differences in 4 EGFR mutations among male and female never smoker patients. This suggests that lung cancer occurring in never smokers, independent of gender, may share common biological mechanisms.

4.3. Risk factors of lung cancer in nonsmokers 

Numerous risk factors have been suggested to explain the occurrence of lung cancer in never smokers, including, environmental smoke exposure, occupational exposure, indoor and outdoor pollution, prior diseases, and genetic factors [9], [23], [44]. Evidence is now clearly established for several of these factors, namely, ETS for both residential and workplace exposure [17], [45]; occupational exposure to asbestos, polycyclic aromatic hydrocarbons (PAHs) [6]; and exposure to radon and radon decay products [46], [47]. However, the frequency of such exposures in never smoker patients with lung cancer is rarely reported [48], [49] in men [39]. A large case-control study including 650 never smoker cases of lung cancer (141 men and 509 women) demonstrated than less than 10% of men and 1% of women had been occupationally exposed to specific IARC-identified pulmonary carcinogens. Based on a subset of this study, Kreuzer et al. reported in 2001 that among male never smokers, only 4 patients had been exposed to residential ETS and 13 patients had been exposed to high levels of ETS outside the home. Conversely, numerous studies have been conducted in female never smokers to assess the role of ETS. Overall, an excess relative risk of 20% associated with ETS in women is often reported [42], [44]. In an IARC monograph on involuntary smoking [50], observed frequencies of ETS exposure varied widely among the cited studies, depending on patient sex, country of exposure, and location of exposure to ETS. Overall, women were found to be exposed more often than men to ETS at home, while the inverse was reported for work-related exposures.

Accordingly, our results confirm these features and provide some details on such exposures. Female never smoker patients experienced ETS exposure more often than men (68.8% vs 17.1%). Also noteworthy is the fact that all ETS-exposed male patients in our study were only exposed at work. Conversely, only 3 women experienced occupational exposure to lung carcinogens, whereas 51.4% of men had been occupationally exposed, mainly to asbestos. Our results confirm that exposure to known occupational lung carcinogens as well as to ETS cannot explain all the lung cancer cases observed in male and female never smokers, as suggested by some authors [9], [44]. Interestingly, consideration of these main factors results in a rate of lung cancer without known risk factor exposure that is roughly similar between male and female never smokers (40% vs 31.2%). However, the low overall prevalence of non-smoking among lung cancer cases does not permit us to support definite conclusions. Accordingly, we currently extend our study design in four French centers, by including prospectively lung cancer cases in never smokers in order to be able to complete our sample and to present more definite results in near future.

4.4. Our study presents several limits which need to be discussed 

Despite the large overall number of subjects enrolled in this study, the number of never smokers is low. Comparisons between never and ever smokers and, moreover, between never smokers themselves are based on a small number of cases and prevents the drawing of definite conclusions. Obviously, this finding has been observed in most of the studies on lung cancer in never smokers, as our percentage of never smokers does not significantly differ from literature data [26], [39], [51], [52]. This observation notwithstanding, our results are in agreement with certain published data.

Possibly more critical is the existence of gender-bias in recall of risk factors, with a differential reporting of exposure between male and female never smokers. This kind of bias is often discussed in these types of studies [23], [30], particularly in the reporting of ETS exposure. Despite the use of standardised questionnaires for smoking characteristics, under-reporting in men could not be ruled out in this study, as our percentage of ETS-exposed men is close to the lowest values in the literature [50]. However, there is only a low probability that men were in fact as exposed as women in this study and that our conclusion about gender differences in ETS exposure was, as a result, incorrect. Such bias can also occur in the reporting of occupational exposures, but appears more questionable. Occupational exposure assessment is based on individual expertise, with both analysis of specific questionnaires and also of career history and industry activities, for which recall bias is unlikely. Moreover, our results are close to previously reported data [39], [49].

Finally, our study does not provide data relating other risk factors, including diet, prior respiratory diseases, family history of lung cancer, and general environmental exposures to lung cancer in never smokers. Most of these factors are under investigation [9] and no definite conclusions concerning their role in lung cancer have been drawn to date. Moreover, associated risk levels for these factors were often thought to be low, so we have assumed that these factors could have only limited effects on our conclusions. Radon exposure is a notable exception to this assumption, since the relationship between radon exposure and lung cancer has been clearly observed [46], [47]. Overall exposure levels to radon and radon decay product are estimated to be low in one of our study regions (ranging between 0Bq/mm3 and 50Bq/mm3 in north of France) and moderate in the second study region (ranging between 51Bq/mm3 and 100Bq/mm3 in east of France) [53]. Lastly, as the synergistic effect with smoking is thought to be responsible for most lung cancer cases attributable to radon [54], the impact of this radioisotope on lung cancer in never smokers is likely to be limited in our study.

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5. Conclusion 

Our study confirms previous knowledge on the specificity of lung cancer in never smokers, such as the over-representation of women and the frequency of ADC. Most interesting is the observation that, despite limitations on assessment of general environmental exposure to radon or outdoor pollution, neither occupational nor ETS exposures suffice to explain the occurrence of such disease in never smokers. Our findings suggest that a sizeable fraction of lung cancer cases, both in male and female never smokers, may share common characteristics, and possibly underlying biological mechanisms, as recently suggested by Toyooka et al. [43]. Although relatively rare, it would be valuable to focus future biological studies on lung cancer cases occurring without known risk factors, in both sexes.

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Conflict of interest statement 

There is no conflict of interest for all the authors.

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Acknowledgments 

We want to thank all physicians of our departments for patient follow-up and their contribution to this study.

This work was funded by the “Programme Hospitalier de Recherche Clinique” (years 2000 and 2004) and the French National Cancer Institute (INCA), within the scope of the “PNES” Project.

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PII: S0169-5002(09)00216-5

doi:10.1016/j.lungcan.2009.04.005

Lung Cancer
Volume 67, Issue 2 , Pages 144-150, February 2010

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