Sex-Related Differences in Bronchial Epithelial Changes Associated With Tobacco Smoking

Stephen Lam, Jean C. leRiche, Yvonne Zheng, Andrew Coldman, Calum MacAulay, Ernest Hawk, Gary Kelloff, Adi F. Gazdar

Affiliations of authors: S. Lam (Department of Respiratory Medicine), J. C. leRiche (Department of Pathology), Y. Zheng, C. MacAulay (Department of Cancer Imaging), A. Coldman (Department of Cancer Prevention), British Columbia Cancer Agency and the University of British Columbia, Canada; E. Hawk, G. Kelloff, Chemoprevention Branch, Division of Cancer Prevention, National Cancer Institute, Bethesda, MD; A. F. Gazdar, Hamon Center for Therapeutic Oncology and Department of Pathology, University of Texas Southwestern Medical Center, Dallas.

Correspondence to: Stephen Lam, M.D., Department of Respiratory Medicine, British Columbia Cancer Agency and the University of British Columbia, 2775 Heather St., Vancouver, BC V5Z 3J5, Canada (e-mail: sclam{at} interchange.ubc.ca).


    ABSTRACT
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
BACKGROUND: Lung cancer is the most common cause of cancer death in North American women. Because smoking-related changes in the bronchial epithelium and in lung function have not been studied in detail in women, we used fluorescence bronchoscopy-directed biopsy to determine the prevalence of high-grade preinvasive lesions in former and current smokers of both sexes. METHODS: Spirometry, white-light bronchoscopy, and fluorescence bronchoscopy were performed in 189 women and 212 men older than 40 years of age who had smoked 20 pack-years or more (pack-years = number of packs of cigarettes smoked per day x number of years of smoking). RESULTS: Carcinoma in situ was found in 1.8% of the subjects, severe dysplasia was found in 6.5%, and moderate dysplasia was found in 14% (all preinvasive lesions). Compared with men, women had a lower prevalence of high-grade preinvasive lesions in the observed airways (14% versus 31%; odds ratio = 0.18; 95% confidence interval = 0.04-0.88), and women with preinvasive lesions had fewer such lesions (two-sided P = .048). The prevalence of preinvasive lesions did not change substantially for more than 10 years after cessation of smoking. Lung function was associated with the prevalence of preinvasive lesions, but the association was weaker in women than in men. If the presence of airflow obstruction was defined by an FEV1/FVC (forced expiratory volume in 1 second/forced vital capacity) value of 70% or less, only 56% of the men and 44% of the women with preinvasive lesions had abnormal lung function. CONCLUSION: In developing strategies for chemoprevention or early detection of lung cancer in high-risk populations, it is important to consider the effect of sex and arbitrarily chosen lung function values on the prevalence of preinvasive airway lesions.



    INTRODUCTION
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Lung cancer has become the most common cause of cancer deaths in North American women. The cumulative probability of lung cancer in the general population for individuals up to 74 years of age is 10%-15% in those who smoke one or more packs of cigarettes a day (1). To develop a strategy that will identify individuals at high risk so that chemoprevention or early detection interventions can be offered, the prevalence of preinvasive (noninvasive) lesions in the bronchial epithelium that are at high risk of progression to invasive cancer should be determined relative to known demographic factors, such as age, sex, and history of smoking. Detailed autopsy studies by Auerbach et al. (2) on the bronchial epithelial changes related to tobacco smoking showed a substantial reduction in the frequency of such abnormalities between the periods from 1955 through 1960 and from 1970 through 1977. This was thought to be due to a change in the manufacturing of cigarettes. These studies were done only in men and are now more than two decades old. Since then, there has been a change in the demographics of lung cancer. Instead of its predominance in men and current smokers, lung cancer is becoming more prevalent in women and former smokers (3,4). The changes in the bronchial epithelium relative to sex and smoking status should, therefore, be re-examined.

The light-induced fluorescence endoscopic device LIFE-Lung (Xillix Technologies Inc., Richmond, BC, Canada) is several times more sensitive than conventional white-light bronchoscopy in localizing small high-grade preinvasive bronchial lesions (5-7). Thus, the LIFE-Lung is an in vivo tool that can be used to examine the bronchial tree to identify changes in the bronchial epithelium in current and former smokers of both sexes. In this study, we used the LIFE-Lung device to determine the prevalence of high-grade preinvasive bronchial lesions (moderate/severe dysplasia or carcinoma in situ) in current and former smokers of both sexes.


