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Ill W orrnen :f;n1.6Ktng arnd Other Risk FactM for L.u~n9 CanUer in Anna H. Wu, Ph.D.,3 Brian E. Henderson, M.D.,3 Malcolm C. Pike, Ph.D.,3•4 and'Mitni C. Yur Ph.D.3.5 ABSTRACT-A case-control study among white women in Los qngales County was conducted~to investigate the role of smoking and other factors in the etiology of lung cancer in women. A total of 149 patients' with adenocarcfnoma (AD'C)' and 71 patients with squamous cell carcinoma (SCC) of the lung andltheir age- and iex-matchedcontrotswere intervievved. Personal cigarette smoking accournted for almost all of SCC and about hatf of ADC in this study population. Among nonsmokers, slightty elevated relative risk(s) (RR) for AtK were observed for passive smoke exposure from spouse(s) [RR=12; 95% confidence interval (CI)=0.5: 3.3J and'at work (RR=1.3; 95%C1=0.5, 3:3). Childhood pneumonia (RR=2.7; 953rCt=111, 6.7) and chitdhotad exposure to coal burning (RR =7:3; 95x CIr1.6, 5.5) were additional risk factors for ADC. For both ADC andi SCC, inereased1 risks were associatedl with decreased intake offi-carotene foods but not for totalpreformed vitamin A foods and vitamin supplements.-JNCI 1985; 74:747-751. I,ungcancer is now the fiourth most common cancer in, women (1)land has been projected to be the lead'ingcause of cancer mortalityamongwomen by the mid11980ts (2). Causes of'lktng,cancer, other than cigarette smoking,(3), have not been clearly identified, but associations with exposure to passive smoking (4-6), exposure to combus- tiom products of heating and cooking fuels (7); and occupationali exposures (8-10) have been suggested. In addircion, lung "scarring" (11) andia liow dietary intake of )'3,carotene (12-14) and preformed vitamin A (15-17) may increase the risk of lung cancer. This paper reports a, case-control study of ADC and SCC of the lung in white females in L'.os Angeles County. Each of the above-mentioned factors was investigated. METHODS Female patients diagnosed with primary ADC or SCC or' tic lung were prospectively identifviediby the CSP, the pt.r,ulation-based1umor registryfor Los Angeles County (18), between April 1, 1981, and August3!1i, 11987. On the basis ofinformation collected routinely by the CSP, we Ii ::ittcd ciitg-tbtlilty tn'wfnl'de l..CSsAngt'les County residents, with no history of cancer (other than non-melanoma skin cancer) and under age 76 at diagnosis; we verified these variables atinterview. W-ealso excluded cases if they were born outside the United States, Canada, or Europe; were not English-speaking; or were not residents of Los angeles County at the date of diagnosis. A total of490 eligible cases were identified. Of these Patients. 190Iiad'died orweretoo ill to participate by the time we contacted tiheir, attending physician. Permission was granted to contact 272 ofthe remaining300 patients. Eight patients were not located, and, 44 refused to be interviewed so that we obtained completed question- naires on 220. On the basis of information on the CSP abstract, no significant, differences were noted between those interviewed and thosenot interviewed in terms of age, marital status, religion,and smoking status recorded on medical records. Hoavever, those who were not interviewed were more likelytohaved'istant metastases at the timeofd'iagnosis (58%) compared to those who were interviewed (111%). Comparable percentages of eligible SCC (43%) and ADC (16%) patients were interviewed. We selected one individually matched neighborhood controli for each intemiewed case. The control had to fulfill ald''thecriteria given above for cases (with reference date taken to be the same as that of the matching,case) and, in addition, was matched with the case on date of birth (±5 yr of birth date). Our control selection algorithm, defined a specified sequence of houses to be visited in the neighborhood where the case lived at date of diagnosis. Our goal was to interview the first eligible resident in this sequence. If no one was home at the time of the visit, we lefu, ani explanatory lptter and made a follow-up visit after several