Navigation

Types Of Lung Cancer

Study objectives: It is well-recognized that the risk of lung cancer declines after smoking cessation. However, the degree of decline in different histologic types of lung cancer is not well understood. We conducted a meta-analysis of peer-reviewed studies to assess the effect of smoking cessation on rates of major histologic types of lung cancer.

Design: Studies published in English between 1970 and 1999 were identified through searches of computerized databases (ie, MEDLINE and CANCERLIT). Combined estimates of relative risk and 95% confidence intervals were calculated for 27 studies using fixed and random effects models. Separate analyses were conducted for men and women.

Results: Smoking cessation was associated with a reduction in the risk of all the major histologic types of lung cancer. The highest reduction was in small cell lung carcinoma (SCLC) and squamous cell carcinoma (SQC), and the lowest reduction was seen in large cell cancer and adenocarcinoma. In women, the combined risks for SQC and SCLC were higher than those in men. The dose-response curve for intensity of smoking was steeper in women.

Conclusion: The findings of this study suggest that smoking cessation results in the greatest reductions for SCLC and SQC. This effect is most marked in heavy smokers, particularly among women. (CHEST 2001; 120:1577-1583)

Key words: case-control; cessation; histology; lung cancer; odds ratio; smoking

Abbreviations: ADC = adenocarcinoma; CI = confidence interval; LGC = large cell carcinoma; In OR = natural logarithm of the odds ratio; OR = odds ratio; SCLC = small cell lung carcinoma; SQC = squamous cell carcinoma;

**********

Lung cancer is the most common malignancy in the United States and is the leading cause of cancer deaths in men and women. (1) The lung cancer incidence is leveling off in men but is continuing to rise at a steady rate among women.

The association between smoking and lung cancer has been studied extensively and is well-established. Eighty-seven to ninety percent of lung cancer cases are attributable to cigarette smoking, and smokers are 22 times more likely to die from lung cancer than nonsmokers. (2)

It is well-recognized that the risk of lung cancer declines after smoking cessation. (3,4) However, it is not known whether this decline varies with the histologic type of lung cancer. Previous studies have shown that smoking is more often associated with squamous cell carcinoma (SQC) or small cell lung carcinoma (SCLC) than with adenocarcinoma (ADC). (5,6) Consequently, it is expected that greater reductions would be seen in cases of SQC and SCLC after smoking cessation. The effect of quitting smoking on the risk of large cell carcinoma (LGC) is not well-understood. In this study, we examined the effects of the cessation of smoking on the risk for the major histologic types of lung cancer.

MATERIALS AND METHODS

The MEDLINE and CANCERLIT databases were searched using key words pertaining to smoking and to histologic type of lung cancer. In addition, the reference lists of identified studies as well as review articles were examined to identify additional studies. This search strategy identified over 600 articles on smoking and lung cancer. Only studies pertaining to lung histology and published in English were reviewed. We excluded case series studies from further review. The search was repeated until no additional articles were found prior to September 2000. Articles were examined, and studies were excluded from the meta-analysis for any one of the following reasons: (1) two or more histologic types were grouped together and no data were presented on the specific histologic type; (2) lack of measures for relative risk; (3) absence of risk comparison to nonsmokers; and (4) the group studied was included in another published study.

Articles were stratified into subgroups based on study design and year of publication. Studies were reviewed and data pertaining to estimator of relative risk were abstracted. A series of meta-analyses were conducted and the results were evaluated in the context of the published literature on the subject. The heterogeneity of the estimators of relative risk was tested using Cochran Q statistics. (7) The fixed-effects model was used to obtain the combined estimator of relative risk (odds ratio [OR]) and its SE. The random-effects model (8) was used in situations in which significant heterogeneity within the groups of studies was detected.

Stratified analyses were carried out according to the type of control used in case-control studies. Separate analyses were carried out for men and women. The dose-response relationship was evaluated for the number of years of abstinence from smoking. At each dose, the OR and 95% confidence interval (CI) were extracted. The SE was calculated from the 95% CI. For a few studies in which the 95% CI was not provided, the OR and SE were calculated using the number of exposed cases and controls.

