Adenocarcinoma of the Lung Is Strongly Associated with Cigarette Smoking: Further Evidence from a Prospective Study of Women

P. Yang1,, J. R. Cerhan1, R. A. Vierkant1, J. E. Olson1, C. M. Vachon1, P. J. Limburg1, A. S. Parker1, K. E. Anderson2 and T. A. Sellers1

1 Mayo Clinic Cancer Center, Rochester, MN.
2 Department of Epidemiology, University of Minnesota, Minneapolis, MN.

Received for publication December 10, 2001; accepted for publication July 19, 2002.


    ABSTRACT
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
In a prospective cohort of 41,836 Iowa women aged 55–69 years with 13 years of follow-up from 1986 through 1998, the authors examined the association between cigarette smoking history and three common histologic subtypes of lung cancer (123 small cell, 115 squamous cell, and 234 adenocarcinoma). Using Cox proportional hazards and additive Poisson regression analysis, they estimated four epidemiologic measures of effect: age-adjusted incidence rate, relative risk, excess risk (or risk difference), and population attributable risk. Of the three major lung cancer subtypes, the excess risk for heavy smokers compared with never smokers was higher for adenocarcinoma (excess risk = 206) than for squamous cell (excess risk = 122) and small cell (excess risk = 104) carcinomas. Adenocarcinoma of the lung is more strongly associated with tobacco smoke exposure than previously recognized.

lung neoplasms; neoplasms by histologic type; relative risk; risk assessment; smoking

Abbreviations: Abbreviations: CI, confidence interval; ICD-O, International Classification of Diseases for Oncology; PAR, population attributable risk.


    INTRODUCTION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Over the past 50 years, studies have shown an indisputable causal role of tobacco smoke in the worldwide epidemic of lung cancer. Each of the three major histologic subtypes of lung cancer, including squamous cell carcinoma, adenocarcinoma, and small cell carcinoma (1, 2), is associated with tobacco-smoking exposure. However, the influence of tobacco smoke on the risk of adenocarcinoma is not considered as great as that of the other two histologic types (35). This concept has been supported by reports that more never smokers and fewer heavy smokers were observed among patients with adenocarcinoma than among those with squamous cell or small cell carcinomas (6, 7). However, nearly all of the reports were from case-control studies (8), and these studies generally had very few never smokers available for analysis (7). Furthermore, prior investigations have focused on relative risk rather than other measures of public health significance, including excess risk and population attributable risk. Particularly in women with primary lung cancer, adenocarcinoma has been the most common histologic subtype (911). Here, we present an analysis from a prospective cohort study of older women on cigarette smoking and the three major histologic subtypes of lung cancer. Our goal is to further characterize the differential risk association of cigarette smoking and lung cancer histologic subtypes.


    MATERIALS AND METHODS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Study population
The Iowa Women’s Health Study is a prospective cohort study designed to identify risk factors for cancer and other chronic diseases in postmenopausal women (12, 13). In January 1986, a questionnaire was mailed to 99,826 women who had been selected at random from a list of women aged 55–69 years who held a valid Iowa driver’s license in 1985. The 41,836 respondents (42.7 percent response rate) form the cohort under study. The cohort was 98 percent Caucasian, and 65 percent lived in towns of less than 10,000 inhabitants. Compared with the nonrespondents, respondents were on average 2 months younger and slightly more likely to live in a rural or less affluent area. Nonrespondents had somewhat higher mortality rates for smoking-related diseases than did respondents (14).

Self-reported items on the questionnaire included reproductive factors, height, body circumferences, current weight, education, medication use, alcohol use, physical activity, and family history of cancer. Data on smoking history included age at initiation, average packs smoked per day, and age at cessation for former smokers. The questionnaire also included a semiquantitative food frequency questionnaire (15).