days. For any patient, 80 housingunits were visited and 3retuirn visits were made before failure to secure a m'atched'control was conceded. In 150 instances the first eligible person agreed to participate, in 55 instancesthe second eligible control in, the sequence was intcrviewed, and' in, 15 instances the thirdeligib9k' control was initerviewedl Cases and controls were initerviewed on the telephone with the use of a, structured questionnaire designed to elicit information on personal smoking habits, exposure to passive tobacco smoke, lung diseases, dietary intake of vitamin A, types of heating and cookingfuels cVer used, and reproductive history. We also obtained, ai lifetime historyof all jpbs(jpb title, activities, and exposure)iof at least 6 months' diuration: For childhood passive smoking exposurt• we asked about the smoking habits (i!e:, amount and years of smoking) of father, mothcr„or, oother householkd'members AenrtEt'tHTI©Ns Ust:n: AiDC=adcnocarcinnma; Cl =c,onbidenrc inrrrval; CSP=Univeraity of Southern CaI'ifornia/t:os Angeles County C:anccr Surveillance Program; RR=rolative risk'(s): SCC=squamous cell car- cinoma. I Rvccived' June 11, 1984; revised November 28. 11984. accoNted' December 11, 19841 2Supported by grant S163 from the American Cancer Society. 3Dtpartment of Family and Preventive Medicine. University of Southern California School of 1ledicine, P3rkti-iew Medical Ruilding B. 2025 Zonal Ave., Los Angeles. ('.A 90033. 4 Prrscnr add-e.ts: lmtterial C.ancerRrsearch Fund's Cancer Epide- miology Unit, Radcliffe lnfirmarll, Oxford Universitr, Oxford O?C2 6HE, Englandi S We thank the word-processing pool for preparation ofthe manw script. 747 J,VC:I. Vt)t_ 71. NO. 4. APRIL 19zf3

n a*{7l'!!rr5"::; . ~ "1/tI, Hiendenon, Pike, and Yu when they lived, with the respondent during her child- hood l and teenage years. For passive smoke exposure during adult life, we asked about, the smoking habits of spouse(s)'and other household members when they lived with the respondent. Passive srnokeexposure at work was assessed'only in terms of the average number of hours per day to which the respondent believed she was exposed at each job. The questions on vitamin A intake specifiical'ly asked about, average frequencies of consumption of 211, vegeta- bles and fruits that are high in fl-carotene and 7 foods that containedI preformed vitamin A during the calendar year 3 years before diagnosis of the case (19). Pattern of use of' vitamin supplements was also assessed for the sarne periodl On, the basis of U.S. Department of Agriculture tables of'food values for standard portion size (common household measure) of each item, (20), we estimated, average daily intake of B-carotene (or vitarnin. A) by summing, the product of the ~-carotene (or vitamin A) content of each food item and' its reported' frequency of consumption. Quartiles of consurnption' w, ° constructed'on the basis of the intake pattern of the 2t,, controls. All cases were diagnosed' microscopically. Their rou- tine patltology, reports were reviewed for mention of lung scarring. Statisticali analysis was conducted with the us'e of multivariate logistic regression methods for individually rnatched case-control studies (21): RR were estimated by odds ratios. A case-control pair was excluded from any gi'vcnanalysi~siftheinformation forei'ther the case or the control was not known for, the relevant variable(s). Since personal smoking will often, i'fl not always, confound other associations„RR for other factors were always given after adjustment was made for personal smoking. For ADC, R'AC for certain factors were given separately for nonsmokers, ex-smokers, and current smokers; this was not done for SCC because the numbers of non- smokers and ex-smokers were too few. RESULTS c iin'terviewed 14'9 ADC and 71 SCC cases and their matiched' controls~. The mean age at diagnosis was 59.7 years for ADC cases and 61.4' years for SCC cases. The meaniages (atdate of diagnosis of'the index case) for the respective control groups were 59.5 and' 6'T.1 years. Prrsonal~ cigareltr smoking.