    METHODS
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Study Population

Current and former smokers 40 years of age or older with a smoking history of 20 pack-years (pack-years = number of packs of cigarettes smoked per day x number of years of smoking) or more were recruited from the community through the Fresh Start smoking cessation program at the British Columbia Cancer Agency, from the Screening Mammography Program of British Columbia, and by advertisement in local radio, newspaper, and television. Subjects with a history of lung cancer, respiratory failure, acute bronchitis or pneumonia within the previous 4 weeks, uncontrolled angina, uncontrolled congestive heart failure, or renal failure were excluded from the study. A total of 401 subjects (212 men and 189 women) participated. The bronchoscopy examination was part of two randomized placebo-controlled chemoprevention trials at the British Columbia Cancer Agency that were approved by the Institutional Review Board. These trials are being conducted to examine the effects of retinol or anetholtrithione on bronchial dysplasia. All participants gave written informed consent before enrollment in the study.

The characteristics of the subjects are shown in Table 1.Go A former smoker was defined as one who had not smoked any tobacco for at least 1 year. This was determined by a detailed questionnaire. The exhaled carbon monoxide level was measured in all the subjects, and cotinine in urine was assayed using a sensitive radioimmunoassay method (8) in 40% of the subjects for confirmation. Subjects were considered to be current smokers irrespective of the history if the exhaled carbon monoxide level was higher than 10 ppm or if the urinary cotinine level was greater than creatinine at 200 ng/mg (9).


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Table 1. Characteristics of the study population

 
Pulmonary Function Test

Lung function was measured by using a flow-sensing spirometer (Presto FLASH; Burdick, Inc. Milton, MI) as recommended by the American Thoracic Society (10). The forced expiratory volume in 1 second (FEV1) and the forced vital capacity (FVC) were measured. The FEV1 was expressed as a percent of the predicted value based on the age, height, and sex of the subject by using the predicted equation of Crapo et al. (11). In addition, the FEV1/FVC ratio was calculated.

Bronchoscopy and Bronchial Biopsy Examination

White-light and fluorescence bronchoscopy examinations were performed under local anesthesia as described previously (5-7). After white-light examination, fluorescence bronchoscopy was carried out with the LIFE-Lung device. Areas suspicious for dysplasia or cancer from either examination were taken for biopsy and pathologic examination. In addition, at least one additional biopsy specimen was taken from an area that was apparently normal under either examination.

Pathologic Analysis

Bronchial biopsy specimens were fixed in buffered formalin and embedded in paraffin. The sections were stained with hematoxylin-eosin. Two pathologists (J. C. leRiche and A. F. Gazdar) who reviewed the slides were blinded to sex, clinical status, tobacco exposure, and bronchoscopy findings. By use of established criteria (7,12), the biopsy results were scored by grade as follows: 1 = normal; 2 = hyperplasia/metaplasia; 3 = mild dysplasia; 4 = moderate dysplasia; 5 = severe dysplasia; 6 = carcinoma in situ; or 7 = invasive carcinoma. To resolve minor differences, the two pathologists consulted each other by telephone. To resolve major differences, both pathologists reviewed the slides again to come to a final diagnosis. Lesions of grades 4-6 were considered high-grade lesions. The risk of progression to invasive cancer was inferred from previous cytologic studies of sputum that showed that approximately 10% of moderate dysplasia and 40%-80% of severe dysplasia progress to invasive cancer on follow-up (13,14).

Statistical Analysis

Descriptive statistics were used to summarize subject characteristics, pathologic evaluations of the bronchial biopsy examinations, and pulmonary function. Since multiple lesions with different histopathology grades could be found in the same individual, each subject was represented by the highest grade of lesion found in the bronchial biopsy specimens. Comparison between groups was done with the Mann-Whitney test. Pearson's {chi}2 test was applied to a contingency table analysis to determine the association of intraepithelial neoplastic lesions with sex and smoking status. All P values are two-sided. A two-sided P value of less than .05 was considered statistically significant.

