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A STUDY OF ASSOCIATION OF FEMALE SQUAMOUS CELL CARCINOMA AND ADENOCARCINOMA IN THE LUNG AND HISTORY OF MENSTRUATION Liao, Mei-lin; Wang, Jian-hwa; Wang, Hwei-min; Ou, Ai-qin; Wang, Xiao-jun; Lung, Wan-qing Shanghai Pulmonary Hospital, Shanghai, China Abstract: 181 cases of female squamous cell carcinoma and adenocarcinoma of the lung and 187 normal female controls were matched to compare the menstrual history of the two groups. The Epi-infor program, the Chi-square test, or the Bartlett test for homogeneity or variances, were used to evaluate if statistical significant differences existed between the two groups. Parameters related to menstrual history included age of menarche, menstrual cycle, number of days of menstrual period, amount of menstrual flow, menstrual pain, breast bloating/tenderness, and total number of menstrual cycles prior to menopause or diagnosis of lung cancer. Results show squamous cell carcinoma cases to have a higher total number of menstrual cycles than controls, suggesting that estrogen may be a carcinogen for squamous cell carcinoma. Adenocarcinoma cases had shorter menstrual periods than controls, suggesting the altered corpus luteum function in adenocarcinoma cases to possibly be related to the occurrence of adenocarcinoma. Expression of estrogen (ER) and progesterone receptors (PR) were also measured in 21 adenocarcinoma surgical specimens; the ones showing a positive ER and PR response were found to have the

onset of menstruation at a later age as well as an earlier menopause. The implications of these findings in relation to adenocarcinoma in females are discussed. The association of smoking and lung cancer is well known. In 1989, WHO reported that over 97% of the nations of the world recognized that 80% of the lung cancers were related to a history of smoking; with squamous cell carcinoma and small cell lung cancer being more closely related to smoking history than adenocarcinoma. Regarding the etiology of adenocarcinoma, risk factors other than smoking have also been studied. A 1988 Shanghai population-based epidemiologic study reported that the development of female lung adenocarcinoma was associated with menstrual and reproductive history, which raised,the possibility that female lung cancer may be related to estrogen levels and/or functional changes. The present study compares data on menstrual history using female lung cancer cases in the Shanghai Pulmonary Hospital and controls drawn from healthy current or retired hospital employees. A detailed questionnaire was administered in order to obtain information on menstrual history. The data were analyzed to determine whether an association possibly exists between menstrual history and lung cancer in females. Our results may contribute to a better understanding of the etiology of squamous cell carcinoma and adenocarcinoma of the lung. - 2 -

Materials and Method From January 1993 to June 1994, the files of all hospitalized, ambulatory, and out-patients in the pulmonary hospital were randomly screened. One-hundred and fifty files were collected from in-patients and partially from out-patients of the Pulmonary Hospital. Only females, with cytologically and histologically confirmed lung squamous cell carcinoma and adenocarcinoma, between 37-77 years of age, were identified and used as cases. 22 surgical cases also had surgically-resected specimens analyzed for female hormone receptors (progesterone (PR) and estrogen receptors(ER)). Controls, aged 35-78 were drawn from healthy current and retired employees who were determined by physical exam to be free of tumors or other serious disease. Controls were matched for age (± 5 years) with cases. Both groups were asked to fill out standardized questionnaires by trained professionals. Inquiries were made concerning the following items: menarche, menstrual cycle (in days); length of menstrual periods, whether menstrual flow was heavy (as to affect physical activities), medium (without affecting activities, although the amount was not scanty) , or light (basically no conscious awareness that there was a flow); degree of pre-menstrual breast bloating/tenderness (scored as never, occasional, slight, medium or strong); and menstrual pain (scored as never, occasional, light, medium or strong). Because the ages of menarche and menopause do - 3 -