-For both ADC and SCC, there was a significant trend in risk associated' with increasing number oLcigarettes smoked per day and'with decreasing age at which smoking began (table 1). Both aspects of smoking remained significant after adjvstrrnent was made for the other. Passive srnoking:-Families tended to share similar smoking, behavior. Controls whose father, mother, or spouse(s)'smoked were m ore likely to smoke, to be heavy smokers, and to start at a younger age than controls whose family members did not smoke. For ADC and SCC, after adjustment was made for personal' smoking habits, there were no signilfica'ntly increasedl risks .for having a mother, a father, or spouse(s) who smokedlor for being exposed at work ('table 2). For nonsrnoking, ADC cases, we did not observe any elevated' risk associated' with' passive smoke exposure frorn either parents (RR=0.6I 9'5%' CI=0.2,, 1.7), from' spouse(s) (RR=1.2; 95% CI=0.5, 3.3), or ar work (RR=1.3; 95% CI=0.5, 3.3). Increasing RR (RR=1.0, 1.2, 2.0) were found with increasing years (0„ 1-30, ?3'P) of' passive smoke exposure during adult life from spouse(s)' andl at work, but the results were not sta- tisticall}• significant. Since the exposur~esrmayhaveoccurred concurrently, the years of exposure represent units rather than chronologic time of exposure. Chulditaod' expestrrrs:-For both' ADC and SCC, no significant association was found with history of lung, diseases (specifically, a'sthma; bronch'itis, pneumonia„ tuberculosis, funigal' diseases, emphysema„ and lung, abscess) diagnosed by a physician at least 5 years before diagnosis of'the case. When th'e analysis was res'tricted'to lungd6sea'srs thati occtrrredibeforeage16 (childhood)„ ai signi'ficantlyelevatcd RR for pneumonia was observed for ADGafteradjustmcnt was made for personal smoking habits (RR=2.7; 95% C1=1.1, 6.7), and the RR for SCC (RR=2.9; 95% C1=0.5, 17.4) was in the same direction. Parental smoking did not explain' this effect. Table 3' shows that for ADC, the effect of chilldhood pneumonia was most apparent arnong nonsrnokers: Of the 29 TA'IILE 1.-!'r+', orrnl'~nroA'iurg nairiie ofawsre und ci;rr.ro,'s S ki t ADC' SCC mo ng sta us RIR' 95% Cl' CCase/control RR 95% CI Case/eontrol. Nonsmoker 1.01 29/62' 1.0 2/30 Ex-smoker' 1.2' 0.6.2.3 21/37' 7:7 0.8.70:3 8118 Current smoker 4.1'6 2.3.7.5' 99/50 35.3" 4.7:267:3 61/23' Current smoker: No. cigarettes/day 1-20 2.7' 1.4.5:4 38/28' 17.7 2.3. 1'38.2 19/14 >_2!1' 6:5" 3.1. 13.9 61/22' 94.4' ' 9.9, 904.6 4'2/9' Current smoker: age started to smoke. y r >_25 1.1 0.4.3.2 8114, 7.8 0.8'. 7317, 6/5 19-24 2.5 1.0.5.8 22/15I 47.1 4.4, 498.6 18,/T' 518 8,01, 3.6. 17.9 69/21 1T5.7+' 9.8. 1375.2' 37r11 " Had'st,oppedlsmoking at least 3 yrbefarre diagnosis year of case. ~ P'(1'inear trend) <.00'1_ JN(;l. t"O;t-,74. KQ: 1. A'PRtL 1985

- ~W,uy ..~cwac uu nromen . ., TASUt: 2: Esposurre to passive tmoking in cases and controls status Smokin ADC' g Adjusted RR° 95% CI Mother smoked 1.7, 0.8.3.5 Father smoked 1.3 0.7,2:3 Spouse(s) smokedP 1.2 0.6.2.5 Exposure at the workplace 1.2 0.8. 2:2 SCC' Adjusted R'R° 95% CI 02' 0.0: 1.5 0.9 0.3.2.9 1501 0.1.7.6 2.3 0.7, 7:9 ' Adjusted for number of cigarettes smoked per day and age at starting to smoke: 'We eliminated from the analysis: 15 pairs of, A'DC and 4 pairs of SCC'in which either the case or the control was never married. ncrosmnking ADC cases, 8' (28%) gave a, history of' c-hulKihood pneumonia. Fahwated RR, adjusted for personal smoking habits, wc*nt. observed for exposure to burning coal used for hrating or cooking in a stove or fireplace during the majprity of'rhildHood'and teenage years (ADC: RR='2:3; cl:,;~Gf=1.0, 5:5: SCC: RR=1.9, 95% CI=0.5; 6:5)'. For :11)C:. elevated RR were observed, in each personal. au0i: ing habit category (tabJe 3')'. T.vnt.t: I-RR and 95e6~cor{fidvue inttrcnls o/ADCof the ~ nceorcl'iueg to childhood pneumonia androal burning by personal smokinS7habit.i RR (9596CI) among: E.xlxrsure Nonsmoker Ex-smoker Current smoker Childhood pneumonia` No 1.0 1.4 (0:6, 2.4) 5.1(2.5, 10:3) Yes 3.1(1.0. 