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Lung Carcinoma Trends by Histologic Type in Vaud and Neuch tel, Switzerland, 1974-1994 Fabio Levi, M.D.1 Silvla Franceschi, M.D.z Carlo La Vecchla, M.O.= Lalao Randimbison, eJ~1 Van-tong re, M.OJ ~ Rsgistre Vaudois des Tumeurs, InstJM unF verslratre de ma(iecine sodale et prGven~ve. ~u~na, and Reolstm ~euch~elols des Tu- maul. ~s ~dolles. Neuch~e[, Swiped. ~Se~iz[o di Eplaemiotooie. Cen~ ei Aifefi- mento On~logico. A~ano, I~ly. s is~o dl Rl~rcfle F~rmacologlche "Merio NegrC' Mi~no, ]~l~ I~tuto di S~stice Med- ~ e Biometria, Un~ve~ degli 5tu~J di Milano, Milano, Item; and Depa~ment ~ Epldemlology, H~d School of Pu~ltc HealS, Bos;on, Mas- sachuse~. The contributions of the Swl~ League Can~e~, Bern, Switzerland (G~ EOR 305.93), and the ~ffs of the Vaud an~ Neuch~t~l Cancer Registrie~ are gratefully acknowledged. Th~ t~o~ thank K Lucchini, E. Negrl, and V. and F. De Ceglie for technical and graphic assistance. Address for reprints: Fabio Levi. M.D., Re~ilstre Vaudois des Tumeurs, CHUV-Falalses 1, Casler 2. CH-1011 Lausa, nne, SwlIzerlan~. Received August 14, 1996; revision received November 12. 1996; accepted November 12, 1996. BACKGROUND. Shifts in rhe dL~rributJon ofhistologJc types have reportedly accom- panied dzanges [n l~ng car~oma incidence in ~¢ ~zt ~o decades, hz the United Stat~, inddence r~te~ Of aqueous cell and sm~ll c~l c~noms have bee~ show- lag a d~ne ~ mal~. aft~ peaks in 1981-82 m;d 1986-87. resp~dvely; however, no de~e has been obeyed In females. In both genders, adeno~inoma inci- dence b In~ea~g. The au~or~ ev~z~ Im~g ~oma Incidence rates In two Sw~ ~¢om Lt ~mzg~ ~ ~en~ b)' gender, b~ cohos, ~d ~mlo~c ~e. M~H0O8. ~e au~o~ en~ dale on populadon-b~ed lung ~r~oma ind- d~ ~om the S~s ~ntons of Veud end Neu~td (¢he pop~afions o~ which [o~ abou[ 7~.000). ~1~s ~ g~uped ~[o ~ major h~tologlc ~ee. Th¢ propo~on o~ ~ce~ no¢ ~s¢olo~y co~m~ ~s appr~e~eJy 8% a~oss ~ ~ tmdy ~lod. ~dd~ Iates w~ age-~d~zed on ~e b~i~ of ~e world s~nd~ population. R~ULT~ Oveta~. of 74~ cancer cases di~nosed in ~e period 1974-1994, squa* mous eel[ c~dnomas accoumed fo~ 3~%. ~ ~U c~omas ~d edenoc~c~o- mas 18% ea~, and o~er'~om~ 16%. Ra[e~ of tqu~o~ ~ll ~d sm~l cell ~cinoma indden~ in mal~ oteil ~ges dropped ~ the lm~ qulnque~i~n, while ~f~pondJag fat~ Jn fem~es ~eesed standby. ~avefsdy, adeno~daoma incidence In.eased ~ bo~ Benders by eppro~ateiy ~5-fold: ~d dudn~ the pe~od 1990-1994, ~ young edits of bofl~ genders, k was morn than 3-fold highe~ • an ~e ~den~ of ~qu~ous call ca~cinom¢ At v~riance wi~ squamous cell ~om~ ~e incid~ of whl~ ~ea~ed IL~ peaks In the 1910-20 birth coho~ In melee and ia ~he I930-40 bi~ coho~s ia females, edenoca~dnome ~e~]ed a dmil~ bi~ coho~ pattern in ~e ~,o genders, ~h s~l no si~ of decline. CONC~IONS. Ai~ough change~ In dlagnosdc prances may have pla~d e role, ~e incidence data p~esented in ~hi~ ~dy ~ug~es[ ~a¢ adenocerclnome is sus- taining a new lun~ c~c~oma epidemic ~ie~y at~butable m ~e ~t~ zo low- ry, fllmred dgare~es. Its pa~e~ seems ~markably stmi/a~ in the ~o Kend~s, ~us, ~e auto,s ~ndude [h~t ~imil~ exposure ¢o [obe~o-releted carcinogens leads to simfl~ ~ates of hismlogic ~e-specific lung ~om~ incidence in m~es and females. ~r 1887;78:~-I~, ¢ 1997 Amer~cen ~cer Social. KEYWORDS: hlstologic type, incidence, lung carcinoma, time trend, tumor registry, Switz~dand. Since the early 1960s, lung carcinoma has been the leading cause of cancer-related deaths among Swiss males. Age-standardized (on ~he world standard populaUon) mortality rates increased f[om 29 per 100,000 in 1955-1959 to 49 per 100,000 in 1975-1979, but leveled off uhereafter.=~ Earlier and larger dec|/nee were seen in middle-aged men. In contrast, lung caxcinoma monalky rates among Swiss females were stable at approximately 3 per 109,000 until the late 1960s but rose appreciably thereafter, to surpass 10 per 100,000 Jz~ 1989-]993 (i.e., d~e third cause of cancer-related death, after breast and colo-