An exponential random-effects approach (9) was used to assess the effect of the number of years since smoking cessation on the risk reduction of lung cancer. For each study, a dose-response estimate was obtained by imposing a linear trend model for the natural logarithm of the OR (ln OR) at each exposure level. The midinterval score was assigned to a dose level at each exposure category. A combined slope or trend was obtained by combining individual slope estimates. The equality of the response across dose levels was tested using a t test.

Publication bias was investigated by constructing funnel plots for the ln OR vs study size for each histologic type. A rank correlation test (10) was used to test for the statistical significance of publication bias.

RESULTS

Forty-eight studies evaluating the association between smoking and major histologic types of lung cancer were reviewed. These studies were published between 1970 and 1999. Fifteen studies (11-25) were excluded because insufficient information was provided on the OR or the SE. Four studies (26-29) were excluded because the histologic types were identified only as "Kreyberg I" and "Kreyberg II." One study (30) presented a combined analysis of case-control studies in China and was excluded because the information on the original studies was not given.

The remaining 28 studies were included in the analysis. Information about these studies is presented in Table 1. There were 27 case-control studies (5,6,31-55) and one prospective cohort study. (56) Population-based control subjects were used in 12 case-control studies.(5,34-36,38,43,45,48-50,53,54) Eleven studies (31-33,37,39-42,46,51,55) used hospital-based control subjects, and only 2 studies (6,44) were autopsy-based. The study of Damber and Larsson (47) used both population-based and autopsy-based control subjects, and data pertaining to population-based control subjects were used in the meta-analysis. The study of Ger et al (52) used both hospital-based and population-based control subjects and was considered as a population-based study in the analysis. Nine studies (5,6,33,44,45,47,51,53,54) were restricted to men, and four studies (35,43,49,50) were restricted to women. Twelve studies(32,34,36-42,46,48,55) reported data separately for both men and women. The most frequent histologic type of lung cancer was SQC, and the least frequent histologic type was LGC.

The combined ORs for histologic types according to smoking status and study design are presented in Table 2. Significant heterogeneity was detected among studies on current smokers and for all histologic types and study designs. For ex-smokers, the heterogeneity test was not significant for SQC and SCLC in studies utilizing population-based control subjects. For SCLC, the combined estimate for population-based control subjects was higher than that for other designs. The highest OR was 72.5 (95% CI, 13.8 to 379) for SCLC and current smokers. The lowest OR was 2.55 (95% CI, 0.82 to 7.89) for ADC and ex-smokers.

Table 3 presents combined ORs for different histologic types of lung cancer by smoking status and gender. In current smokers, the combined OR for SQC and SCLC in women was higher than that in men. This gender difference was less marked for ADC. We could not ascertain the gender differences in LGC due to the limited number of studies. Among ex-smokers, there was a consistent decline in combined ORs across all histologic types of lung cancer. In ex-smokers, women had greater reductions in risk for SQC and SCLC compared to men.

Fourteen studies (5,6,32,35,40-42,44,46,48,50,53,54,56) provided information on the number of years since smoking cessation. The pooled dose-response test was significant in all the four histologic types (Table 4). The reduction in risk was steeper in SCLC in comparison to other subtypes (Fig 1). Combined estimates for the number of years since the cessation of smoking are presented in Table 5. Between 1 year and 4 years of cessation, there was a 19% reduction in the risk of SCLC. The lowest reduction was for ADC (12%). After [greater than or equal to] 10 years, there was a 65% reduction in SCLC and only a 47% reduction in ADC.

[FIGURE 1 OMITTED]

A plot for the ln OR in ever-smokers vs the inverse of the SE was generated for each of the four histologic types. None of the plots showed a relationship between In OR and study size. The test for publication bias by histologic type indicated no evidence of bias due to study size for all histologic types of lung cancer.

DISCUSSION

The findings of this study suggest that the risk of lung cancer decreases significantly after the cessation of smoking and for all histologic types of the disease. The magnitude of reduction varies among the histologic types of lung cancer. The cessation of smoking showed the greatest reduction in the risk of SQC or SCLC. The OR decreases progressively as the number of years of abstinence from smoking increases, and this is true for all histologic types. The risk reduction was most noticeable for SCLC followed by SQC. ADC displayed the least risk reduction. Our findings concerning risk reduction with abstinence are corollary to the effect of smoking on the occurrence of the major histologic types of lung cancer. The association between smoking and SCLC or SQC is stronger than that for ADC. (5,6,32,40,42,44,46,48,50,54) We also noted that the effect of smoking cessation on LGC was greater than that on ADC.