To adjust for the effect of various factors on the likelihood of developing high-risk preinvasive lesions, we used a multiple logistic regression analysis. This analysis included the following variables: age, sex, smoking status (current or former smoker), pack-years, average number of cigarettes smoked per day, duration (years smoked), years quit (in former smokers), FEV1 (percent predicted), and FEV1/FVC. All analyses were unconditional, and tests of statistical significance and confidence intervals (CIs) for odds ratios (ORs) were based on the log-likelihood test.


    RESULTS
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
The mean age of the women (55 years; 95% CI= 54-56) was similar to men (57 years; 95% CI = 56-58). There were more current smokers than former smokers among women (81% of women versus 63% of men). The women had a lower smoking intensity (pack-years) and better lung function than men (P = .008; Table 1Go).

We obtained data from 1849 fluorescence bronchoscopy-directed and random biopsy specimens from the 401 subjects. The changes in the bronchial epithelium are shown in Fig. 1.Go Overall, carcinoma in situ was found in 1.8% of the subjects, severe dysplasia was found in 6.5%, moderate dysplasia was found in 14%, and mild dysplasia was found in 40%. Routine chest radiograph was not part of the study. However, approximately 50% of the subjects had a chest radiograph within the previous 6 months as a routine examination by their family physicians or before enrollment in our chemoprevention clinical trial. Two of them, both women, were found to have peripheral invasive lung cancer. One had a stage IA adenocarcinoma and the other had a stage IIIA large cell carcinoma. Fourteen percent of the women and 31% of the men had high-grade preinvasive lesions. In those who did have such lesions, the number of lesions was statistically significantly lower in women than in men (Fig. 2).Go On average, 1.8 lesions per subject (95% CI = 1.5-2.1) were found in men and 1.4 lesions per subject (95% CI = 1.0-1.8) were found in women (P = .048; Mann-Whitney test). If lesions that were mild dysplasia or worse were considered, the corresponding figures were 2.4 for men and 2.0 for women (95% CI = 2.1-2.7 and 1.7-2.3, respectively; P = .007). Three or more lesions classified as moderate dysplasia or worse were found in one woman (0.5%) and in 10 men (4.7%) (Fig. 2)Go.



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Fig. 1. Histopathologic changes in the central bronchial epithelium of current and former smokers by sex. Pathologic grades are as follows: 1 = normal; 2 = hyperplasia/metaplasia; 3 = mild dysplasia; 4 = moderate dysplasia; 5 = severe dysplasia; and 6 = carcinoma in situ.

 


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Fig. 2. Multiplicity of high-grade preinvasive lesions in central bronchi of current and former smokers by sex.

 
Results of logistic regression analysis showed that the risk of a high-grade preinvasive lesion was influenced by sex (OR = 0.18, women versus men; 95% CI = 0.04-0.88) and by measured FEV1 (OR = 0.67 per 1-L increase in volume; 95% CI = 0.49-0.90). Similar results were obtained if FEV1 was replaced by FEV1 (percent predicted) or by the FEV1/FVC (OR = 0.68 for 10% increase in FEV1/FVC; 95% CI = 0.51-0.93). These results used measures of lung function as linear predictors; consideration of nonlinear terms did not provide substantial improvement. Measures of smoking exposure were also considered (status as a current smoker and number of pack-years, cigarettes smoked per day, and years quit). None of these terms contributed to the fit of the model with or without the inclusion of lung function terms. Interaction terms with sex, age, and smoking status were also tested, but none had a P value less than .05.

The frequency of high-grade preinvasive lesions among current and former smokers is shown in Table 2.Go The percent of subjects with mild dysplasia was lower in the former smokers. However, the percent of subjects with high-grade lesions that were moderate dysplasia or worse was similar for the former and current smokers, even more than 10 years after smoking cessation (Fig. 3).Go


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Table 2. Distribution of the lesions with the highest pathology grade

 


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Fig. 3. Effect of the length of smoking cessation on histopathologic changes in the central bronchial epithelium.