rectal carcinoma.=) Reflecting ~he different pattern of age-specific trends over the last decades, male-to-leo male ratios declined from more than 10 in the late 19609 to approximately 4 in the early 19909 and to 2 in young adults {age 20-44 years}. On a Puropean scale, Swiss lung carcinoma mortality rates are Inrermed~ate for both genders.~ The mortality to incidence ratio of lung carcinoma is persistently one of the highest among cancers at differen~ sites, i.e., over 08 in both genders, thus making incidence trends very similar to mortality ~rends. Shifts in histologic types have been reported accompany, ~ several parr~ of r_he world, changes in lung carcinoma incidence. Relative and absolute in- creases in adenocarcinoma of the lung were recog- nized two decades ago" and observed In several glans of the United Stores.s'~ Consistem upward trends for adenocarclnoma incidence were reported from Europe by the Netherlands~= and fzorn Asia by Hang Kong,a~ lapan,'= [smd,u and Korea," but these reported ~ends occurred later than in the U.S. T~ends for various histologic types o~ cancer are of interest in the evaluation of the global impact of changes in cigarette manufa~ure, because low-tar, Iow-nlcotlne, filtered cigarettes have contributed to the overall decline of lung ca~dlnoma and mos~ nota- bly squamous cell carclnoma,~ but have increased the risk of certain peripheral ~umo~s, such as adenocarci- name. ~" In order to elucidate the issue further, we took advantage of incidence data from the cantons of Vaud and Neuch~kcl in French-speaking Switzerland, where population-based cancer registration systems with high proportions at histologic confirmation have been tn operaiion since 1974.~'~ MATERIALS AND METHODS The current analysis is based on the data flies of the Vaud and Neuch~te[ Cancer Registries, which contain ~nformadon concerning ~ncident cases of mallgnan~ neoplasms in the cantons, whose populations, ac- cording to the 1990 census, were about 600,000~z and 160,000,t" respectlvely. In these can~ons, cancer regis- tration systems have been implememed since 1972, and population-based Incidence data has been avail- able slnce I974.~v'~" Notification is based on a volun- tary agreemer~t bet~veen the recording medical institu- ~iohs of the cantons and the registries. All hospitals. all pathologic laboratories, and most practitioners are asked to report all new cases of cancer. Information collected by the registries includes general demo- graphic characteristics of the patient (age, gender, and municipality of residence); site and histologtc type of the tumor, according to the World Health Organiza- tkm's International Classificatio~ of Disea~ .for On- col0g),~:'; and date of diagnostic confirmation. Lung Ca~inoma In:idenc~ by Hlstolagi¢ Type/Levi et aL The current series comprised 7423 cases of pri- mary lung carcinoma (in 6119 males and 1304 fe- rns/as), which ~¢curred during the period 1974-1994 (Table I). Cancers were grouped into r.he following hlstologic types, based on ~e morphologic cha~acter- Isdcs of the minarets: squamous cell carcLnoma (M.' 8070); small cell carcinoma (M: 8041-8045}; adenocar- cinoma, including b~onchioloalveolar caxcinoma. 8050, 8140, 8190, 8250, 8260, 8290, 8310, 8430, 8480, 8490, 8550. 8560}; other caxclnoma.