The results of our meta-analysis affirm that cessation of smoking is effective in reducing the risk of lung cancer in both men and women and that this effect is significantly greater for SCLC and SQC. Interestingly, women appeared to experience greater reduction in the risk of SCLC and SQC compared to men. However, the difference between women and men is not significant for ADC. Recent epidemiologic studies suggest that, given the same level of lifelong exposure, women may be more susceptible to tobacco carcinogens than men. (31) Mollerup et al (57) found that women had significantly higher levels of pulmonary DNA adducts (ie, modified DNA resulting from the binding of polynuclear aromatic hydrocarbons to the p53 gene) per pack-year than did men. The gender difference may be related to circulating female steroid hormones. A recent study (58) suggested that polymorphisms in CYP1A1 and GSTM1 contribute to an increased risk of lung cancer in women.

The steeper dose-response relationship with cessation of smoking was more noticeable for SCLC, particularly for women. This finding is clinically significant, as SCLC incidence appears to be increasing more rapidly in women than in men. (59-61) Increased efforts toward smoking cessation in women would yield earlier and greater reductions in SCLC.

The dose-response for LGC was not calculated in women due to insufficient data, and therefore no conclusions can be drawn. Several morphologic features of LGC are shared with other cell types. In the Surveillance, Epidemiology, and End Results program, LGC was not categorized before 1978. (62) We can only speculate that the reduction of risk in women is similar to that in men.

We noted that the progressive reduction in lung cancer incidence continued for > 10 years, suggesting a continued benefit with abstinence from smoking over time. Although the risk in ex-smokers was significantly reduced in comparison to current smokers, the risk never approached that in nonsmokers, even after > 10 years of smoking cessation. This finding reinforces the importance of the need for continued abstinence from smoking indefinitely. These findings also suggest that cigarette smoking can act as both an initiator and a promoter of lung carcinogenesis. The initiation and promotion of lung cancer is thought to result from a series of genetic mutations, including point mutations, chromosomal abnormalities, gene amplification, and altered gene expression. (63) Tobacco smoke contains > 100 diverse mutagens and carcinogens, including polycyclic aromatic hydrocarbons, N-nitrosamines, and aromatic amines. The metabolites of these carcinogens are direct mutagens and may cause DNA damage. (64) The promoting activity may be diminished immediately after the cessation of smoking and specifically for SCLC and SQC. However, the initiating activity remains for an extended period after the cessation of smoking and for all the histologic types of lung cancer.

There are several limitations that need to be taken into consideration before interpreting the findings of our analysis. These limitations stem from the studies included in the analysis and the inherent limitations of meta-analysis. Our meta-analysis involved studies from different parts of the world, and thus the accuracy of the classification of the histologic types of lung cancer may not be consistent. The diagnosis of lung cancer was not necessarily performed in a uniform manner across hospitals in different parts of the world. Most of the studies are retrospective and relied on recall information for exposure assessment leading to recall bias. The validity of the information on years of cessation from smoking (especially in the remote past) is difficult to determine. We limited our search to studies published in the English language, and we may have missed some published and unpublished work, particularly that stemming from smaller studies. However, this is unlikely to affect our results substantially since we have included studies from different continents.

Some studies were limited by the small number of cases for particular histologic type and gender. The accuracy of ORs may not be reliable, especially for LGC. Three types of control subjects were employed in case-control studies, and the OR probably reflected a design-specific bias. For deceased patients and control subjects, the data were collected from the next of kin. The use of proxy respondents as a source of data on smoking status may not be reliable. As smoking is also related to causes of death other than lung cancer, a comparison with deceased control subjects probably underestimated the true risk of lung cancer. Living control subjects may outlive the patients by many years and may, therefore, cause an overestimation of risk. The use of hospital control subjects may lead to an underestimation of an effect if the causes for hospitalization are also associated with smoking. Our meta-analysis also is limited by the degree of heterogeneity, as noted by the wide CIs. However, the decrease was consistent in the same direction, suggesting a stability for risk reduction with smoking cessation.