not completely show the cyclic nature of endocrine functions or changes in females, a formula was used to calculate the menstrual cycle index (MCI) using the equation: MCI = (age at which menopause occurs or age at which lung cancer was diagnosed - age of menarche) x 365 + menstrual cycle (in days). The data, divided into three groups - squamous cell carcinoma group, adenocarcinoma group, and control group - were entered into Fox Base and then analyzed for statistical significance using the Epi-infor software, the chi-squared (x2) test, or the Bartlett test for homogeneity or variances. For P < 0.05, indicating an abnormal distribution of data points, the Kruskal-Wallis H method was used to calculate statistical significance. For P > 0.05, indicating normal distribution, the ANOVA F method was used to calculate statistical significance. Results A total of 368 females were analyzed, These included 181 non-small cell lung cancer cases - 19 squamous cell carcinoma (10.5% of total) and 162 adenocarcinoma (89.5% of total) and 187 controls. 1. Comparison of Menstrual History Between Sctuamous Cell Carcinoma Cases and Controls. a - 4 -

The ages of both groups showed a similar normal distribution and were statistically non-significant (P > 0.05). With regard to menstrual history, no difference was observed regarding age of menarche, length of menstrual period, menstrual cycle, degree of pre-menstrual breast bloating/tenderness, menstrual flow, menstrual pain, and age of menopause (each with P > 0.05). However, when the total number of menstrual cycles prior to menopause or to diagnosis of lung cancer (MCI) was subjected to tests of homogeneity or variance, a mean value of 453.17 and 413.3 were obtained for cases and controls, respectively. After homogeneity of variances tests, the variance value = 0.34, degree of freedom = 1, P= 0.559668, showed normal distribution. F value = 4.818, P = 0.027489, showed statistical significance. This indicates that squamous cell carcinoma cases have a higher total number of menstrual cycles than the controls. 2. Comparison of Menstrual History Between Adenocarcinoma Cases and Controls. The ages of both groups also showed a normal distribution (P > 0.05). The adenocarcinoma cases however, had shorter menstrual periods (mean = 4.85 days) than the controls (mean = 5.29 days) . When these values were tested for homogeneity or variance, a value of 6.638 was obtained, P = 0.01, suggesting that the difference was statistically significant. In addition, breast - 5 -

bloating/tenderness was also different between these two groups (variance = 30.84, P = 0.000032). The adenocarcinoma group had only slight and infrequent "breast bloating/tenderness" and history of menstrual pain (variance value = 14.56, degree of freedom = 4, P = 0.00570990), which was highly significantly different from the controls. There were no apparent differences in the total number of menstrual cycles, age of menopause and age of menarche between the two groups. - 6 -

Table 1 Relationship Between History of Menstruation and Female Pulmonary Squamous Cell Carcinoma and Adenocarcinoma LUng Cancer Squamous Cell _Carcinoma Adenocarcinoma Control P Value (1):(2) (1):(0) (2):0 (1) (2) (0) F,H P F,H P F,H P Cases 19 (total 181) 187 Age of inenarche (in years) 14.579 15.488 15.309 6.085 <0.05 1.858 >0.05 2.197 >0.05 Menstrual cycle (in days) 27.895 28.895 28.802 1.369 >0.05 0.211 >0.05 1.602 >0.05 Length of Menstrual period (in days) 5.368 4.852 5.289 3.211 >0.05 0.053 >0.05 8.703 <0.01 Amount of Menstrual flow (Heavy) 0 28 52 >0.05 >0.05 <0.05 (Medium) 17 98 114 (Light) 2 26 21 Premenstrual bloating (tenderness) Never 10 104 110 occasional 5 35 13 Light 2 20 42 >0.05 >0.05 <0.0001 Mediun 1 1 9 Heavy 1 2 13 Menstrual Pain Never 11 108 125 Occasional 5 29 13 Light 1 18 29 Medium 1 3 7 Heavy 1 4 13 Age of Menopause 50.500 49.774 48.774 1.622 0.202103 2.4360 0.116084 1.025 0.313157 Number of life-time menstrual cycles 453.176 413.319 413.269 5.014 0.024772 4.818 40.05 0 0.990867 Nunber of menstrual cycles = CAge of menopause - Age of Menarche x3651 + menstrual cycle (in days) 3. Comparison of Menstrual History Between Squamous Cell Carcinoma and Adenocarcinoma Cases. There is no difference between the age of the two groups because normal distribution was found in the analysis. The mean menstrual onset ages were 14.6 and 15 respectively, which, when tested for statistical significance, gave a value of P = 0.014, - 7 -

