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I I I I I I I I I I I I I / I I 1 I ETIOLOGY OF LUNG CANCER IN WOMEN Du Yine-xiu Guangzhou Research Center for Lung Cancer, Guangzhou, China Epidemiological studies have shown that there are more male smokers than female smokers, yet female lung cancer rates remain very high. For example, for the over-age-15 population in Guangzhou, 65 % of the males, but only 5% of the females are smokers. (Table 1) Yet the lung cancer death rate for many years has maintained a male to female ratio of 1.8:1.0, implying that in female lung cancer there may be other risk factors beside smoking. Table 1. A Comparison of Smoking Rates with Male/Female Lung Cancer Death Rates Smoking Rate Lung Cancer Death Rate Male Female Relative Ratio Male Female Relative Ratio Guangzhou 65,000/105 5,000/105 13.0 45/105 25/105 1.8 In addition to active smoking, many studies have emphasized the importance of environmental tobacco smoke (ETS) as a risk factor for lung cancer. Since case studies have shown that over 50% of the female lung cancer cases are nonsmokers, leaving aside the question of whether ETS-exposure is actually related to lung cancer, it is hardly reasonable to attribute 50% of all nonsmoking female lung cancers to exposure to ETS. Clearly, further research on all the potential risk factors for female lung cancer is needed. It is generally accepted that the etiology of a disease is closely related to the mechanism of disease development; thus, in any etiology research, the methodology should include data obtained from both epidemiological and experimental results. Lung cancer mortality rates have risen dramatically in recent decades. One explanation is that lung cancer is caused by environmental carcinogens, since the influence of genetic factors is usually relatively constant and rarely triggers sudden changes in a relatively short time. Since there is an apparent difference in the relative distribution of cell types between male and female lung cancers, it seems possible that different mechanisms are involved in the induction of different histological types of lung cancer. At the same time, some studies have reported the tendency of lung cancer to be clustered in families. Whether the rapid rise in lung cancer death rate is due to external or to endogenous factors or, alternatively, to their interactions, remains to be investigated. There are as many as 13 cell types in lung cancer, the four most common of which are squamous cell carcinoma, adenocarcinoma, small cell carcinoma and large cell carcinoma, with squamous cell carcinoma and adenocarcinoma constituting more than 80% of the total lung cancer cases. These two malignant cell types have many different biological characteristics. (Table 2) I

' Table 2. Comparison of some Biological Characteristics between Squamous Cell and Adeno Cell Carcinoma of Lung Squamous Cell Adenocarcinoma Etiology Frequently seen in cigarette smokers and Frequently seen in women patients with chronic bronchitis Cell Origin Arises from bronchial epithelium and has Arises from mucous cell of the undergone squamous metaplasia bronchial glands or lung alveolar cell Morphology Cells are in sheets, cords and bundles The neoplasm is composed of columnar separated by varying amounts of vascular cells and usually with mucin-containing connective tissue vacuoles in many cells Tumor location Located in the larger bronchus near the Located in the smaller or smallest hilum and at central sites within the lung bronchus and at peripheral sites of lung Doubling times 100 days 187 days Stains Keratin + - Mucin - + K-ras oncogene Mutation in squamous cell needs further Mutation frequently seen in study, but never seen in small cell adenocarcinoma of lung carcinoma Biochemical characteristic Low serum cytokeratin-19 level High serum cytokemtin-19 level, capable of endocrine secretion Cell Membrane Receptors Low positive estrogen receptors High positive estrogen receptors The cell type differences in male and female cancer patients have clinical significance. Squamous cell carcinoma is the most frequently seen lung cancer cell type in males (approximately 55 % of the total cases), with adenocarcinoma being the next most frequent (approximately 25 % of the cases). (Table 3) The reverse is true in female patients: the most frequently seen cell type is adenocarcinoma (approximately 60% of the cases), with the next most frequent being squamous cell carcinoma (approximately 25 % of the cases). It is apparent, then, that in the investigation of the etiology of female lung cancer, the research focus should be on the adenocarcinoma. Furthermore, as many recent reports have indicated, proportion of lung adenocarcinoma continues to rise in lung cancers, emphasizing the vital importance of the cell type to the research in lung cancer. _2_ I I I I I I I I I I I I I I I I

I I I I I I I I I I I 1 I I I I i I Table 3. Comparison of Lung Cancer Cell Types Between Male/Female Smokers and Nonsmokers in Both Male and Female Cases* M ale Fe male Smoker Nonsmoker Smoker Nonsmoker No. % No. % No. % No. % Squamous cell carcinoma 438 59.03 25 40.32 51 36.17 33 22.30 Small cell carcinoma 56 7.55 2 3.23 12 8.51 12 8.11 Adenocarcinoma 170 22.91 22 35.48 57 40.43 83 56.08 Large cell carcinoma 14 1.80 1 1.60 1 0.71 1 0.67 Others 64 8.62 12 19.36 20 14.18 19 12.84 TOTAL 743 100.00 62 100.00 141 100.00 148 100.00 * A total of 1094 (male 805, female 289) cases were used. 1. Smoking and Female Lung Cancer. Smoking is generally recognized as an important risk factor for lung cancer in both men and women. However, the relative significance of smoking in female lung cancer seems to be lower than that for male lung cancer. Because a large number of female lung cancer patients are nonsmokers, the odds ratio (OR) for smoking in women is lower than the OR for men. When the cell types of smoking and nonsmoking male and female patients are compared, the results show that among male smokers, the rate of squamous cell carcinoma is decidedly higher than that of the adenocarcinoma, but among female smokers the rates are similar. Among nonsmokers, the squamous cell carcinoma and adenocarcinoma rates are similar in men, but the adenocarcinoma rate is much higher than the squamous cell carcinoma rate for women. (Table 4) Table 4. Comparison of Sqtramous Cell Carcinoma and Adenocarcinoma in Male and Female Smokers* Male Female Smoker Sqm (59.03) > Ade (22.91) Sqm (36.17) _ Ade (40.43) * A total of 1094 (Male 805, female 289) cases were used. The results clearly show that in men smoking may induce squamous cell carcinoma; but in women, there must be other risks for the high incidence of adenocarcinoma. -3- !

