fNiHlVW^*-^ ^ k ^ W w *"» 1.4 ^ • --*. . £r//W; tow.' f.///.v/.-.„vw/ McJicU: 197-i. 31. >3i-303 A study of the histological ceil types of lung cancer in workers suffering from asbestosis in the United Kingdom - r . v * F. WHIT-WELL, MURIEL L. NEWHOUSE', AND.DIANE R.-BENNETT. S ^ < ^ TUC Centenary. Institute cf Occupational-Health, London School of Hygiene and Tropical ~Medicine," Keppe! SlreeL London WC1 £ 7HT Vhilwelt, F., Ncnhouse, Muriel, L . and Bennett, Diane R. (J 974). British Jcuntcl of Ir.d.atricl Medicine, 31, 295-303. A A I toy- of the historical cell types or Sung cancer ir. workers suffering from asbestosis in the United Kingdom. The present stcdy concerns ike predominant cell type of lung cancer in workers w.'th certified asbestosis who died cf carcinoma of the lung in the United Kingdom between 1562 -rd 1972. d r i e s ! dsta. necropsy reports, histological Sections, and in some cases pzraffm clocks were obtained from the nine pneumoconiosis panels in the country £nd from hospitals where the- patients hid been treaied. Hisio-ogical analysis was confined to '.he &S male sne nine ferrule esses in which adtq^jis postmortem tissue had been obiafred. The number of female cases was considered to be too small to b« of value as a separate, series. Amsr.j ;he males, ad-rcocarcir.oma was l!:e commonest i>pe of lung cancer found ir. ?4 k n . Ir.fc.-maiion sbrcut the smoking habits of 69 of the SS men v»as obtained; all had smoked at some i-tne. T.icre wis Unit difference between tr.i smoking habits cf any group " whatever the eeli type of carcinoma. The riimc-jlty in fir.uir.g *• comparable series of noaaibes!os-*»posed individuals is pointed out. jt is the usual practice to hold a necropsy on any patient when asbestosis has been certified wherever the place of death. This series therefore has a wider basis of selection than 3ny hospital-based series. Cigarette smoking can exert a carcinogenic effect on different parts o( the bronchial tree, producing squamous cr oat-cslled i urrO'jrs prcxirnaliy and adenocarcincrna distaliy. Asbestos dust ]>ingin distal parts of the lur.g may exert a eo-carcinogeiic probably a multiplicative effect with tobacco smoke, producing adenocarcinoma of the distal part of ihe icspir* alory tract Lung cancer occurs much more commonly in asbestos workers than in comparable populations who have had no asbestos exposure (Doll, 1955; SeJikorT, Churg, and Hammond. J954; Jaccb and Anspach, 1965; Kcvhoase, JSu9; NiniiOiuC, Berry. Wagner, and Ti.rcJc. 1972). However, SelikorT, Chwg. and Hammond (19£S) have shown thai lung cancer is rarely found in non-sntoking ssbestos workers, and rccrr.! evidence(Berry, N'ewhouse.and Turok, 1972) suggests lh3t asbestos and cigjreile 'RtsersM fur reprints IO Dr. M. L. N«*hi^ie. smoke have a multiplicative carcinogenic effect. In the United Kingdom Jury: cancer is not itself a prescribed disease in asbestos workers, the granting of industrial compensation being dependent upon the presence of isbestcsis. There have been very few studies of the cell-type frequencies of lung ccnccr ir. these with asbestosis, most accounts being based upon very small series. Hucper (1966) collected published cases and fo^nd an unusually high percentaje of adenocarcinoma. Hourihaitt and McCsughey (1966) examined J7 cases and found that adenocarcinoma occurred with 298 ^o o6i G i *w«m u u p i w i n ••mi A ftuJy of tUf hhio'zcgiral celi typts ofluiz: ranter in osbtuos workers 299 unexpected frequency. Spencer (19CS) slates lhat Kctomy specimen. In seme pestmcricx. eases there had asbestos cancers lend lo be of the peripheral udenc- been previous su'clccl rcmov-l of the C'Riours and histocarcir.oma variety. On ihc o:hcr hand. Kreybcr^ Icrlca! sceticris cf these were aiso »\a;Ubie. 5cct:ons «.cre siair.cd only with hccmatoxvlx. 3.-4 {1965)considers1hat !unjt cancers caused by entiresmental factors such as tobacco sr.-.o!sC or asbestos eosin bat tomci:.-.ws tissues had been stained with van Gicscc Perls', and mucin stains. dust tend u> be squamous or oat-ccll carcinomas, and recently Kannerstein and Churc. (1972) have Clasvificaliua of tuir.t-.irs found n o difference in the ec'il-lvpe frequency in a The his'.ctoplcal ci;ssii";ca:ion of lung tumours used was series of lung cancers in asbestos workers combated a sixpiilted form of the World Health O.