In conclusion, the findings of our meta-analysis suggest that abstinence from cigarette smoking is associated with a reduction of risk for all histologic types of lung cancer, with the reduction being greater for patients with SCLC and SQC. This reduction is more marked in women. Cohort studies are needed to corroborate our findings as the incidence of SCLC is leveling off in men but continues to increase in women. The continuous increase in the prevalence of smoking in developing countries demands the means to address this serious health problem. The findings also suggest that cigarette smoking has the strongest effect on SCLC and the weakest effect on ADC. It is possible that other exposures are involved in the etiology of ADC. Further studies are needed to delineate these other risk factors for ADC. Our study highlights the lack of data on the effect of smoking cessation on LGC risk reduction. We suggest that further studies be conducted to assess the effect of smoking cessation on the risk of LGC and that they be conducted in women particularly.

Table 1--Summary of Studies Used in Meta-analyses of Smoking
Cessation and Lung Cancer *

                                             Patients, No.

                                                              Control
       Study/Year              Country         M       F       Type

Khuder et al (5)/1998
  ([dagger])                United States      482     --     P
Barbone et al (6)/1997
  ([dagger])                Italy              755     --     D
Zang and Wynder (31)/1996   United States    1,108      781   H
Lubin and Blot (32)/1984    Western Europe   5,864      772   H
Vena et al (33)/1985        United States    1,002     --     H
Brownson et al (34)/1987    United States       50       52   P
Wu et al (35)/1985          United States     --        220   P
Gao et al (36)/1988         China              733      672   P
Shimizu et al (37)/1994     Japan              413      192   H
Sobue et al (38)/1988       Japan            1,660      423   P
Shimizu et al (39)/1986     Japan              603      148   H
Brownson et al (40)/1992    United States    9,384    5,212   H
Muscat et al (41)/1997      United States      228      154   H
Osann et al (42)/1993       United States    1,153      833   H
Schoenberg et al
  (43)/1989                 United States     --        994   P
Jedrychowski et al
  (44)/1992                 Poland           1,432     --     D
Siemiatycki et al
  (45)/1995                 Canada             857     --     P
Morabia and Wynder
  (46)/1991                 United States      851      507   H
Damber and Larsson
  (47)/1986                 Sweden             537     --     D, P
Risch et al (48)/1993
  ([dagger])                Canada             403      442   P
Lam et al (49)/1987         China             --        445   P
Svensson et al (50)/1989
  ([dagger])                Sweden            --        210   P
Stayner and Wegman
  (51)/1983                 United States      420     --     H
Ger et al (52)/1993         Taiwan            All       131   H, P
Pohlabeln et al (53)/1997
  ([dagger])                Germany            370     --     P
Pezzotto et al (54)/1993
  ([dagger])                Argentina          215     --     P
Sobue et al (55)/1994       Japan            1,082      294   H
Prescott et al (56)/1998
  ([dagger]) ([section])    Denmark            864   30,874     --