~, including large cell and undifferentiated carcinomas (M: 8020, 8030), malignant carcinoid (M: 8240), not otherwise specified carcinomas (M: 8010]; and nonepithelia/ neoplasms. In 611 lung tumors (8.2%), no microscopic confirms- clan was available. This percentage did not change across the years studied. Age-stands/direr (on the world standard popula- tion~) incidence rates for all ages and for ages 35-44, 45-64, and 65 years and older were computed fo~ ma- ~or hisiologic types (i.e., squarnous ceil, small ceil, ade- nocarcinoma, and othe~s) and all lung carcinomas for different calendar periods (1974-1979, 1980-1984, 1985-1989, 1990-1994). In addition, for squamous cell carcinoma, small cell carcinoma, and adenocarci- name, age-specific rates for ages 35-44, 45-54, 55- 64, 65-74, and 75 years and older were plotted against the median year of birth for each cohort (separately for the two genders). The points corresponding to the same age ~oup were joined to provide more clearly spaced graphs. Thus, the cshon effect can be read in the ordinate. Analyses of cohorts of birth for small cell carcinomas are not shown because of the low number of cases in young cohorts and among women. They were. however, similar to those of squamous cell carci- noma. Finally, for each gender and major hlstologic tTpe,. a log-linear Poisson model with arbitrats, constraints on the parameters was also fitted to the matrix of age- specific rates between the period 1974-1979 and ~he period 1990-19~4, to separate the effects of age, pe- riod of diagnosis, and birth cohor~ on incidence rates.~= A problem of unidendfiability of the parame- ters. caused by the structural relations between age, period, and cohort, was overcome by giving arbitrary constraints to the data. The model used minimized the sum of the Euclidean distances bet~,een the three possible hvo-factor models.= Given the arbitrariness of the constraints imposed, these models should be interpreted with caution. Nevertheless, they may offer some interesting clues to the interpretation of the inci- dence rates. For each gcndez and histologic type, che age effect was plotted on a graph, the cohort and pe- riod effects were plotted on another graph, and the effects were expressed in relative terms against their weighted average set to tmi~.

CA~CF.~ March 1, 1997 ! Volume 79 / Number 5 D|s~bufion of Invasiv~ Lung C~rdnoma by H/s{o/og/c Type and Pa~len~ Gender in Camon$ o~ V~ud and Neuch~td, Switzerland, 1974- ] 994 Ad~t~toma ~ 14.8 401 30~ 13~ 17.~ ~ and ~ ~omas 913 14J 291 N~elJ~ n~plas~ ~ 0.4 13 1.0 ~8 0.5 U~bJe I~$ ~ ~ 2.5 1~7 2.5 Tot~ 611g 1~}.0 1304 I00.0 ~423 100.0 RESULTS Table 1, in which the current series of invesive lung carcinomas is described, shows that ha the period 1974-2994. squamous cell carcinoma was the pre- dominant histologic tTpe overall (36.8%) and also among males (40.9%). Among females, however, ade- nocaxcinoma (30.8%) surpassed all o~er histologlc types. The proportion of small cell carcinoma inci- dence was similar for males (18.5%) and females (16.6%]. Other carcinomas accounted for 14.9% of cases among males and 22.3% among females, and nonepithellal neoplasms accounted for 0.4% and 1.0% of cases, respectively. UnclassLfiable cases and cases not histologically confirmed accounted for similar pro- portions among males (i0.5%) and females (11.9%). Age-standardized incidence rates of lung carci- noma Coverall ~nd by hismlogic rlpe) are given in Ta- ble 2 for the two genders over four consecutive calen- dar periods, together wiuh corresponding male-to-fe- male ratios. For males, rates of squamous cell carcinoma remained stable, at approximately 26 in I00,000, during the period 1974-1989, but decline'd by approximately 30% in 1990-1994 to 19.1 per I00,000. Corresponding rates for females increased by 77% (from 1.3 to 2.3 in I00,000) and were raht~s 20-fold lower than rates for males in 1974-1979 but only 8,3-fold lower in i990-]994. With respect to small cell carcA- home, incidence rates among males first increased from 10,2 in 1974-1979 to 12.0 In 1980-1964, then plateaued and eventually decreased by 17% from 12.5 in 1985-1989 to 10.4 in 1990-1994. At the same t/me, corresponding rates among females increased from 1.0 to 2.6 in 100,000. Adenocarcfnoma incidence rates steadily rose for both genders, from 5.5 to 13.3 per I00,000 for males and from 1.9 to 5.0 per 100,000 for females. With end 2.6-fold increases