Baseline exclusions and cohort follow-up
Women reporting previous cancers at baseline other than nonmelanoma skin cancer were excluded (n = 3,830). The total cohort at risk for incident lung cancer was 38,006 women. Follow-up questionnaires were mailed in 1987, 1989, 1992, and 1997 to update address changes and vital status. Deaths were ascertained by linkage to the Iowa death certificate data, supplemented with linkage to the National Death Index. Incident lung cancer cases occurring from 1986 through 1998 were identified through the State Health Registry of Iowa, part of the National Cancer Institute’s Surveillance, Epidemiology, and End Results Program (16). A computer match was performed annually between the list of cohort members and the records of Iowans with incident cancer in the registry. Data regarding the diagnosis were abstracted by registry personnel from medical records and pathology reports according to Surveillance, Epidemiology, and End Results’ protocol (17) and were coded according to the International Classification of Diseases for Oncology (ICD-O), second edition (18). Using ICD-O morphology codes, we categorized lung cancer (codes 34.0–34.9) as adenocarcinoma (codes 8140–8380, 8480, 8481), squamous cell (codes 8050–8076), or small cell (codes 8041–8045).

Statistical methods
The length of follow-up for each individual in the study was calculated as the time from completion of the baseline questionnaire until the date of lung cancer diagnosis, date of move from Iowa, or date of death. If none of these events applied, the woman was assumed to be cancer free and living in Iowa through December 31, 1998. All analyses compared established lung cancer risk factors with regard to each of the three major histologic subtypes. Through 1998, a total of 598 cases of lung cancer were identified in the Iowa Women’s Health Study cohort (234 cases of adenocarcinoma, 115 cases of squamous cell carcinoma, 123 small cell carcinoma, and 126 other subtypes).

In descriptive analyses, we used means and standard deviations for all continuous variables and frequency distributions for all categorical variables. We compared continuous variables using t tests and analysis of variance methods, and categorical variables were compared across lung cancer classifications using chi-square tests. We examined the subtype-specific incidence rate of lung cancer in relation to cigarette smoking exposure, adjusting for age using standard Poisson regression with a log link function. The Poisson model is well suited for rate estimation of rare diseases. The cigarette smoking-related variables examined in this study included age at initiation, age stopped smoking (for former smokers), number of cigarettes per day, number of years smoked, years since quitting (for former smokers), and cumulative pack-years smoked. In our analysis of dose-response relations between smoking history and lung cancer subgroups, the variable, pack-years, was used as the overall exposure indicator. Inclusion of other smoking-related measures in multivariate analyses was considered unnecessary because of the high correlation among all six smoking-related measures; inclusion of such variables in a multivariate model could lead to overadjustment.

Excess risk or risk difference, also called causative risk difference (1922), provides an absolute measure of exposure effect on lung cancer risk among smokers compared with never smokers. The excess risk for smoking-related variables was calculated using an additive form of the Poisson generalized linear model (23). Each model was fit by specifying a Poisson distribution and an identity link function instead of the usual log link function. This modeling process allowed us to examine the association between subtype-specific lung cancer risk and smoking on an absolute scale, rather than on a relative scale. Age was included in each model as a continuous linear variable; however, additional models explored different characteristics of age, such as the addition of squared and cubic terms.

Cox proportional hazards regression (24) was used to calculate relative risks and 95 percent confidence intervals. For all Cox models, survival was modeled as a function of age instead of time on study (25), since age is a better predictor of lung cancer risk than length of follow-up time in this study. Separate Cox models were fit for each histologic subtype of interest. Population attributable risk estimates were calculated on the basis of coefficients generated by the Cox models and the distribution of smoking-related variables in the cohort (26). Confidence intervals were generated using bootstrap resampling methodology (27). Each population attributable risk estimates the percentage of decrease in subtype-specific lung cancer incidence that would result if smoking were completely eliminated from the population.

The following potential confounding variables were incorporated into all multivariate models: age at the study baseline; education (below high school, high school, and above high school); physical activity (low, moderate, and high); body mass index (based on quintiles); waist circumference (based on quintiles); alcohol use (never, below the median of use, above the median of use); and fruit consumption (based on quintiles). These variables were selected on the basis of previous results from the same population cohort or other studies (1114, 28). All statistical tests were two sided, and all analyses were carried out using the SAS (SAS Institute, Inc., Cary, North Carolina) and S-plus (Mathsoft, Inc., Seattle, Washington) software systems.