                              Histologic
       Study/Year                Type         OR       95% CI

Khuder et al (5)/1998
  ([dagger])                All 4 types       9.35   7.05-12.4
Barbone et al (6)/1997
  ([dagger])                All 4 types       9.91   7.01-13.8
Zang and Wynder (31)/1996   SQC, ADC         12.2    10.4-14.3
Lubin and Blot (32)/1984    SQC, SCLC, ADC    5.85   5.20-6.59
Vena et al (33)/1985        SQC, SCLC, ADC    8.43   7.90-8.99
Brownson et al (34)/1987    ADC               6.86   5.50-8.55
Wu et al (35)/1985          SQC, ADC          2.82   1.84-4.31
Gao et al (36)/1988         SQC, SCLC, ADC    3.53   2.90-4.31
Shimizu et al (37)/1994     SQC, ADC          2.16   1.49-3.13
Sobue et al (38)/1988       All 4 types       3.91   3.51-4.36
Shimizu et al (39)/1986     All 4 types       3.60   2.77-4.68
Brownson et al (40)/1992    SQC, SCLC, ADC   10.7    10.0-11.5
Muscat et al (41)/1997      LGC              12.2    8.70-17.2
Osann et al (42)/1993       SQC, SCLC, ADC   16.6    13.7-20.1
Schoenberg et al
  (43)/1989                 SQC, SCLC, ADC   11.5     8.1-16.3
Jedrychowski et al
  (44)/1992                 SQC, SCLC, ADC    3.80   2.35-6.13
Siemiatycki et al
  (45)/1995                 SQC, SCLC, ADC   12.1    6.60-22.3
Morabia and Wynder
  (46)/1991                 All 4 types       1.3     1.2-1.5
                                                     ([double
                                                      dagger])
Damber and Larsson
  (47)/1986                 SQC, SCLC, ADC    7.30   5.10-10.7
Risch et al (48)/1993
  ([dagger])                All 4 types       8.89   6.07-13.0
Lam et al (49)/1987         Ail 4 types       3.81   2.86-5.08
Svensson et al (50)/1989
  ([dagger])                SQC, SCLC, ADC    3.44   2.17-5.46
Stayner and Wegman
  (51)/1983                 SQC, SCLC, ADC    3.30   2.60-4.30
Ger et al (52)/1993         SQC, ADC          1.67   0.92-3.03
Pohlabeln et al (53)/1997
  ([dagger])                SQC, SCLC, ADC   10.0    6.00-16.8
Pezzotto et al (54)/1993
  ([dagger])                SQC, SCLC, ADC   19.3    7.02-53.1
Sobue et al (55)/1994       All 4 types       2.50   1.93-3.24
Prescott et al (56)/1998
  ([dagger]) ([section])    SQC, ADC          7.79   4.95-12.3

* H = hospital; P = population; D = dead; F = female; M = male.

([dagger]) Adjusted for number of pack-years of smoking.

([double dagger]) Compared to current smokers of 1 to 19
cigarettes per day.

([section]) Prospective cohort study and not included
in the meta-analysis.
Table 2--Combined OR of Lung Cancer According to Smoking
Status and Study Design

                           Current Smoker        Ex-Smoker

               Studies,
  Variables      No.       OR      95% CI      OR      95% CI

SQC
  Hospital        10      25.9    18.4-36.3   13.9    9.65-19.9
  Population      13      21.3    7.46-61.0    6.11   3.26-11.5 *
  All             23      25.4    18.4-35.1   11.3    8.28-15.5
SCLC
  Hospital         7      37.9    18.5-77.9   17.1     8.9-32.9
  Population      11      72.5    13.8-379    17.2     4.2-70.5 *
  All             18      42.0    21.7-81.2   17.1    9.46-31.0
ADC
  Hospital        10       8.61   4.92-15.1    5.73   2.87-11.5
  Population      13       5.42   3.81-7.70    2.55   0.82-7.89
  All             23       6.18   4.59-8.32    4.59   2.54-8.30
LGC
  Hospital         3      12.2    4.49-33.4    6.48   3.90-10.8
  Population       3       5.90   1.20-29.5    5.90   1.10-31.1
  All              6       9.94   4.25-23.3    6.42   3.94-10.5

* Nonsignificant heterogeneity test.
Table 3--Combined OR of Lung Cancer According to
Smoking Status and Gender

                           Current Smoker          Ex-Smoker

                Studies,
  Variables       No.       OR       95% CI      OR      95% CI

SQC
  Men              18      19.9    12.2-32.4    10.4    6.98-15.4
  Women            15      29.5    22.0-39.5    12.9    7.09-23.4
SCLC
  Men              17      20.3    12.1-34.2     8.17   6.54-10.2 *
  Women            11      79.9    37.4-170.5   29.9    22.4-39.8 *
ADC
  Men              20       7.48   3.97-14.1     5.72   2.76-11.8
  Women            16       8.15   5.18-12.8     3.26   1.38-7.71
LGC
  Men               7      10.3    4.05-26.0     6.54   3.46-12.4
  Women             1

* Nonsignificant heterogeneity test.
Table 4--Dose-Response Analyses for Quitting
Smoking