9.9) 1.5 (0.2; 10.8) 10.9 (2.1• 5'T:9) t'hildhoodlcoal burning" No 1.0 1.5 (0.6; 3:5) 6!3 (3:0, 1'33) Yes 3.2(0.9.11.8), 4!3(1.0,17.8)~ 9:5(2;1,41.9) i{,•fore age 16. The,analysis was based on 149 case-control',pairs „ :11)t.: lncludes heating or cooking with coal burned in a stove or firrplacc during childhood and teenage years. The analysis «•as ha<cd on 143 case-control pairs of ADG. Dietary vitamin A'.-Table 4 presents RR for ADC, adjusted for personal' srnoking, habits, by quartiles of indices of vitamin A consumption. Because of the smaliler sample size of'SCC cases, the indices wered'ichqtomized. For ADC, a significantly increased risk was observed only for those in the lowest qiuartile of .8-carotene consump- tion (<2,000 IUJday)' compared to those in the highest quartile (>4,000 IU;/day), but no appreciably increased', risks were observed'for those in:the intermediate groups. For SCC, an elevated, but not statisticallysigniificant, RRR was observed for wornen with fl-carotene intake below the median: When those in the lowest quartile of Q- carotene consumption, i.e., less than 2,000 IU/day, were compared to those consuming more than 2,0001IUXday, the unadjustied RR was increased to 1_7' (from 1.3), but afteradjustment the RR was not greater than comipari- sons above and below the median, (both, R'R=1.5): There was no association with an; index of totat preformed vitamin A(i.e., dairy products, eggs, liver, and'i vitamin supplements) fbr either cell type. However, fbr ADC and, SCC; an association was observed' for dairy products and eggs (table 4). Other jactors.-Wc couldi find no association between a~ny occtnpationior occupational category and risk of ADC' or SCC, but there was an excess number of cooks (4' cases and, 2 controls) andi beauticians (8 cases and 5 controls) among cases: both occupations have been suggested in previous studirs. Eleva.ed RR ad'justed'. for pe; sonral TAHt.t: 4.-Dicttzry intake oJS-carotcne, total preformed citnmimA', avrdidaiiry prroducta and eggs among eaxes and controls Quartile B-Canotiene' Total preformed vitamin Ab` Dairy products and eggs'' Adjusted RR'c 95% Cl Adju;;ted RRd 9596 Cl Adjusted RK4' 95% CI ADC' I (high) 1'.01 1.0 1.0 2' 0.8 0.3.2.0 0.6 0.3. 1.4 1.7 0:8: 3.9. 3 1.3 0.6. 2.7 1.1 0:5, 2.5 2.2' 1.0; 4.8 4 2.5 1.1, 5:7 1.2 0,5: 2:8 2.7 1.2.5.8 SCC 1 and 2 1.0 1.0 1.0 3and4 1.5' 0:6;,3.8' 1.0 0.4,2.4 1.6 0.7,3:9 'lncludes 21 vegetables and fruits: leafy lettuce, other leafy greeni broccoli, carrots, tomatoca, green peas, green beans, lirna besna, uparaRus, summer aquash, winter squash, sweet potatoes and/or yams, green pepper, redlpepper, hot red chili pepper; cantaloupe, +•atermelon, peaches, aprieots; nectacrines, and tomato andy,or V8 juice. Analysis was based on 147 paira of'ADC and'.69 pairs of SCC: ' 1 noludes eggs; cheese;,butter and/or margarine, cream, mi Ik, beef andJor cai fliven, ch icken and/or turkey /iver,,and vitamin supplements . ~.Anaiyais waa ba.sed on L47'pairs of, ADC'and 71 pairs of'SCC. Adjusted for number of cigarettes smoked per day. JfnCt. VOL 74. NO. 4. APRIL t985 Ion i I //~.~.r~~~`~~ ~a

smokutg; habits were observed' for a history of hysterec- •'tomy_. (RR =167; 95% CI=Q.9, 3.2) and nulliparity (fLR=1:7; 95',K' CI=0.8, 3:7)l ambng, ADC cases and' aa history of miscarri;age (RR=1.5; 95% CT-0.5, 4:9) among. SCC cases. Multiple logistic regression analysis was conductedito assess the possible confounding effects of personal smoking, habits, childhood pneumonia, childhood, coal burning, and'P-carotene intake. The results weresirnilar to those when each factor was adjusted for personal smoking habits alone. DIS CUSSirDN I This case-control study examined risk factors for the two main cell types of lung cancer in women-ADC and SCC. Although histologic typing was done by the individual' pathologist ae each participating hospital, studies cornparing,interobserver and inrcraobserver varia- bility ini classification of lung cell types reported a high concordance rate for cell types other than large cell' carcinoma, which was excl'uded, in this study (22, 23). In this study population, abouchallf'of ADC and almosr all of SCC can be attributed to personal