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I I I I I I I I I I I I I 0 I I i THE RELATIONSHIP BETWEEN HISTOLOGIC TYPES OF LUNG CANCER AND CIGARETTE SMOKING Zhou Bao-sen, He An-guang and Wang Tian-jue China Medical University, Shenyang, China Abstract This paper discusses 1056 cases of lung cancer which were identified by pathological examination in the Department of Thoracic Medicine of the China Medical University from 1978-1994. The sections were stained in order to identify the specific type of lung carcinomas. In the 1056 cases diagnosed by histologic examinations, squamous cell carcinoma accounted for 516 cases (439 male and 77 female), adenocarcinoma for 345 cases (219 male and 126 female), small cell carcinoma for 128 cases (91 male and 37 female), large cell carcinoma for 46 cases (37 male and 9 female), and other types for 21 cases (18 male and 3 female). A relatively high proportion of cases in our study (101 cases, 9.76%) were under 40 years of age (73 male and 28 female). To correlate the number of cigarettes smoked per day, and the duration and index of smoking with lung cancer development as well as the histologic types of lung cancer (WHO classification), we retrospectively analyzed the data for 1035 inpatients with lung cancer and compared them with 116 (48 smoker and 68 nonsmoker) inpatients without malignant diseases by means of the Mantel-Haenszel Method. The results show that squamous cell carcinoma (total, 516 cases; 378 smoker and 138 nonsmoker), large cell carcinoma (total, 46 cases; 32 smoker and 14 nonsmoker), and small cell carcinoma (total, 128 cases; 83 smoker, and 45 nonsmoker), are correlated with cigarette smoking status. The computed odds ratio (OR) values are 3.88 (95% Cl: 2.49-6.05, P=0.001), 3.24 (95% CI: 1.47-7.23, p=0.0001), and 2.64 (95% CI: 1.52-4.62, P=0.01), respectively. All three types have dose-response relations with the amount, index and duration of cigarette smoking. The results show that the OR increased both with the amount of cigarettes smoked per day and with the duration of smoking. The excess risk for the heaviest smokers was 4.84-fold for squamous cell carcinoma, 2.45-fold for small cell carcinoma and 4.35-fold for large cell carcinoma. By contrast, adenocarcinoma did not correlate with cigarette smoking (OR 1.22; 95% Cl: 0.78-1.92, P=0.35). Thus it may be concluded that the amount, duration and index of cigarette smoking are high-risk factors for squamous cell, small cell, and large cell carcinomas. Introduction This paper reports on data from a study that examined the pathology and epidemiology of lung cancer in northeast China, where there is a high incidence of lung cancer in youths. Specifically, we aimed to study the possible relationship between histologic type of lung cancer and cigarette smoking. I

I Materials and Methods Of the 1360 cases of lung cancer enrolled in the Department of Thoracic Medicine at the China Medical University from 1978-1994, 1035 cases were confirmed by examination of the stained pathological specimens and typed in accordance with the WHO classification (1981). Other diagnostic information came from studies of chest X-ray films, CT, and clinical evaluations. The 116 controls with no malignant diseases were randomly selected from inpatients at the same hospital. Information on the history of cigarette smoking, daily cigarette consumption, and the duration of cigarette smoking was obtained from the medical records. Smoking index refers to years smoked times the amount of cigarettes consumed per year. The odds ratio (OR) and P values were calculated according to the Mantel-Haenszel method. Results Table 1 shows that among the 1035 cases of lung cancer diagnosed by histologic examinations, squamous cell carcinoma accounts for 516 cases (439 male and 77 female), adenocarcinoma for 345 cases (219 male and 126 female), small cell carcinoma for 128 cases (91 male and 37 female) large cell carcinoma for 46 cases (37 male and 9 female) and other types for 21 cases (18 male and 3 female). About 10% of the cases were subjects under 40 years of age (total, 101 cases; 73 males and 28 females). In the lung cancer cases, 72.9% of the males and 32.7% of the females were cigarette smokers. By comparison, 53.2% of the males and 17.9 % of the females in the control group were smokers. The potential relationship between lung cancer and cigarette smoking was analyzed by the Mantel-Haenszel method. A significant increase in risk was shown for lifetime cigarette smokers (OR 2.38, 95 %CI: 1.59- 3.58). In the case of males, the OR was 2.36 (95 % CI: 1.43-3.89) whereas in females an OR of 2.22 (95 % CI: 0.89-5.74) was obtained (Table 2). Table 1. Age and Sex Distribution in Relation to Hi.stology of Lung Cancer Alstnlo8ical Age Type Sex Tuul (%) M+F (%) 540 41~60 >60 Squamaus Cell Ca. M 34 299 106 439 (55.85) F 3 60 14 7 (30.92) 516 (49,86) A4rno. G. M 19 145 55 219 (27.80) F 13 90 23 126 (50.68) 345 (33.33) Small. Cell G. M 16 60 15 91 (11.58) F 12 22 3 37 (14.86) 128 (12.37) Tolil M 73 531 182 786 (75.94) F 28 180 41 249 (24.06) 1035 (100.00) M+F 101 711 223 1035 % 9.76% 68,70% 21.55% 100% I I I I I I t I I I I I I