Variables   [beta]    SE     p Value

SQC         -0.071   0.015     0.001
SCLC        -0.084   0.022     0.003
ADC         -0.051   0.021     0.023
LGC         -0.062   0.012     0.004
Table 5--Adjusted Risk Ratio for Year of Quitting for Major
Histologic Types of Lung Cancer

                       SQC                SCLC

  Years Since
 Quitting, No.      OR     95% CI      OR     95% CI

0                  1      1           1      1
<1                 0.97   0.95-0.98   0.96   0.94-0.98
1-4                0.84   0.78-0.90   0.81   0.73-0.90
5-9                0.61   0.49-0.75   0.56   0.41-0.75
[greater than or
  equal to] 10     0.41   0.28-0.60   0.35   0.21-0.60

                       ADC                LGC

  Years Since
 Quitting, No.      OR     95% CI      OR     95% CI

0
<1                 0.98   0.95-1.00   0.97   0.96-0.98
1-4                0.88   0.79-0.98   0.86   0.81-0.91
5-9                0.70   0.52-0.93   0.65   0.55-0.77
[greater than or
  equal to] 10     0.53   0.31-0.88   0.46   0.34-0.62

REFERENCES

(1) Landis SH, Murray T, Bolden S, et al. Cancer statistics. CA Cancer J Clin, 1999; 49:8-31

(2) United States Surgeon General. Reducing the health consequences of smoking: 25 years of progress. Washington, DC: US Government Printing Office, 1989

(3) US Department of Health and Human Services. The health benefit of smoking cessation: a report of the Surgeon General. Rockville, MD: Department of Health and Human Services, 1990; DHHS Publication No. (CDC) 90-8416

(4) Ockene JK, Kuller LH, Svendsen KH, et al. The relationship of smoking cessation to coronary heart disease and lung cancer in the multiple risk factor intervention trial (MRFIT). Am J Public Health 1990; 80:954-958

(5) Khuder SA, Dayal HH, Mutgi AB, et al. Effect of cigarette smoking on major histological types of lung cancer in men. Lung Cancer 1998; 22:15-21

(6) Barbone F, Bovenzi M, Cavallieri F, et al. Cigarette smoking and histologic type of lung cancer in men. Chest 1997; 112:1474-1479

(7) Cochran WG. The combination of estimates from different experiments. Biometrics 1954; 8:101-129

(8) DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Thais 1987; 7:177-188

(9) Tweedie RL, Mengersen KL. Meta-analytic approaches to dose-response relationship, with application in studies of lung cancer and exposure to environmental tobacco smoke. Stat Med 1995; 14:545-569

(10) Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics 1994; 50: 1088-1101

(11) Kreuzer M, Kreienbrock L, Muller KM, et al. Histologic types of lung carcinoma and age at onset. Cancer 1999; 85:1958-1965

(12) Hegmann KT, Fraser AM, Keaney RP, et al. The effect of age at smoking initiation on lung cancer risk. Epidemiology 1993; 4:444-448

(13) McDuffie HH, Klaassen DJ, Dosman J. Determinants of cell type in patients with cancer of the lung. Chest 1990; 98:1187-1193

(14) Tsugane S, Watanabe S, Sugimura H, et al. Smoking, occupation and family history in lung cancer patients under fifty years of age. Jpn J Clin Oncol 1987; 17:309-317

(15) Auerbach O, Hammond EC, Garfinkel L. Changes in bronchial epithelium in relation to cigarette smoking, 1955-1960 vs 1970-1977. N Engl J Med 1979; 300:381-386

(16) Lam WK, So SY, Yu DYC. Clinical features of bronchogenic carcinoma in Hong Kong: review of 480 patients. Cancer 1983; 52:369-376

(17) Shimizu H, Preston-Martin S, Casagrande JT, et al. Epidemiological characteristics of adenocarcinoma of the lung in Los Angeles County. Natl Cancer Inst Monogr 1982; 62:161-164

(18) Kennedy A. Relationship between cigarette smoking and histological type of lung cancer in women. Thorax 1973; 28:204-208

(19) Weiss W, Boucot KR, Seidman H, et al. Risk of lung cancer according to histologic type and cigarette dosage. JAMA 1972; 222:799-801