 
Men with high-grade lesions had statistically significantly lower lung function than those with mild dysplasia or a more benign pathologic type. The mean FEV1 (percent predicted) was 81% (95% CI = 77%-85%) versus 72% (95% CI = 66%-78%, respectively; P = .008). The FEV1/FVC was 71% (95% CI = 69%-73%) versus 67% (95% CI = 64%-70%; P = .016) (Table 3).Go In women, the difference in lung function between those with and without high-grade lesions did not reach statistical significance. The distribution of FEV1/FVC in those with or without high-grade lesions is shown in Fig. 4.Go If the presence of airflow obstruction were defined by a FEV1/FVC value of 70% or less and used as a criterion for eligibility for bronchoscopic examination, 56% of the women and 44% of the men harboring high-grade lesions would be missed.


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Table 3. Pulmonary function of study population*

 


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Fig. 4. Distribution of pulmonary function (forced expiratory volume in 1 second/forced vital capacity [FEV1/FVC]) by worst pathologic grade observed in current and former smokers. Pathologic grades are as follows: 1,2 = normal, hyperplasia/metaplasia; 3 = mild dysplasia; and 4-6 = moderate/severe dysplasia or carcinoma in situ.

 

    DISCUSSION
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
In this study, we used a sensitive fluorescence bronchoscopic technique to localize areas of high-grade preinvasive (noninvasive) lesions at high risk to become invasive cancer and invasive cancer in the tracheobronchial tree accessible to an adult-size fiberoptic bronchoscope. The method is several times more sensitive than conventional white-light examination in detecting high-grade lesions (5-7); lesions as small as 1 mm can be localized with this technique. The negative predictive value of fluorescence bronchoscopy with the LIFE-Lung device is more than 0.85 (7). Therefore, it is unlikely that a substantial number of lesions that are moderate dysplasia or worse in the areas examined would be missed in our study.

Changes in the bronchial epithelium due to tobacco smoking were found to be different between women and men in this study. The prevalence and multiplicity of central preinvasive lesions were substantially lower in women. In men, the prevalence of squamous cell carcinoma in situ was similar to that observed by Auerbach et al. (2) in their autopsy study of smokers with a smoking history of one to two packs per day who died between 1970 and 1975. This is in keeping with recent epidemiologic studies that showed that the frequency of squamous cell carcinoma had dropped only slightly in men since 1975 although the frequency of adenocarcinoma has been increasing in both men and women (15,16).

The lower prevalence of lesions in women may appear to contradict evidence that, at every level of exposure to cigarette smoke, the risk of lung cancer is 1.2-fold to 1.7-fold higher in women than in men (17). In a cross-section of smokers, DNA adduct levels in histologically normal lung tissue were also found to be higher in women than in men when adjusted for cigarette dose (18). However, in women, the major histologic lung cancer cell type found is adenocarcinoma, whereas, until recently, in men the predominant cell type was squamous cell carcinoma (15-17). Most adenocarcinomas arise from epithelial cells in the peripherally located bronchi, bronchioles, and alveoli that are beyond the range of an adult-size fiberoptic bronchoscope. The relative paucity of lesions that we observed in women raises the possibility that, in women, epithelial cells in the central airways are less susceptible to carcinogens in tobacco smoke but that epithelial cells in the peripheral airways are more susceptible. It has been suggested that sex differences in nicotine metabolism, variations in cytochrome P-450 enzymes, and the effect of estrogen may account for the higher susceptibility to tobacco carcinogens in women (17). Preferential expression of P-450 enzymes in bronchiolar Clara cells versus bronchial epithelial cells has been reported previously (19,20). A difference between the sexes in metabolic activation and detoxification of lung carcinogens or DNA repair capacity of the epithelial cells in the peripheral versus the central airways has not been investigated but would be important to study.

Sex difference in the prevalence of high-grade preinvasive lesions may explain, in part, the differences between our study and that by Kurie et al. (21). In a study that contained 39 former and current smokers, 46% of whom were women, Kurie et al. found no high-grade preinvasive lesions by either white-light or fluorescence bronchoscopy. However, they found 2.7 times more lesions with mild dysplasia by fluorescence bronchoscopy than they found in a historic control group by use of white-light bronchoscopy alone. Pathologic interpretation of the bronchial biopsy examinations was a potential problem (22,23). In an independent review of the biopsy results, an outside pathologist found 18 dysplastic lesions compared with the original eight (21). The severity of the dysplastic lesions graded by the reference pathologist was not reported. Interpretation of the fluorescence images and performing biopsy examinations of small preinvasive lesions also require an experienced endoscopist. Many of these preinvasive lesions are very small and are easily missed by the endoscopist during training. In contrast, all of the fluorescence bronchoscopy examinations in our study were performed by an endoscopist with extensive experience in this field (5-7) and all the biopsy specimens were reviewed by two expert pulmonary pathologists (J. C. leRiche and A. F. Gazdar). These differences and the small number of subjects (half of whom were women) in the study by Kurie et al. (21) may explain the paucity of high-grade lesions observed compared with the number of high-grade lesions that we observed in this study and that others (5-7,24-27) have reported.