2. Exposure to ETS and Female Lung Cancer. This is a difficult subject for research which will yield accurate results. First, lung cancer has a long latency; it usually takes more than 10 years for active smokers to develop lung cancer. It is not unreasonable to assume that it may take even longer for the effects of ETS exposure to be observed, if ETS is capable of inducing lung cancer. During such a long latency, data and conditions of the nonsmokers' exposure, such as numbers of cigarettes smoked by the smokers, the extent of close contacts with the smokers, the conditions of the shared living space, can be dynamic and variable. Moreover, in order to obtain accurate results on the effects of ETS exposure on lung cancer, not only must the study subjects be truly nonsmokers, other risk factors or confounders, such as effects of air pollution and occupational exposures, must be excluded. All these elements are realistically difficult to control. Secondly, since the smoking-related lung cancers are known to be squamous cell carcinoma in the center of the lung, it follows that ETS-related lung cancers should also be of the same cell type, not the adenocarcinoma located in the periphery of the lung which is the prevalent cell type in female lung cancer. This contradiction notwithstanding, it needs to be noted that although the relationship between ETS and lung cancer has not been established at the present, ETS still should not be dismissed as a health risk. 3. Indoor Air Pollution and Female Lung Cancer. Reports from many areas of China have clearly demonstrated a significant relationship between indoor air pollution and lung cancer in women. A major source of indoor air pollution is coal-burning for cooking and heating. Our combined epidemiological survey and laboratory study demonstrated that female lung cancer is likely to be related to indoor air pollution, because indoor coal-burning increases B(a)P concentration in the indoor air. Housewives in coal-burning households are shown to have significantly higher levels of urine B(a)P than housewives in households using liquefied gas for cooking. Our correlated epidemiological studies also indicate that indoor air pollution is associated more with female lung cancer than with male lung cancer. In addition to coal-burning as a source of indoor air pollution, Gao and coworkers also reported a relationship between lung cancer and pollutants generated by certain cooking oil and cooking practices. (Table 5) -4- ? I I I I I I I I I I I I I I I I

I I I I I I I I I I 1 I I I I I I , Table 5. Comparison of Air Pollutants and Urine B(a)P Levels in Housewives Coolung with Coal or Propane Cooking With Coal Cooking With Propane Gas Coal/Propane S02 (µ/M3) 279 58 4.81 NOx (µ/M3) 3 76 63 1.21 CO (p/M ) 9,424 2,340 0.03 TSP (µ/M3) 332 188 1.77 SD (glM2/month) 12 5 2.40 B(a)P ((u/100M3) 11.9 2.2 5.41 Radon (Bq/M3) 18.6 16.6 1.12 Thoron (Bq/M3) 42.5 28.3 1.50 Urine-B(a)P (ng/t) 4.0 2.8 1.43 However, many questions remain unanswered: coal has been in use for cooking and heating and vegetable oil has been used for frying for many years; why, then, have lung cancer rates been on the rise only during the past 20 or 30 years? Environmental carcinogenic chemicals have been known to induce squamous cell carcinomas, but why are female lung cancers predominantly adenocarcinomas? Since indoor air pollution sources and characteristics are different for industrialized and developing countries, why have all nations experienced similar trends of higher female lung cancers, dominated by adenocarcinomas? 4. History of Respiratory Disease in Female Lung Cancer. Several epidemiological studies have indicated that lung cancer patients often have a history of bronchitis. This is easy to understand in the case of women, since in cooking, women are more likely to be exposed to smoke from burning-coal and other irritants generated by deep frying and stir-frying. A question that begs for our attention is that it has been reported that the disturbance of the microbial population may cause the metabolic disturbance of the intestine and lead the metabolized procarcinogens to be activated as ultimate carcinogens, which, in turn, can induce colon cancer. In the case of lung cancer, can large doses of antibiotics used to combat chronic bronchitis result in the disturbance in the microbial population in the lung, causing the procarcinogens in the lung to be activated as ultimate carcinogens? 5. Estrogen and Female Lung Cancer. Estrogen disturbance and female lung cancer may be a question worthy of our consideration. It has been reported that prophylactic use of estrogen for heart disease is correlated with an increase in lung cancer incidence. Some researchers consider early menarche, long menstrual periods, shortened menstruation cycles and delayed menopause as some of the risk factors of female lung cancer (Gao Yu- tang, Liao Mei-lin). Others have reported that the level of estrogen receptors on the surface of -5- t

adenocarcinoma cells is higher than other lung cancer cell types (Kabayashi). Still others have suggested that female lung cancer may be related to use of oral contraceptives (Wang Sheng-yong). Physiologists have long recognized that the lung is not only an air exchange organ but also has endocrine functions. Further research into the relationship between estrogen disturbance and lung cancer, especially in relation to adenocarcinoma which is known to have mucus secreting characteristics, is urgently needed. Research aimed at examining endocrine disturbances in relation to lung cancer must proceed in parallel with the research on the cause of the rapid increase of lung cancer. Without the understanding the etiology of a disease, the effective prevention of the disease cannot proceed. Research into the etiology of lung cancer should be considered as the key to halt the rapid rise of lung cancer. -6- I I I I I I I I I I I I I I I