-car.isation with lung cincers in non-asbestos-exposed indivi- classification and h;s been used previously in a surrey - d u a l s in whom the cancer was presurr-ably.cisareUe-. _ Of lung cancer in Liverpool (\Vhit*ci; 19ila. b). In this classification squamo-is lu'mours are' so'called only if induced. This conflict o f opinion as to ihe predominant tumour cells are seen to be forming keratin or fortninj priefcie cc:i»; ac^.-.-jcircir-omas reveal acinar structure cell type of lun? cancer associated with asbesiosis ar.d cr m-jcin secretion. A esse of malie-ant pulmonary has stimulated the present i'>-iy. which has been adenomatosis or aiveo!ar<e!i carcinoxa w-cs cro-jped concerned with assessing the significance of the ceil- with the adenocarcinomas. Oa:-celicarciROx.asall showed type frequency found in a large series of workers the characteristic scull ova! n^cje; in eosinophilic cytosuffering from asbesiosis who died of lunj cancer. piasMv which rsrely showed cell margins, and these tjmoursscnelimes snowed aci-sr formation. Carcinomas with none cf these features were classified as carcinoma Present inttsligalioo simplex, in which gro-p also were included i."art«ll and In the United Kinjdorri workers suspected of having clear-cell carcinomas. To.-noJrs show inj a rnixed cellular asbesiosis are referred 10 pricimccoitiesis medical panels pattern were grouped tojether as such and were mainly which ire situated to Lo.-.don, the major jndasuial ader.osquar.ous catcino.-nas. Where a tamcar was Ur£t!y undiiTe.-er.tiated but eoncentre? in E n j ! and and Wales, and in Glasgow in Scotland. The worker is examined clinically ard radio- tained some differentiated arses it was grouped accordirqf logical!}" and his pulmonary function ise-.aluated. If the to the duTerenliated tissue. panel confirms lite cla.nosts. he h certified as suffering from asbestosis and becomes ei:jible .for eomj-ensaiion. Grndinu cf asbesiosis He is re-examined and reassessed annualiy and a: death It his bjen assumed that at postmcneiR exax.inations is the subject of necropsy foliated by a coroner's inquest. the lung tissues selected for nncroscopic esarr.i.-.aiion had It is the usual practice for panels to pieserve a!i ciir.:cal been taken from the rr.osi severely 3ffe::ed areas. records o f these patients together with rcdicjrcpfcs and The lu.-g tissues hive Leers graded as follows: r.ewopsy repels, and cTten histological sitdes from sur- 1. Normal: AsUs:o> bodies w-tre w-aliy present ia srrail or nsodtrsie numbers bjt were within the ji^al or necropsy specimens. bronchioles 2nd distal air-spaces with no interstitial In the present invesiication we were fortunate in having fibrosis. access to lists, compiled by the then Medical Division of the Department of Employment (now the limploytftcn: 2. Miid si'ccstcsis: A similar number of asbestos bodies was present but many of these weie in the inlerMedical Advisory Service) of 2ll deaths from Jung cancer Stitial thsues cf the lurg where there w-a» slight, occurrint, in those suffering from asbesiosis ss certified often focal, interstitial fibrosis with seme irregular by the pneumoconiosis panels between 1962 and 1970. emph>sema. Wc circulated these lists to the various panels with requests for the loan of clinical notes, necropsy reports, and 3. Moderate asbesiosis: Usually mare asbestos bodies were present and the la-.g tissue shewed extensive any histological slides. ir,:ersti:ial fibrosis with oblileration of alveoli, Tfee total material of (his study consists of the cases cystic dilatatlsn of bronchioles with epitheiia! hyperreceived from the pr-comoconissis radical panels occurpiasia, irregalar emphysema, and co'Jaie-c^i ring between 1962 and iS70, additicral eases front pleural ihicljer.ine. Scotland from 1970 until the er.d of J 972. and a further 23 patients *:so had worked at a London East End 4. Severe asbesiisis: The numbers of asbestos bodies present were variable, being usually numerous. asbestos factory ar.d had died of 1-jng cancer, al! but Fibroses was advanced to a degree where it was three of vshora suiTere:1 from certified asbesiosis (NewdisViCuli to rcco;riire the tissue as l^r.f. There was house, 1969/. The clinics; rotes were nbstracted. ar.d frequent cystic dilatation cf bronchioles wilh adenowhere necessary further in'ormction abcu: past occupaKiatcus and sc/ja.v.ous rrelaplasia. frretular emphytions, srr.ctinj habits, bronchoscopy, radtofraphs, ard sema and pleural coltas;er,izat:o.