for males and females, respec- tively, adenocarclnoma was, therefore, the only histo- logic type forwhic' mate-to-female ratio was stable Cat approximately 3 per ] 00,000] over the period studied. Among males, other carcinomas showed nearly stable rates (except in the first period studied), but a twofold increase was observed among females. Overall, the in- cadence of Im~g carcinoma among males increased from 55.6 per I00,000 in 1974-1979 to 62.7 in 1985- 1989, chert declined to 57.5 in 1990-1994. Among fe- males, overall rates increased steadily from 6.7 per i00,000 in 1974-1979 to Ig.0 in 1990-1994 (Table 2). Age-standard/zeal incidence rates of lung carci- noma by histologic type for the two genders and differ- ent age groups are shown in Figure L Declines in squa- mous cell carcinoma incidence among males between 1985-1989 and 1990-1994 were observed in all age groups. Tapering increases emerged among young and middle-aged women, while upward trends were ob- served among elderly women, t:or small cell carci- noma, some decline was f6und only among young males, whiIe among females upward trends persisted. Rates for women aged 35-44 years, however, must be interpreted with caution, due zo small numbers of cases per quinquennium (oRen <5). Steady increases in the incidence of adenocarclnoma were common among both genders and all age groups but were espe- cially marked emong middle-aged women [more than ~rcefold increases). Rates of the incidences of other lung carcinomas were stable for males, whlle they in- creased significandy for females. For young adults, the incidence rates of squamous cell carcinoma and ade- nocarcinoma fur the most recent calendar period stud- ied were both 40% higher among men d~an among women, and the ratios between adenocarcinoma and squamous cell carcinoma rates were the same {Le., 3.5 for men and 3.4 for women). Age-speclfic incidence rates of squamous cell car- cinoma and adenocarcinoma were also examined by the median year of birth for each cohort, as shown in

Lung Carcinoma incidence by Hh;to~oglo Type/Levi et el, 909 TABLE 2 /i~e-Standard£zed (on the World $~lerd Population) ~ddence ~ p~ 1~,000 of In~e L~g ~noma by C~d~ P~od, Patient ~r ~d H~mlo~c ~(s}. ~ ~o.~e B~ (g/~ ~ ~c ~m~ o~Vaud ~d Neu~t~ S~ 1974-1994 cs.-d~ma r, ardnoma M~aca.,~noma ca.,c~omu kip Cslend~ ...... Im'iod g F M/P g l= M/F M l= M/F g F M/P g 1= MIP ~974-1979 26.0 13 2~,0 102, 1.0 102 5.5 1.9 2.9 7.6 t.S 4.S 5~.S ~.7 ~;3 I-~80-1984 24.5 '.'.~ If8 IZ0 l.S 8.0 I].3 2.2 3.8 9.1 2.0 4.6 59.6 7.7 7.7 19~-1989 27.1 L'. IZ.9 12.~ 13 6.6 g~ 3.$ Z7 . 9.0 2.6 _a.~ 62.7 II:" 5.6 1990-1994 19.1 Z~ &3 10.1 Z5 4,0 |33 5.0 2.7 9.8 3-2 3.1 57.5 14.0 4.1 ~ 0f changP -27 .-77 +2 ÷160 +142 +163 +29 +IC0 +3 +109 Figure 2, For males, the age-specific incidence rates of squamous cell carcinoma peaked in the 1910-20 cohorts but declined thereafter, most markedly among tttosc born after 1945. Conversely, age-specific rates for adeuocarcinoma incidence among males increased at least up to the 194S birth cohort, and possibly stabi- lized thereafter. The analyses of the youngest birth cohorts were hampered by the small numbers of cases. At variance with the rates for males, age,specific inci- dence rates of squamous-cell carcinoma for females increased at least up co the 1930-40 birth cohorts, and plateaued thereaher. Some decline was obserced among older women born at the turn of the century, although the effect of chance cannot be ruled out. The pattern of adenocarctnoma incidence resembled the one for males, with increases in subsequent birth co- horts (Fig. 2). This pattern ts strengthened by the data shown In Figure 3, which presents the parameter estimates for age, period, and cohort effects. Different scales were used for males, females, and different histologie types. Cohort effects for the incidence of squamous cell and small cell carcinomas varied substantially