smoking habirts; 1amount smoked and the age at which smokiingbegan were strong determinants of' risk of disease. However, there are rrnarkedldiifferences in the strengph of'association between smoking, and cell type of lung cancer, as has been noted previously (24; 25). The role of' passive smoking in the etiology of ADC among, nonsmokers is not clear. Our data are not consistent with the findings with regard to nonsmokers obtained by Hirayamal (9) and Trichopoulos et al. (5) who reported'a twofold to threefold'increased risk due to passive smoking. However, the histology of'the cases inn these studiies is not clear, and their data, suggest that any effect of passive smoking is larger for SCC cases (5; 6)i Of our 29 nonsmoking ADC cases, 12 were bronchoalveolar cell carcinomas, and, this cell type is specifically menl- tioned by Correa et al. (6) to have a weaker association with Nassive sm-)king: The cffect of passive smoking by . cell type of lung cancer needs to be investig;tted'furtlier in studies wiith, much larger numbers of nonsmokers. "hiildhood lung,disease may have a role in lung cancer et..,lbgy. Certain features of the lung of a child! (e.g.. susceptibility to airway, elosure and high peripheral resistance) might make it more vulnerable to residual abnormalities from respiratory illness (26): This notion is supported' by observations that both smokers and nonsmokers with childhood respiratory diseases have irnpai'red'lung function capacity, that their rate of decline in ventilatory function capacity with age is more rapid thani that in individuals without childhaod' respiratory problems, and' that, they have higher nates of clinical diagnosis of' chronic obstructive pulmonary disease (27, 28). Women with childhood respiratory problems may have incurred epithelial damage to the airway resulting in airway hyperreactivity and are more susceptible to ouhr•r insults to the lung. We cannot rule oun the pcussibilityof a chanceffnding or of preferential recall of' JNCti VXYI_ 74. NO. 4. A'I'RiII. 19d5 childhood' pneumonia by cases. However, • ouir dita: appear to be internally consistent, since we found" a significantly higher frequency of lung scarring rnen- tioned in the pathology reports among cases with previous childhood pneumonia (12/30=40%) compared to those without (39j/189^21%'). The association of' lung cancer risk with exposure to coal heating or cooking warrants further investigation. Although coal was identified as the major heating or cooking fuel used during childhood and teenage years of a significantly higher proportion of cases, we did not have detailed information on the years of use. Excess risks of lung,cancer have been reported for coke oven workers (29, 30) and British gas workers (31) who were heavily exposed' to products of coal carbonization. Studies of men suggest that their lung cancer risk is lowered by greater dietary Q-carotene (12=14, 32, 33) an& vitamin A intake (15, 17, 32, 33)j but the evidence for women is less clear (12,, 13, 32, 33). We observed a significantly increased risk for ADC ~with the lowest leve'l'of fl-carotene consumption and a similar association for SCC. These results are consistent with findings for females in Singapore (12),and in Japan (13'), but tiheyare not supporitive of data for females in Hawaii (32) and England (33!). Our observation of no association with an index of total preformed vitamin A(ii.e:, dairy products, eggs, liver, and vitamin supplements) and no association, with total vitamin A intake (preformed vitamin A and Q-carotene-data not s otvn due to domination by preformed' vitamin A) is consistent with findings for femalesinHia.vaii (32): Conflictiutgfindings have been reported for subgroups of preformed virtatrtin A foods andi supplements. A higlnerconsumptiionlof liver and vitarniin, supplements has been reported previously for female cases as comparell to controls, but the opposite results have been observed' for malcs (33, 34). Our data, show no case-control difference in, the intake pattern of vitamin supplements and a higher consumption of liver aniong cases. Our finding