Table 2. The Relationship Between Lung Cancer and Cigarette Smoldng I I I I I I  I I I Csse Crntrd OR 95% CI P P or L'mc Tmd Smoker + 853 48 - 507 68 2.38 1.59-3.58 0.00 Male + 740 41 9wkcr - 275 36 2.36 1.43-3.89 0.00 Femzle + 112 7 S1noker 231 32 2.22 0.89-5.74 0.06 Smoke 0 507 68 I Amuua 1- 61 5 1.64 U.60d.80 0.30 10- 211 14 2.02 1.08-3,85 0.02 20- 581 29 2.69 1.68<.33 0.00 0.00 smoke 0 507 68 1 Ynrs 1- 170 12 0.91 0.54L53 0.71 20. 678 36 3.95 2.37-663 0.00 0.00 Smoke 0 507 68 1 Indcx 1- 432 25 2.32 1.41-3,84 0.00 11 500- 416 23 2.43 I 45d,08 0.00 0.00 The possible relationship between cigarette smoking and the histologic types of lung cancer were also analyzed by the Mantel-Haenszel method (Tables 3-6). The results suggest that squamous cell carcinoma (OR, 3.88, 95 %CI: 2.49-6.05, P=0.001), small cell carcinoma (OR, 2.64, 95 %Cl: 1.52-4.62, P=0.01), and large cell carcinoma (OR, 3.24, 95% Cl: 1.47-7.23, P=0.001), were correlated with cigarette smoking and showed dose-response relationships with the amount, index and duration of cigarette smoking. The excess risk for the heaviest smokers reached 4.84-fold for squamous cell carcinoma, 2.45-fold for small cell carcinoma and 4.35-fold for large cell carcinoma. There was no correlation between cigarette smoking and the incidence of adenocarcinoma (OR, 1.22, 95%CI: 0.78- 1.92, P=0.35). -3- I

Table 3. The Relationship Between Squamous Cell Carcinoma and Cigarette Smoking Ca3e Canrtol OR 95% Cf P P nf Une Tratl Smoker + 378 48 138 68 3.88 2.49-6.05 0.00 Male + 343 41 Smoker - 96 36 3.14 1,83-5.37 0.00 Female + 35 7 Smoker - 42 32 3.81 1.38-I0.93 0.01 Smokc 0 138 68 1 Amawl 1- 15 5 1.47 0.484.88 0.46 100. 78 14 2.75 1.39-5.48 0.00 20- 285 29 4.84 2.92-8.06 0.00 0.00 Smoke 0 136 68 1 Years 1- 60 12 2.50 1.21-5,17 0.00 20- 315 36 4.38 2.72-7.05 0.00 0.00 Smokc 0 136 68 1 Ldex 1- 161 25 3.22 1.88-5.56 0.00 500- 214 23 4.65 2.69-8.09 0.00 0.0D Table 4. The Relationship Between Small Cell Carcinoma and Cigarette Smoking Cese Canvd OR 95% CT P P af LNe Tsmd Smoker + 83 48 45 68 2,64 1.52-0.62 0.01 Mete + 74 41 Smoker 17 36 3,82 1.80-8.17 0.00 Femile + 9 7 Smoker 28 32 1.47 0.4b5.18 0.49 Smake 0 45 68 1 Amaw1 1- 11 5 3.32 0.98-11.88 0.03 10- 26 14 2,81 1.23-6.38 0.00 20- 47 29 2.45 1.29,4.65 0.00 0A0 Smokc 0 45 68 1 Yeers I- 2C 12 3,02 1.29-7,18 0.00 20- 60 36 2.52 1.39-0.59 0.00 0.00 Smoke 0 45 68 1 IMex 1- 58 25 3.51 1.84-6.70 0.00 500- 26 23 1.71 0.82-3.55 0.11 0.00 -4- N ~ i t 1 I I I I I I I