    RESULTS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
As shown in table 1, the mean age of the study population at baseline was 62.2 years in 1986, and there was no difference in mean age across the three subtypes of lung cancer. Two thirds of the study population were never smokers in contrast to 25 percent, 8 percent, and 4 percent of adenocarcinoma, squamous cell carcinoma, and small cell carcinoma cases, respectively. Among the cases with these subtypes, women with adenocarcinoma had the highest proportion of never smokers and, for those who did smoke, the fewest pack-years among former smokers. The distributions of other lung cancer risk factors were similar across subtypes with three exceptions: Women who developed squamous cell carcinoma appeared to consume more alcohol and less fruit than did women with the other two subtypes of lung cancer, and those who developed small cell lung cancer had higher waist circumferences than did those having the other subtypes. These risk factors were also compared between smokers and never smokers who developed lung cancer, as shown in table 2. Cases who smoked were less likely to finish their high school education and more likely to drink alcohol, to eat less fruit, and to be physically less active than never-smoking patients were. There was no significant difference observed for these risk factors between current and former smokers.


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TABLE 1. Selected descriptive characteristics of the study population and specific lung cancer histologic classifications within the Iowa Women’s Health Study, 1986–1998
 

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TABLE 2. Selected characteristics of lung cancer cases by smoking status, Iowa Women’s Health Sudy, 1986–1998
 
Detailed measures of cigarette smoking history and the comparisons of these variables across the case groups are provided in table 3. Lung cancer cases were significantly different from noncases with regard to all the variables compared. Among the cases, women who developed adenocarcinoma tended to smoke for fewer years and had less total pack-years of cigarettes than did women with other histologic types.


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TABLE 3. Cigarette smoking-related variables and specific lung cancer histologic classifications within the Iowa Women’s Health Study, 1986–1998
 
Table 4 shows the strong, graded positive associations between smoking (none, 1–19, 20–39, 40–59, >=60 pack-years) and each histologic subtype by all three risk measures: incidence rate, relative risk, and excess risk. Age-adjusted incidence rates per 100,000 person-years (figure 1) were highest for adenocarcinoma, and the incidence rate increased with increasing smoking for each histologic subtype. The slopes (the magnitude of increase) of the three incidence curves are almost parallel, indicating a similar dose-response relation between smoking and all three lung cancer histologic subtypes. The incidence trends were similar between former and current smokers, although in general the incidence rates were lower among former smokers for all pack-year levels.


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TABLE 4. Incidence rates, relative risks (risk ratios), and excess risks (risk differences) of specific lung cancer histologic classifications within the Iowa Women’s Health Study, 1986–1998
 


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FIGURE 1. Age-adjusted incidence rates per 100,000 person-years by smoking status, pack-years of cigarettes consumed, and lung cancer histologic subtype, Iowa, 1996–1999.

 
Relative risk estimates (table 4) were adjusted for age only and for additional covariates including physical activity, education, body mass index, waist circumference, alcohol use, and fruit consumption. The substantial attenuation in relative risks by multiple confounders, particularly for squamous cell and small cell lung cancers, suggests that other risk factors besides age and smoking may contribute to the risks. Based on relative risks, the strongest association of smoking was with small cell lung cancer, intermediate for squamous cell carcinoma, and lowest for adenocarcinoma. The lower relative risks for adenocarcinoma reflect the higher incidence rate of this tumor type among never smokers (19/100,000) than the incidence rates of squamous cell (3/100,000) and small cell (2/100,000) carcinomas.

Given the wide variation in incidence rate of lung cancer subtypes among never smokers, we also calculated an absolute measure of risk increase, the excess risk (or causal risk difference), by increments of pack-year exposure (table 4). This measure of association demonstrates that women were at the highest excess risk for adenocarcinoma at all four smoking exposure levels. This pattern held for age-adjusted excess risk and multivariate-adjusted excess risk. Taking 60 or more pack-years as an example, we found that the multivariate-adjusted excess risk for developing adenocarcinoma was 206/100,000 as compared with 122/100,000 for squamous cell carcinoma and 104/100,000 for small cell carcinoma. Therefore, the absolute effect of cigarette smoking on the risk of developing adenocarcinoma appears to be greater than on the risk of the other two subtypes.