among males (stable or declining trends) and females (up- ward trends and/or delayed plateau). However, the strongest and most consistent effects were seen for adenocarcinoma of the lung, for which marked in- creases emerged for both genders up to the youngest generations. DISCUSSION Two maior findings have emerged from our artalyses of trends of Itmg carcinoma Incidence by histologic type in the Swiss can~ons of Vaud and Neuch~tel. The first wee the persistence of increases for all types of lung carcinoma among females in the 1980s and early 1990s, while males were showing stable, or, for squa- mous. cell carcinoma, decreasing incidence rates. The male-to-female ra~ios thus declined (from 8.3 in 197~- 1979 to 4.1 in 1990-1994) for all types of lung carci- noma. The mos~ importan~ finding was, however, the steady and slrnflar rises of adenocarcinoma among both genders. Such tendencies reflect a general change in the lung carcinoma epidemic that has been taking place over the last decades, albeit to different degrees, in most developed countries. Declines or tapering increases for all lung carci- noma types among males were first seen in Hn~and, the United Kingdom, and the United States in the 197Os,s'='=~ theft in severa~ rtorthern and certtral Euro- pean countries, Including Switzerland.~ Incidence rates for females have been getting cIoser to those for males in Switzerland in the last three decades, though in 1990-1994 they were still approximately fourfold lower than for males. In Switzerland, m~tlsmoking campaigns began only after 1970,z~ and health warnings and tar yidds on cigarette packs became compulsory in 1980.= Smoking prevalence increased among men up to the 1920 gen- eration and declined thereafter)Among women, ciga- rette smoking was very rare (i.e., >80% had never smoked in their lives) for those born in the earlier decades of the current century, but it increased con- siderably In successive cohorts. By the 1950-1959 birth cohort smoking prevalence among women was almost equal to that among men (37% vs. 41% of cur- rent smokers). With respect to histologlc types of lung carcinoma, population-based data from the National Cance~ Ins~i- mte's Surveillance, Epldemiology, and End Resuhs

910 CANCER March 1, 1~7 1 Volume 79 1 Number 5 Per;o "! et MA~.E~, ~,5-6~ Y£AR5 FEM~,LE5, ~ 65 YEARS Calende¢ P~rled Period I ] Squ~moas-¢.ll : : Adenoc&rcinoma -t- ................ + Smzll-cell Other FIGURE 1. Trends are shown In age-standardized (on ".he world standard population) lung cardnoma incidence rates per 100,000 for ill ages and for ages 35-44, 45-64, ~nd 65 years an~ older, according to gender and hlstologic type. The cantons of Vaud and ~euch~tel. Sw~erland, 1974-1994. ('significant trend. P < 0.05). 0 O~ CO 0

Lung Carcinoma IP~Jdence by til~tologio Type/~vi ~t aL 911 lllgO |~<)~ IglO 1~20 I I~.I0 14~ 1~ Cefllrol y~oP Of birth SQUAMOUS-CF.I.'I. CARCINOMA. SM~,LL-C£LL CARCINOMA, M~I.ES C•ntr~l yaa r or b;•|h ADENOCARCtNOMA, M,&LE5 100 Ce~Pro| yq~P 4f b|rfh Co~fr'=| y~lur Of birf~ FIGURE 2. Age-speclf{c Incidence r~teS (for ages 35-44, 45-54, S5-64, 65-74, and 75 yesrs and older) of squzmou~ cell carcinoma, small cell c~fcinoma, and ~enecsr¢inom~ of the lung ~re shown by patients' median year of birth and gender. Tl~e ¢anto~= of Vaud and Neucl~tel, Swltzerl~ncl, lg74-1994. (SEER) Program for I973-198?= showed increases in age-s~andardlzed rates among white males in the U.$. for ~m=ll cell carcinoma (+38%) and adenocarcinoma C+47%). whereas squamous cell carcinoma decreased in absolute and ~elafive te~ms. Among white women, h~cidence fates of each hlstologlc type Increased, i.e., +65% for squamous cell carcinoma, +109% for small cell cozcinoma, and +87% for adenocarclnoma. In 19~3-1987, ~he numbars of ~denocarcinoma cases among all genders and ages had surpassed rhe num- bers of squarnous cell carcinoma cases,a Also in the cantons of Vaud and Neuch/~el, adeno- carcinoma has been the only his~ologic q~pe of lung carcinoma to increase substantially (approximately 2.5-fold) among both genders. However, in ].974-199~, overall case numbers and incidence rates of squamous cell carcinoma remained much higher than those tar adenocarcinoma, also because of the less advanced