(20) Joly OJ, Lubin JH, Caraballoso M. Dark tobacco and lung cancer in Cuba. J Natl Cancer Inst 1983; 70:1033-1039

(21) Doll R, Peto R. Cigarette smoking and bronchial carcinoma: dose and time relationships among regular smokers and lifelong non-smokers. J Epidemiol Commun Health 1978; 32:303-313

(22) MacLennan R, Da Costa J, Day NE, et al. Risk factors for lung cancer in Singapore Chinese: a population with high female incidence rates. Int J Cancer 1977; 20:854-860

(23) Deaner RM, Trummer MJ. Carcinoma of the lung in women. Thorac Cardiovasc Surg 1970; 59:551-554

(24) Vincent RG, Pickren JW, Lane WW, et al. The changing histopathology of lung cancer: a review of 1682 cases. Cancer 1977; 39:1647-1655

(25) Muscat JE, Wynder EL. Lung cancer pathology in smokers, ex-smokers and never smokers. Cancer Lett 1995; 88:1-5

(26) Chan WC, Colbourne MJ, Fung SC, et al. Bronchial cancer in Hong Kong 1976-1977. Br J Cancer 1979; 39:182-192

(27) Osann KE. Lung cancer in women: the importance of smoking, family history of cancer, and medical history of respiratory disease. Cancer Res 1991; 51:4893-4897

(28) Benhamou S, Benhamou E, Tirmarche M, et al. Lung cancer and use of cigarettes: a French case-control study. J Natl Cancer Inst 1985; 74:1169-1175

(29) Harris RE, Zang EA, Anderson JI, et al. Race and sex differences in lung cancer risk associated with cigarette smoking. Int J Epidemiol 1993; 22:592-599

(30) Yu SZ, Zhao N. Combined analysis of case-control studies of smoking and lung cancer in China. Lung Cancer 1996; 14(suppl):S161-S170

(31) Zang EA, Wynder EL. Differences in lung cancer risk between men and women: examination of the evidence. J Natl Cancer Inst 1996; 88:183-192

(32) Lubin JH, Blot WJ. Assessment of lung cancer factors by histologic category. J Natl Cancer Inst 1984; 73:383-389

(33) Vena JE, Byers TE, Cookfair D, et al. Occupation and lung cancer risk: an analysis by histologic subtypes. Cancer 1985; 56:910-917

(34) Brownson RC, Reif JS, Keefe TJ, et al. Risk factors for adenocarcinoma of the lung. Am J Epidemiol 1987; 125: 25-34

(35) Wu AH, Henderson BE, Pike MC, et al. Smoking and other risk factors for lung cancer in women. J Natl Cancer Inst 1985; 74:747-751

(36) Gao YT, Blot WJ, Zheng W, et al. Lung cancer and smoking in Shanghai. Int J Epidemiol 1988; 17:277-280

(37) Shimizu H, Nagata C, Tsuchiya E, et al. Risk of lung cancer among cigarette smokers in relation to tumor location. Jpn Cancer Res 1994; 85:1196-1199

(38) Sobue T, Suzuki T, Horai T, et al. Relationship between cigarette smoking and histologic type of lung cancer, with special reference to sex difference. Jpn J Clin Oncol 1988; 18:3-13

(39) Shimizu H, Hisamichi S, Motomiya M, et al. Risk of lung cancer by histologic type among smokers in Miyagi Prefecture. Jpn J Clin Oncol 1986; 16:117-121

(40) Brownson RC, Chang JC, Davis JR. Gender and histologic type variation in smoking-related risk of lung cancer. Epidemiology 1992; 3:61-64

(41) Muscat JE, Stellman SD, Zhang Z, et al. Cigarette smoking and large cell carcinoma of the lung. Cancer Epidemiol Biomarkers Prey 1997; 6:477-480

(42) Osann KE, Anton-Culver H, Kurosaki T, et al. Sex differences in lung cancer risk associated with cigarette smoking. Int J Cancer 1993; 54:44-48

(43) Schoenberg JB, Wilcox HB, Mason TJ, et al. Variation in smoking-related lung cancer risk among New Jersey women. Am J Epidemiol 1989; 130:688-695