All of our excess risk models were fit including age as a continuous, linear variable. It could be a concern that the association of age with excess risk may change in a nonlinear fashion; thus, we also explored alternative approaches to model age, including adding an age-squared or age-cubed term to the model. These approaches yielded results nearly identical to those of our original models (data not shown).

Population attributable risks were calculated to estimate the potential public health significance if active cigarette smoking were completely eliminated. Multivariate-adjusted population attributable risks (PARs in percentage) were the highest in small cell carcinoma (PAR = 93, 95 percent con-fidence interval (CI): 85, 98), followed by squamous cell carcinoma (PAR = 87, 95 percent CI: 77, 94), and the lowest in adenocarcinoma (PAR = 60, 95 percent CI: 43, 68). For each histologic subtype, smoking represents the most important avoidable risk factor.


    DISCUSSION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
When using relative risk as the measure of effect, we found that our data are consistent with results from previous studies showing that the association between cigarette smoking and lung cancer risk is stronger for small cell and squamous cell carcinomas than for adenocarcinoma. Our results also show that, when we used an absolute measure of exposure effect (excess risk), cigarette smoking is a very important risk factor for adenocarcinoma in postmenopausal Caucasian women. It has been widely accepted that the three major histologic subtypes of lung cancer are differentially associated with cigarette smoking on the basis of the smallest relative risk observed in adenocarcinoma. However, concerns have been raised that the higher relative risk (or odds ratio) in women with small cell or squamous cell carcinoma might simply reflect lower baseline risks in nonsmokers of these two subtypes as compared with adenocarcinoma (29). Our results validate this concern.

It seems that our results of relative risk and population attributable risk are inconsistent with those based on incidence rate and excess risk; that is, the lowest relative risk and population attributable risk versus the highest incidence rate and excess risk are from adenocarcinoma. In fact, relative risk and population attributable risk are relative measures and more strongly driven by the background risk, specifically, by the incidence rate among never smokers. This is most likely due to a significant heterogeneity in the etiology of adenocarcinoma and a relative homogeneity in the etiology of squamous cell and small cell carcinomas in our study population. This paradoxical population attributable risk could also be a reflection of its intrinsic drawback; that is, attributable risk factors beyond the known one(s) are either unmeasured or unknown (30, 31). In other words, adenocarcinoma was likely to have other causes beyond a history of active smoking, for example, exposure to environmental tobacco smoke. In contrast, virtually all cases of squamous cell or small cell carcinoma were related to cigarette smoking. Nevertheless, the population attributable risk for smoking with adenocarcinoma was estimated to be 60 percent (95 percent CI: 43, 68), and it seems unlikely that there is an unknown risk factor with such a strong population attributable risk.

Prospective cohort studies of the association between tobacco smoke and lung cancer histologic subtypes are lacking, particularly those that include an adequate number of never smokers. To our knowledge, the only population-based prospective study reported on this topic, from a Danish population, had only four cases of adenocarcinoma, four cases of squamous cell carcinoma, and no cases of small cell carcinoma among never-smoking women (7). The authors had to pool the male and female cases across all subtypes to generate the baseline risk for never smokers, which obviously could not address the issue of differential association between smoking and lung cancer subtypes in women. In our study, 72 never-smoking lung cancer cases, 58 with adenocarcinoma, nine with squamous cell carcinoma, and five with small cell carcinoma, were observed over a 13-year follow-up period. Our study provides the first report with reasonable sample size and adequate follow-up on the differential association between cigarette smoking history and three major histologic subtypes of lung cancer in older women.