of an elevated lung cancer risk associated with lionv levels of intake of dairy products hass leot been reportedl for fcmales; ailthough, similar results have been observed'for males (15-17'): Our results on thee role of /3-carottne and preformed vitamin A were similar for ADC and'SCC: despite sttggestions that vitamin A (or ,ld-carrotrne) ismnrn strronvlv, prntarrive amainc_ SC'~ than against ADC (17'). Initial reports of an inverse relationship between blood - retinol levels andlsubsequenit-risk oEcancer at all sites (35', 36) have not been supported by recent studies (37, 38). This situatiionemhhasixes the need to reexamiineeven the consistently observed association of vitamin A (or /3. carotene) intake with male lung cancer. Possible sources of bias in our data must be considered. Both lung, cancer cases and controls were derived from population-based samples. However, because this disease is debilitating andlrapidlly fatal, 190 patients had died or were too ill to particijpatebythe, time ofinitiall ciontact:., N'Ve did not conduct proxy interviews because questions on chiildhood exposures and dietary history could not be assessed adequately. As expected, the group wholwas not . 1 .:`,,::',yw•~~'y i ~ 11 lom i ii~ ~~~

;~-'ttAtt?rY[CI~R l1r'a3 Q 1 i.Cll~alO naVCntelaS[au QlseidSe'dt. iOCcCantpCr`ut ytnc:• ..caacau • cac~ uw.aauul ~;a ~r ra vwa: 3u' tn ~ll dem ht osu n i og p m~ c , ag d U s+ ~ , (VY) $)ta.tttl:DietazyvttnrtttnAandhumanlungpnt:er lntJdrr measuttl: ~ddtuen;~tiiformatM1O'n~abstrartrd; from *~~,: ", y; t97s: ts 5s1-ss5: '~ riiedical'rYCOids ihotived similar srn oking status for tliose h[rrrt.trr'C, GRaMAxt S. SwANSON M. Vitamin A and lung aiscer: interviewed and'thost no"t interviewed. If cases who wete JNCt 191s; s2 t435-143s ; not interviewed beaause' of pbor surviival diffeied from ,.,' (17) KvALE. G. B1EUE E. CARr JJ: Dietary habits and lung cancer risk, those who survived longer and were interviewed in-t~crrns `• :` Int J'Cancer 1983: 3!1:397r•l05. ~ of the other ri3k fat tots under study, this "cti haNe= (18) MACK TM. Cancer Surveillance Program in Los Angeles Cflttntq. Natl Canccrlnst Monogr 1977; 47:99-101. biased our rt?SUlts.' Howe'ver,~this appears tonl'iikely sinice ` (19) CRAtt;ut S,,MertruNC Fiber and otherconstituenu of vegetables our data showed'that histories of childhood pneumonia in cancer epidemiology. 1n: Newell GR„ Ellison NiM; :eds:. and' exPosurC'_tt)`:Cma~i. fires Weie' similar among GasGS Nutritionandcanceretioiogyand treatment. Mew York. Raven regardless of stagebf disease at diagnosis. There is also no ' Press. 19st;t89-215:. ,. :(?D) MAats C. Nutritive value o[ American foods:in common unitaL evidence that eantxi' survival' is associated with dtetary .. U.S. Department o[ Agriculture Handbook No. 456. Washing, vit3tnin' A intake. ton„DC: U.S. Depanment'of Agriculture. 1975. The etiology of SCC can be explained' alffiost `entirely :•r (+21), Bwt.ow hIE, DAY 'ME. Statisti cal methods in ant:er rescarch. Vol by eigaretttt•:smokutg ~Cigarette stYlbking, itowever;'ex I-The analysis o[ ase~ontrol studies. IA'RC Sci Publ I980; Plains.onlY about half `of the ADC cases On the basis of (22) YrsrrEtt R;, GEms B;.AtJnRaAtat O. Application of ~the World. this study, childhOod' lung disease and1 exposure to coal` Health Organization classification of lung carcinoma to biopsy fires in childhood explain at least another 2296 of ADC material. Ann'Tt~orat: Surg 1965;1~3-49. cases. Passivasmokin and vitamin A ma be involwed ''. " (~)` Yr.snrER R C`RrER' D. Pathology of~arcinoma of the lung Clin ~' Y ~ Chest Med 1992; 3:257-289 : , but more research is needed to clarify their roles in, lung" `' ~Z4) Dou. R, 1tttL AB,'KREYaERG LL Thrsignifidnt:e of cell type in cancer etiology. relation to the aetiology of lung cancer. Bt J' Cancer 1957:. 1'J:43-48. (2S)'SYITDER EL;'CosJY LS, Atxtsutttt tC Lung cancer in xromen: Presenrand future trends. JINatI Cancer Inst 1973; 51:39'I'~•l01. (26) KA-r-rAN M. Long-term sequelae of respiratory, iillness in'infancy REFERENCES and'childhood. 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