indicating an earlier menstrual onset for squamous cell carcinoma cases compared to the ones with adenocarcinoma. There was no apparent difference in the age of menopause, the length of menstrual period, menstrual cycle, the amount of menstrual flow, and menstrual pain between the two groups. The total number of menstrual cycles was higher for squamous cell carcinoma cases (4532) than for adenocarcinoma cases (413.3). The difference was statistically significant (P = 0.02). 4. Analysis of Estrogen and Proc{esterone Receptors and History of Menstruation in the 22 Surgical Cases of Female Sauamous Cell Carcinoma and Adenocarcinoma. Of the total 22 surgical cases analyzed, 21 were adenocarcinomas and only one case had squamous cell carcinoma. Positive estrogen receptors (ER) were found in 16 cases (72.7% of total cases) which included the single case of squamous cell carcinoma. Positive progesterone receptors (PR) were found in 14 cases (representing 63.6% of total cases and 66.6% of adenocarcinoma cases). They were all adenocarcinoma cases. Several criteria related to menstruation in the adenocarcinoma group showing a positive sex hormone receptor status were compared to the ones that had no detectable hormone receptors (Table 2). - 8 -

Table 2 A Comparison of Positive and Negative Female sex F1(ormone Receptors and Menstrual History in Female Lung Adenocarcinoma Cases (Mean Value) ER+ EF2.» PR+ PR Menarche (Age) 15.1 13.8 15 14.2 Number of Days of Menstrual Period 5 5 5 5 Menstrual Cycle (Days) 28 28.6 28.1 28.4 Menopause (Age) 45.7 48.4 47.3 49.8 Positive ER and PR adenocarcinoma cases had menarche at a later age than negative ER and PR cases. In addition, the age at which menopause occurred was also earlier (45.7) in the ER (+) cases, compared to the ER (-) cases (48.4). There was no difference in the number of days of the menstrual period or menstrual cycle; and no difference in breast bloating/tenderness, menstrual pain and amount of menstrual flow. Discussion In attempting to understand the etiology of lung cancer in females, effort has gone into studying risk factors other than smoking. For example, the association of vitamin A deficiency and the occurrence of lung cancer has been established both in epidemiological research and animal experiments, and has been recognized internationally. In China, there have been many studies - 9 -

of non-smoking risk factors the most noteworthy of which are cooking fumes3, history of tuberculosis4, burning of coal5, and menstrual historyZ. This study is a statistical analysis of the menstrual history of 181 female lung squamous cell carcinoma and adenocarcinoma cases and 187 normal female controls, matched for age. The purpose was to find out whether similarities or differences existed in the menstrual history of the squamous cell carcinoma and adenocarcinoma cases. A second objective was to correlate the occurrence of female lung squamous cell carcinoma/adenocarcinoma with the status of sex hormones. The results of our study show that the total number of menstrual cycles prior to menopause or before lung cancer was diagnosed significantly higher for squamous cell carcinoma cases (453) than for controls 417. Other parameters related to menstruation showed no appreciable differences between the two groups. A greater number of menstrual cycles was correlated with an elevated estrogen level. Estrogens are known to stimulate growth of cells. By affecting the proliferation of the epithelial cells of the bronchial tree, estrogens may be a candidate for induction of squamous cell carcinoma. The total number of menstrual cycles for the adenocarcinoma cases were not higher than the controls. In fact, - 10 - i