In the establishment of an epidemiologic association between an exposure and a disease, both the risk or rate ratio and the risk or rate difference in the exposed and unexposed populations are important measures of association (1922). In our study, the relative risks indicate how much more likely smokers are to develop lung cancer than are never smokers, whereas the excess risks indicate the excess lung cancer incidence among smokers compared with among never smokers. These results suggest that people who develop adenocarcinoma are at least as susceptible to the carcinogens contained in tobacco smoke as those who develop squamous cell or small cell lung cancer. Indeed, our results in table 1 and table 3 suggest that patients with adenocarcinoma had less smoking exposure (shorter duration and fewer pack-years) than did other lung cancer patients, and they also experienced a prolonged excess risk after removal of the exposure (longer time since quitting and at a higher proportion among former smokers). These data suggest that continued smoking seems not as necessary for developing adenocarcinoma as for the other two subtypes.

A review of the predominant lung cancer histologic subtypes a century ago, before the tobacco epidemic, also supports our findings that adenocarcinoma is caused mainly by carcinogens contained in tobacco smoke. As it was rare to diagnose lung cancer in living patients, even autopsy-identified cases were scarce (3235). Between 1899 and 1911, a report from the University of Minnesota found no lung cancer in 1,032 consecutive autopsies, and another from Vienna, Austria, in a similar time period reported 68 lung cancers out of over 40,000 autopsies (less than 1 per 1,000) (35). It is difficult to find data on histologic subtypes from that era that can be compared with current classification schemes. However, one exceptional report of 50 consecutive lung cancer cases, published in 1902, found 32 (64 percent) squamous cell, two (4 percent) adenocarcinoma, and 16 (32 percent) other lung cancer types. Thus, from this historical document, adenocarcinoma was not the predominant type of lung cancer in the absence of tobacco smoke. If the nonsmoking-related risk were the same between contrasting histologic subgroups, the excess risk and relative risk would be all very similar.

A limitation in our study was the lack of information on the type of cigarettes used by the study participants. This information would be useful in confirming results from other studies that changes in the cigarette composition and smoking pattern may have caused the shift in distribution of lung cancer histologic subtypes (36, 37). Smoking behavior leading to tumor histology shift has been explained by the specificity of polycyclic aromatic hydrocarbons (rich in unfiltered cigarettes) with squamous cell carcinoma and of N-nitrosamines (rich in filtered cigarettes) with adenocarcinoma (38, 39).

Another limitation of our study is the relatively small number of former smokers who developed lung cancer (n = 99 for the three subtypes in the study). Stratified analyses, though suffering from lack of statistical power, indicated lower incidence rates across all exposure levels for former smokers compared with current smokers. However, the incidence trends by exposure level were almost the same in former smokers and current smokers.

An additional limitation of this study is the generalizability of our results. Our study is based on a cohort of midwestern postmenopausal women in the United States. In addition, although recruitment of the cohort was population based, smokers were somewhat less likely to participate than were nonsmokers. We have subsequently shown that the lung cancer incidence rate is higher among the nonparticipants (14), which would make our results more conservative.

In conclusion, our findings indicate that adenocarcinoma of the lung is clearly smoking related. The absolute increase in excess risk among smokers (excess risk) is the highest for adenocarcinoma in Caucasian women. From a public health perspective, our results do not agree with the notion that adenocarcinoma is not as strongly associated with cigarette smoking as are squamous cell and small cell carcinomas. Instead, our results suggest that adenocarcinoma of the lung is more strongly associated with tobacco smoke exposure than previously recognized. From the point of view of etiology, these findings do not support a subgroup-specific strategy in targeting causes to reduce lung cancer burden.


    ACKNOWLEDGMENTS
 
This work was supported by National Cancer Institute grant R01CA39741. Dr. Cerhan was supported in part by grant K0764220. Dr. Yang has been partially supported by grant R01 CA80127 from the National Institutes of Health.

The authors acknowledge the help of Dr. Aaron Folsom and Ching-Ping Hong. They also thank Susan Ernst for her technical assistance with the manuscript.


    NOTES
 
Correspondence to Dr. Ping Yang, Department of Health Sciences and Cancer Center at Mayo Clinic/Foundation, 200 First Street SW, Rochester, MN 55905 (e-mail: yang.ping{at}mayo.edu). Back


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 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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