912 CANCER March 1, 1997 1 Volume 79 1 Number 6 MALES FEMALES $QUAMOU$ CELL VAI.UE (x ~0o,0o0) AGE V/CUE (x ~oo,o~) , 0: , , ,, .,, , 0 ~ , lOO 1~ I~'1~'I~ 1~ 2~0 ~ 1~ AGE ~DAR Y~AR AG~ ~UAMOU8 CELL 1 1~00 1G20 1~40 lg~O lffilO 2000 CALEN~R YEaR 1~o ~.~, 1 1.0. SMALL CELL SMALL CELL AGE VAUJE ~X CO,OAt' PG~IOO OF OI~IN GO'] 8 4' 0 - . ..... . 0 CAI.FNDAR YEAR CALENDAR YEAR FIGURE 3, Est~maces are shown of t~e effects of age, cohort of birth, and period of diagnosis on Dung oarcinorns Incidence by Gender and major histolo0ic type, dedved fro,'r 4 Iog-lineer sge, period, and cohort model.=~'~z The c~nton~ of Vaud and Nsuch~tel, Switzerland, 1974-1994. phase of the lung c~rcinoma epidemic among Sw/ss women as compared with women in ~e U.$. • As in some U.$. data,~ analyses ~n ~is study of incidence r~es for specific age ~oups and b~h co- horts helped elucidate ~fferences across major histo- logic ~es. For men, ~e ~oremen~toned dedlnes were a~fibutable to steady decreases of squ~ous cell c~dnoma incidence in coho~ born ~er ~e 1940s, whereas ~tes of sm~ ce~ ~cinoma incidence showed a less cle~ ~d !a~er tenden~ to decide. ~so, ~ young ~d middle-zged women, squamo~ cell ~r- cinoma incidence rates tended m stabilize. A ve~ early drop in squamous cell ~rc~oma incidence among women (but no~ ~0ng men) born in 1900-1910, ~ compared with those born at the end of last century, w~s also observed in Swiss lung carcinoma mormllty rates=* and incidence rates in Connectlcutv and may be due ~o some improvements in living conditions, indoor pollution, or lung disease prevalence for gcncr- arlons born a~ the turn of the century.=s Upward trends in adenocarcinoma rates in all birth cohorts were com- mon m both genders. In 1990-1994, similar rates were observed for this histologic v/pe in the group age 15- 44 years (I.5 per 100,000 males ~nd 1.2 per 100,000 femMes). This shift in Ihe incidence of different histologic t3rpes of lung carcinoma reflects changes in smoking patterns in previous decades, chiefly smoking cessa-

tion and changes in cigarette manufacture,la Adeno- carcinoma represents The majority of lung carcinomas among nonsmokers of both genders=~ and increases, ~s a proportion, with increasing duration of smoking cessation.~v~ This may be became nontobacco lung carcinogens are more deeply inhaled and reach the peripheral regions of the lung.z7 Furthermore, between the mid-19S0s and the mid-1980s, fiker-fip cigarettes largely replaced until- tared cigarettes, and sales-weighted averages in the yields of tar and nicotine in the U.S.L6 and most other developed countries, including Swltzerland,~ have declined approximately threefold. The consumption o~ cigars, pipe ~obacco, and handrolled cig~ettes was higher than that of manufactured cigarettes in Swk- ze.'.land before World War If, but it quickly diminished t_hereafter,z~ Although the use of filter ~ips and t.he decrease in ~ar yield have contributed to the observed downward trends ofsquamom cell and small cell car- cinomas (i.e., the lung carcinoma types most strongly associated with cigarette smoking~S-z"~o), especially among men, abe fall in nicotine yield may have had a mote complex outcome. To satisfy a craving for nicotine, a smoker of Iow-yleld filtered cigarettes tends to compensate by increasing the number and depth of puffs. Therefore, the bronchioloalveolar re- gions and the smaller bronchi, which lack protective epithelium and where adenocarcinoma generally arises,~) are exposed to disproportionately higher amounts of certain smoke constituents, including smaller