(44) Jedrychowski W, Becher H, Wahrendorf J, et al. Effect of tobacco smoking on various histological types of lung cancer. J Cancer Res Clin Oncol 1992; 118:276-282

(45) Siemiatycki J, Krewski D, Franco E, et al. Associations between cigarette smoking and each of 21 types of cancer: a multi-site case-control study. Int J Epidemiol 1995; 24:504-514

(46) Morabia A, Wynder EL. Cigarette smoking and lung cancer cell type. Cancer 1991; 68:2074-2078

(47) Damber LA, Larsson LG. Smoking and lung cancer with special regard to type of smoking and type of cancer: a case-control study in north Sweden. Br J Cancer 1986; 53:673-681

(48) Risch HA, Howe GR, Jain M, et al. Are female smokers at higher risk for lung cancer than male smokers? A case-control analysis by histologic type. Am J Epidemiol 1993; 138: 281-293

(49) Lam TH, Kung ITM, Wong CM, et al. Smoking, passive smoking and histological types in lung cancer in Hong Kong Chinese women. Br J Cancer 1987; 56:673-678

(50) Svensson C, Pershagen G, Klominek J. Smoking and passive smoking in relation to lung cancer in women. Acta Oncol 1989; 28:623-629

(51) Stayner LT, Wegman DH. Smoking, occupation, and histopathology of lung cancer: a case-control study with the use of the Third National Cancer Survey. J Natl Cancer Inst 1983; 70:421-426

(52) Ger LP, Hsu WL, Chen KT, et al, Risk factors of lung cancer by histological category in Taiwan. Anticancer Res 1993; 13:1491-1500

(53) Pohlabeln H, Jockel KH, Muller KM. The relation between various histological types of lung cancer and the number of years since cessation of smoking. Lung Cancer 1997; 18:223-229

(54) Pezzotto SM, Mahuad R, Bay ML, et al. Variation in smoking-related lung cancer risk factors by cell type among men in Argentina: a case-control study. Cancer Causes Control 1993; 4:231-237

(55) Sobue T, Suzuki T, Fujimoto I, et al. Case-control study for lung cancer and cigarette smoking in Osaka, Japan: comparison with results from Western Europe. Jpn J Cancer Res 1994; 85:464-473

(56) Prescott E, Osier M, Hein HO, et al. Gender and smoking-related risk of lung cancer. Epidemiology 1998; 9:79-83

(57) Mollerup S, Ryberg D, Hewer A, et al. Sex differences in lung CYP1A1 expression and DNA adduct levels among lung cancer patients. Cancer Res 1999; 59:3317-3320

(58) Dresler CM, Fratelli C, Babb J, et al. Gender differences in genetic susceptibility for lung cancer. Lung Cancer 2000; 30:153-160

(59) Beard CM, Annegers JF, Woolner LB, et al. Bronchogenic carcinoma in Olmsted county, 1935-1979. Cancer 1985; 55:2026-2030

(60) Dodds L, Davis S, Polissar L. A population-based study of lung cancer incidence trend by histologic types 1974-1981. J Natl Cancer Inst 1986; 77:53-56

(61) Wu AH, Henderson BE, Thomas DC, et al. Secular trends in histologic types of lung cancer. J Natl Cancer Inst 1986; 77:53-56

(62) Ries LAG, Hankey BF, Miller BA, et al. Cancer statistics review 1973-88. Bethesda, MD: National Cancer Institute; National Institutes of Health, Publication No. 91-2789

(63) Birrer MJ, Minna JD. Molecular genetics of lung cancer. Semin Oncol 1988; 15:226-235

(64) Shields PG. Molecular epidemiology of lung cancer. Ann Oncol 1999; 10(suppl):S7-S11

* From the Department of Medicine, Medical College of Ohio, Toledo, OH.

Manuscript received October 2, 2000; revision accepted May 17, 2001.

Correspondence to: Sadik A. Khuder, PhD, Department of Medicine, Medical College of Ohio, 3120 Glendale Ave, Toledo, OH 43614-5809; e-mail: skhuder@mco.edu

COPYRIGHT 2001 American College of Chest Physicians
COPYRIGHT 2001 Gale Group