I I I I t I I I I I I I I I ,i I 1 I Table 5. The Relationship Between Large Cell Carcinoma and Cigarette Smoking Case -. Cwtd . OR 95% CI . . P P ef L'me TrenC Smoker + 32 48 14 68 3.24 1.47-7.23 0A0 Male + 29 41 SmoYCr - 8 36 3.18 L19-8.T/ 0.01 Female + 3 7 ' Smdcer 6 32 2.29 0.34-14.86 0.31 Smoke 0 14 68 1 Amau¢ 1- 0 5 - 10- 6 14 2.08 0.59-7.I9 0.19 20- 26 29 4.35 1.86-10.29 0.00 0.00 Smoke 0 14 68 I Yeen 1- 6 12 2.43 0.67-8,63 0.12 20. 26 36 3.51 1.53-8,12 0.00 0.00 Smoke 0 14 68 I Index 1- 14 25 2.72 1.05-7.11 0.02 500. 18 23 3.80 1.51-9.65 0.00 0.00 Table 6. The Relationship Between Adenocarcinoma and Cigarette Smoking Case Cmvol OR 95% CL P Smoker + 161 48 184 68 1.22 0.78-1.92 0.35 Male + 131 41 Smoker 88 36 1.31 0.75-2.29 0.31 Frnah + 30 7 Smoker - 96 32 1.38 0.51-3.89 0.48 -5- K) O 00 .a V ~ W W tn W I

I I Discussion A histological analysis in 1035 cases of lung cancer collected in northeast China over a 6-year period shows the following distribution: squamous cell carcinoma 49.8%, adenocarcinoma 33.33%, small cell carcinoma 12.37%, and large cell carcinoma 4.44%. These results are largely in agreement with previously published results (1). In terms of age distribution, 9.76% of the cases came from the 40 year-old and younger group, 68.70% from the 41-60 age group, and 21.55% from the group age 60 and above. The overall ratio of male-to-female was 3.16, as compared to a ratio of 2.6 in the young-age group. Interestingly the proportion of small cell ckrcinoma was 27.73 % in the latter, as opposed to 12.37% in total cases, 11.53% in the 41-60 age group and 8.07% in the group age 60 and above. The incidence of adenocarcinoma has previously been reported in subjects younger than 35 years (2) and in the 45 year old age group (3). Results of this investigation also showed that smoking is the most significant risk factor for lung cancer in northeast China, affecting squamous cell, small cell and large cell carcinomas. The risk of lung cancer increased with the daily dose and duration of cigarette smoking, with the trend being the most significant for squamous and large cell carcinomas. These features are consistent with results of worldwide epidemiological studies of lung cancer and smoking (4). Thus, it is possible that cigarette smoking induces lung cancer in northeast China in a manner which is qualitatively and quantitatively similar to what has been reported in other parts of the world. Detailed analysis shows that cigarette smoking is a significant risk factor for male smokers and is associated with the incidence of squamous cell, small cell and large cell carcinoma in men. By contrast, among women, only squamous cell carcinoma is correlated with smoking. Since adenocarcinoma constitutes the predominant cell type in females living in northeast China and elsewhere (5-8), constituting as much as 50.6% of the histologic cell type in female lung cancer cases, it is unlikely that cigarette smoking is responsible for the high rates of lung adenocarcinoma among females in our study. Conclusion Our study reported a high proportion of lung cancer in youth in northeast China. Cigarette smoking was determined to be a major risk factor for squamous cell carcinoma, small cell carcinoma and large cell carcinoma. The incidence of adenocarcinoma is not correlated with cigarette smoking. I I I I I I I I , I I I I ~ ~ O W W N .P O O -6-

I I I I References He, A., et al. Study on the Difference of Histological Type and Age Distribution of Lung Cancer Between China and Japan. Journal of China Medical University 1989; vol 18 I 2. supplement: 31. Homb, L, et al. Adenocarcinoma of the lung in patients younger than 35 years. JAMA 1984; 252 (15):2007. I 3. Gian, C.R., et al. Lung Cancer in the young. Chest 1985; 87(4):456. I 4. International Agency for Research on Cancer. Tobacco Smoking. IARC Monographs on evaluation of the carcinogenic risk of chemicals to humans. Vol.38.pp. 203-44.Lyon. IARC, 1986. I 5. Gao, Y., etal. Lung Cancer and Smoking in Shanghai. International Journal of Epidemiology 1988; Vol. 17. No. 2:278. I 6. Kung, I, et al. Lung Cancer in Hong Kong Chinese: Mortality and Histologic Types 1973-1982 . Br. J. Cancer 1984; 50:149. I 7. Koo, L.C., et al. An Analysis of Some Risk Factors for Lung Cancer in Hong Kong. Int J _ . Cancer 1985;35:149. I 8. Maclennan, R, et al. Risk Factors for Lung Cancer in Singapore Chinese a Population with High , Female Incidence Rates. Int. J. Cancer 1977; 20:854. I I I I I N C ~ I ~ ~ -7- ca W I Ch <J1 I