corpuscular carcinogens, volatile aldehydes, polynuclear aromadc hydrocarbons, aromatic amines, and N-nitrosaminesJ(~ Market shifts from black tobacco to blended or bright tobacco are also llkely to have played a role in changing lung carcinoma incidence in European countiesa" because the alkaline smoke of black ciga- rettes, like the smoke of pipe and cigars, cannot be deeply inhaled. The Influence of factors other than smoking (e.g., diet,:~- asbestos,:~" and female hor- mones~) on the shift in the incidence of histo[ogic types of lung carcinoma cannot be excluded. How- ever, the slmtlaricy observed in our study of recent adcnocarcinoma incidence trends among the two genders suggests that the pred[lectiorl Of this hlsto- logic type for women was largely attributable to the predominance of different lung carcinoma risk fac- tors, including the different smoking patterns ob- served in women as compared with men. Moreover, among lifetime nonsmokers, adenocarclnoma counts for about 70% at" lung carcinoma among both gerlders wor[dwide.:~':~'~ The observed shifts in hlstologic type among both genders may also be, In part, a diagnostic attefacL In addition to some modifications in the definition of Incidence by HlstolooIc Type/Levi et ah 913 adenocarcinoma,~i-~ new biopsy techniques (e.g., needle and mmsbzonchlal biopsies) have grearJy Im- proved the access, for diagnostic purposes, m r.he rlphe~ of the lung, the size where mos~ adenocarcino- mas a~se. R seems, however, that diagnostic pzaalce~ alone cannot account for The increases in adenocarcio name Incidence:"t Finally, most lung carcinomas are h~stologically heterogeneous,~ and interobserver vari- ability in the histologlc classification varies from 2% m 42%, depending on the tissue sample size and the degree of differentiation of the cancers.~ Norwlthstandlng these problems and the rela- tively low numbers of cancer cases observed in some birth cohorts, az least among women, our report con- firms, also in ]!uropean populations, important s~fzs in The incidences of different histologic types of lung carcinoma, especially squamous cell carcinoma and edenocarclnoma. The lazier seems to be at the origin of a new lung carcinoma epidemic, primarily attribut- able ro changes in smoking patterns consisting chiefly of shifts to low-yield filtered cigaretms. Rises in adeno- carcinoma Incidence seem remarkably slmflar among men and women, with rates of adenocarcinoma incl- dence among young adults in the early 1990s mo~e than threefold higher than rares of squamous cell car- cinoma incidence among both genders. This suggests that similar exposures to (tobacco) carcinogens lead similar histologic v/pe specific rates of lung carcinoma incidence among men and women. REFERENCES L La Vecchia C, Levi F, Decarli A. Wtefllsbacb V. Need E, Gutz. wfller F. Trends in smoking and lung cancer mortality Swltzeriand. pre~ Mad 1988:17:712-24. 2. Levi ]~. Te VC, F, andimbtson L, La VecchiR C. Trends in ca a car incidence and rnortaJi~y In Vend, Sw/merland, 1993. Ann O~col 1996;7:497-504. 3. La Vecchia C, Lucchi~fi i=, Ncgrt F_, Boyle P, Mai6onneuve P, Levl I:. Trends In cancer mortality- in l~urope, 1955-1989: Respiratory. tract, bone, connective and soft dssue sarcomas. and sldn. E~rl C~z~cer 19.q2;28:SI~.-99. 4. Vincent I~G, Pickren JW, Lane WW, Brass L, T'a~dtR H, Honten Let aL ~he changing hJs[opa~ho/ogy, of lung cancer. C,~neer 1977; 39:1647 - 55. 5. Anton.CuIver H, Culver I~D, Kurosald T, Osann I(~. Lea |B. Incidence o[ lung cancer by his[ologicnl type from a popula- tion-based registry. C~ncer Res 198S;48:6580-3, 6. Devesa $$, Shaw GL, /liar WL Chang/ng patterns o[ lun~ cancer incidence by h~s~o[oglc Wpa. Cancer ~.pldemiol rn~rker~" Pre[~ i99 I: 1:29-34. Zheng T, Holford T, ]~oyle P, Chert Y, W~rd BA, ~lannery I, et el. Time trend and the age-pefiod-¢oho~ effect on incidence of hismlogic types of lung cancer in Connecticut, 19~o-1989. C.ancer 1994;74:1556-7. Travis VV'D, Tray, s Ll], Devesa SS. Lurtg cancer. C~nce.r 75:191-202, Trn~.ds IarD, Lubin I, R[es L, Devesa SS. United Sr.ates lung carcinoma incidence trends: declining for most typ¢s amo*-tg males, increasing among femaie.¢. Caw.'er 1996:77i2464-70. 9.