A second important finding in this study is that airflow obstruction has a stronger association with the presence of high-grade preinvasive bronchial lesions in men than in women. Airflow obstruction has been considered an independent risk factor for the development of lung cancer (28-31). However, with one exception, these studies were done in men. In the only study (31) that included women, there were only 20 subjects, and seven of them were nonsmokers whose airflow obstruction, presumably, was due to environmental exposure. In the study by Nomura et al. (30), a statistically significant correlation between airflow obstruction and lung cancer was found in those with squamous cell carcinoma or tumors that were centrally located but not in those with peripheral tumors. Sex differences in airway responses to tobacco smoke were also observed in previous lung function studies. For example, in the Lung Health Study in smokers with airflow obstruction, there was a higher prevalence of bronchial hyperresponsiveness among women than among men (32). The abnormality was found in 85.1% of the women compared with 58.9% of the men. The difference could not be attributed to age, cigarette use, diagnosis of asthma, or baseline degree of airflow obstruction. A statistically significant correlation between the initial lung function as measured by FEV1% (percent predicted) or FEV1/FVC and the subsequent rate of decline in FEV1 was found in men but not in women smokers (33). Whether the mechanism underlying these sex differences in lung function is somehow related to the carcinogenic process is not known. However, the strategy to use lung function to screen those most likely to harbor preinvasive lesions in anticipation of entry into studies of sequential detection methodologies or interventions (34) needs to be carefully examined. In our study, 56% of the men harboring high-grade preinvasive lesions had an FEV1 value that was more than 70% of the predicted value and 44% of such men had an FEV1/FVC value that was more than 70%. The efficiency of any early detection or chemoprevention study in the general population would be greatly diminished and the results may not be representative if half of those at risk were excluded from the study.

Our third finding in this study is the persistence of high-grade preinvasive lesions present more than 10 years after smoking cessation. This is in keeping with the observations by Halpern et al. (35) that, in long-term smokers, the risk of lung cancer plateaus at the age of smoking cessation. In these smokers, the risk does not decrease but actually rises again after about 10 years, presumably because of aging and environmental exposure. We (36) and others (37) have also reported previously that genetic alterations of allelic loss at sites of known or putative tumor suppressor genes present in current smokers are frequently found in former smokers even years after smoking cessation. However, the present study shows that, although the effect of field cancerization (38) could be observed, only a small proportion of individuals were found to have a multiplicity of high-grade preinvasive lesions. This offers hope that chemopreventive agents that can promote terminal differentiation or induce apoptosis within these lesions (39) might prove to be effective in preventing the development of invasive lung cancer.

In summary, our study shows that statistically significant sex differences exist in the prevalence and multiplicity of preinvasive bronchial lesions in current and former smokers. The results underscore the importance of including women in early detection and chemoprevention studies. These studies may require different approaches because peripherally located cancers predominate in women (15,16). In developing strategies for chemoprevention or early detection of lung cancer in high-risk populations, although the presence of airflow obstruction may identify those with greater risk, it is important to consider the size of the population harboring preinvasive lesions that may be excluded by arbitrarily chosen lung function values.


    NOTES
 
Editor's note: Dr. Lam currently conducts research using the LIFE-lung device that is sponsored by Xillex Technologies Corporation, the manufacturer of the device.

Supported by Public Health Service grant U01CA68381 and by contract N01CN65030 from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services.

We thank Suzan Ross, Carol Astrop, Myles McKinnon, and Sukhinder Khattra for their technical assistance in subject recruitment, bronchoscopy, and data management.


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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Manuscript received October 7, 1998; revised January 29, 1999; accepted February 12, 1999.


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