I0. l~ussen-Heijnen MLG, Nab HW, van Rek I. van tier Hc|Jden LH, Schlpper I~ Coebersh ]~V~. S~ng ~g~ fn smo~ beha~our and l~g ~ ~den~ ~ h~tolo~ ~e SOU~-~t Ne~ed~, 19~0-I991. ~r ] ~ncer 19~5: ~1:949-5~ ~r 1984;50~81-8. 12. H~ ~ Be~ T, ~uj~o~ L M~ ~. ~mp~son ~cer incfden~ rat~ ~ ~s~gi~ ~e ~ ~ and low ~dence ~, wkh mf~en~ m zhe ~mhed ~le o~ smogs. ]p~ ] ~ncer ~e~ (~nn) 19~;79:445-5~ 13. Renner~ C. ~enne~ ~S, ~s~e~ ~ ~g c~ ~oln~' major e~nl~ ~ups among the Jews, ~smeL 19~- 1982. ~. ~an~n~ ~r~ds in h~s~olo~c ~e~ o~lung ~r d~r~s • e l~ decade (1981-1990) ~ ~re~ a hosplt~-based s~dy. L~mg Oncer 1994: 15. Pete R. Ov~l~ of ¢anc~ ~e-~end s~u~e, ~ r~aflon to ch~ge~ ~ cig~e mandate. Im ~ D, Pete Scientific Pu~llcazlon No. 74, Lyo~ ~adon~ ~en~ for ~es~ch on Caner. 1986~1~-~. 1~ W~der ~ Ho~ D. ~o~ ~d l~g ~cen eden- 95, 17. ~ F, Te VC, ~b~son ~ ~ Veccht, C. ~a ~ Stads~c~ ~m ~he re~s~ of ~e ~on oE Vaud. S~t~r/and, 1983-1987. In: P~ DM. Muk ~. ~eJan 5L Gao ~, Feflay L Pow~ L edl~f~. ~cer ~den~ In five continent. Volume ~. ~C S~en~c PubIl~flon No. 120, Lyon: Inlema~on~ Agen~ for Re~e~r~ on ~cer, I B~2:762-5. 18. Pe~a~ S, Levi ~, M~an ~ S~a~ f~m ~e ~e~,w of the ~[oa of Neu~t~, 5~n~ 1B83-1987. ~: DM. M~r CS, ~d~ SL Gao ~, F~layJ, Powell ], edho~. ~ncer Inddence in five confln~. VoI~a ~. ~RC Sden- flflc Publlca~on No. 120. Lyon: International Agen~ for s~ch on Cancel 1992:754-7. I~. World H~Szh Org~n~a~lon. Int~aflon~ d~sificafion o~ disease~ for oncolo~ {I~-O). ~n~a: ~O, 20. Do~ R, Smith PG. Compa~on he~een re~e$: a~e-atan- d~di~d fates. In; Wat~house J~, Muir CS, a~ K, edi~om. C~c~ incld~ce ~ five cont~en~. Vol. IV. IARC S~lent~c Publicaldon No. 42. Lyon: International Agency for Research on Cancer, 1982:671-5. 21. O~o~ C, fi~cr ~. Age, pefiud ~d ~hon mod~s ap- plied to ~cer mo~W ~tes. Star Ned 1982:1~45-59. ~. Dec~ A, ~ Ve~hla C. Age, p~lod ~d coho~ models: ~ o~ ~owl~dge and impl@men~on In G~M. A~119~;~0~97-4 IO." ~. Nl~d~-Ra~ W~d N, Fcr~ B, ~e P, editors. In~er- naflo~l sma~ statistics. ~ndon: O~ord U~v~ 24. ~ F, D~ ~ ~ Ve~ia C, ~nd~/h~oa A. ~ncer mom~ In S~ReH~d, IB51-1984: eff~ of age, birth ~ho~ ~d p~i~d of d~lh. ~ch~ Me~ Wocfie~chr 1988:l18(Supp/28):17-85. ~. Gee ~. Blot ~, ~eng W, ~how AG, Hsu CW, et ~. L~g c~r among ~nese women. In~ 1987;40:604-9. 25. ~ba~ ~, S~{man SD, W~der ~ ~el~ion be~een ~o- s~e ~o ~mnmen~ tobacco smok~ and l~g c~cer l~etime nonsmoker. Am ] Eplde~,iol 1995:142:141-8. 27. M~ca¢ I~ ~ader EL L~g ~cer pa~olo~ ~ ~o~rs, ~-smo~ ~d never ~ok~. ~r ~ 19~5;88:1-5. ~. Tong L Spi~ M~ Fueget ]], Amos C]. Lung c~dnoma ~o~ smo~. ~r 1996;78:1004-10. ZB. B~ou S, Be~amou ~ Ti~ar~e M, Plam~t R. L~g c~ ~d use of dga~[t~: a Fmn~ ~e-coauol ~zudy. NmI ~n~r l~t 1985; 74: I ] 89- 30. ~t ~ Ste~n SD~ ~der ~. ~atlon be~een ~po- ~e to en~om~ent~ tobac~ smoke ~d lun~ canc~ in l~eflme ~nsmo~r$, ~ ] Zp~emIo[ 1995; i~2:141-8. 31. Tra~ DW, Und~ L Mac~y B. Q~sffica~ion, his;oI~w, cy- ¢olo~, ~d ~ec~on mi~s~py. Im Pass HL Mkche~ Johnson DH, Tu~si AT, e~tofs. Lung cm~ce= prlndples ~d p~cdce. Ph~adelp~¢ Lipplnco~-~v~, 1996:361-95. 32. Bye~ T, Ven~ I, MeCtlJn ~ $~nson M, Grah~ 5. ~ A and lung c~cer risk an ~ysis by hi~olo~c sub~e$. Am ] ~pidemlol 19~; 120:769-76. 53. Mo~o P, Plra ~ Plola=o G, Bd~s D, Budo P, ~dreo~ e~ ~ Lung adeno~r~oma ~nd indIca~ors af asbestos ~po- sure. Inf ] ~ncer 1995~60:289-9B. 34, T~oli E, W~der EL ~docfine ~a~ors and adenoca~oma of ~e lung ~ women. ]N=d Cancer l~t 1994;86:869-70. 35. Koo IC, Ho IHC. WoHd~de epide~ologic patterns of canc~ in nonsmokers. In;l Ep~emIo11990; 19(5uppl I): 14 - 36. C~f D. Hi,topatholo~ of ]~g c~cer l~z ] 19~0; ig(Suppl I):8-10.