-> were usuzliy blstopatholojy were sought frcm the hospital where the present. patient had beer, treated. Pathological mefcriat The material ccrsisted of histological sections and scineflmes paraffin blocks of lissLe which had been prepared mainly fro.T. postmortem c*am:"V3i:cns but occasionally from fcror.ebial bicpiies, ar.d lobectomy and preurno- Results Of the 197 patienis listed, clinical and pathological material was obtained in 545 cises ( 6 6 / 0 . The >>5 F. ti'i'uiHv/f. Mtnicl L. .Wa/wuf, wJ Oiane R. Bcwxtt TABLE 1 PRELIMINARY ANALYSIS OF SrFClMINS Melt Fema'e Tc.M,' 23 10 It M 2 2.< i; 12 97 irnitq^llc jnaitria! MtscihdiOTj or other tumour Opetuim uus.t ott'y &*liifj;:ory pcHCortcm (issues Tout cajej examined t 9 j 122 I 13 J Hi results of ihe preliminary sorting arc shown in Tfblel. - In the'eases grouped as inadequate there was insufficient tumour tissue in the sections obtained at biopsy or operation or from subsequent necropsy to be aWe 5o consider it representative of the nsain tumour. There were 11 cases uhere the appearances were ' not those of a primary lung cancer, seven of them probably beir.5 mesotheliomas and the others seco.-.dary carcinomas. For these reasons the histological analysts has been confined to the 97 esses where there was adequate postmortem tuniour tissue end, except in two cases, adequate lung tissue. The number of female cafes is too small to be of value as a separate scries, and as the histological cc!!-t>pe frequency In women may differ from that found in men the feina'e casts have been listed separately to avoid one factor which confuses celi-lvpe frequency studies. This has Jeff TABLE 2 HISTOLOGICAL TYPE or TUMOUR Molt % Sqtunoux o*t Adenocarcinoma Simplex Mii*«S 19 23 30 12 4 21-6 26-1 J4-I 13-6 4-6 Total M Ftn-oU 7c::l — 21 25 33 13 4 9 97 2 3 3 1 88 ms!c asbestos luna cancers for analysis. Ths histo'cgical typing ol' the lumnurs is shown in Table 2 with the pcrccr.tacc Uiuribuiion of the male cases. Adenocarcinoma was the commonest type of lunt cancer, fotnd in 34% of cases. Jf asbcs:osis hss any ni1ucr.ee on the cell-lyre frequency :r. thv scries it is likely that this would be shown by comparing the ccli-iypc frequency jn the less severe -ase» of asbestosis with the more severely affected. J.i "-'..b'c 3 the ceii'type- frequency of .the cases with norma! and.mi'd asbestosis is compared with thai found in those with moderate and severe asbestosis. Two cases nave been omitled where there •was inadequate lung tissue" ic classify by the type of asbestosis. The table shows that in norma] and mild asbestosis 2S% of the tumours were adenocarcinoma, whereas in the more severe asbestosis 3S % of the tumours were adenocarcinoma. However, this difference was not siatbtically slzpiSsant. . ,. Site of tumour An attempt Has made to assess whether the tumour arose in the upper or lower lobes and centrally or peripherally, usir.j necropsy reports fc£«her with reports of straight radiographs, tomography, bron* choscopy, and surgery. Jn 65 of the series there was a c!tar indication of the lebe cf origin; 19 (63%) of the 30 tumours classified as adenocarcinoma and 32 (55%) of the other eel! types of the tumour appeared to originate in cr.e or ether lower lobe. In 75 cf the mate seres i! was possible to make a j-j^gment uhether the '.un-.o'^r was central or peripheral in origin. Of the adenocarcinomas, 15 (^0%) were described as peripheral compared to 16 (27%) of the tumours of other histological types. Other features of the series During the examination of pneumoconiosis panel notes and hosp.'tal records (he opportunity was taken to note smoking habits and certain other aspects of the disease. TABLE 4 SMOKING HABIT BY CFLL Type TABLE 3 HISTOLOGICAL TYPE o r TUMOUR IS* S6 LUNGS GRADED BY Stvsttm OF ASBESTCSJS CtUiypt Ncri>zr' L*g end rA'J Oi&fttctii Ss. Oat Adteotairi.'iomi Oiitr t 7 7 6 hiiit st'tre csbruosl: Nor.-wnoier Ex-Knoker < F0 cigarette] 10-20 <ijirc;:«s 23 -r dcitcitn II 16 22 9 19-0 2J-6 37* 15-2 S.-noli.-.g habit 1. covin SmaxL-g hshli not k.-.owo % 2»6 25-0 25-0 21-4 Sn.iJ.ing Sfjzr-.cxt and Adt*o~ Other Ton! 0 6 8 12 * 0 3 5 7 7 0 2 J 7 3 0 11 14 26 It 34 22 13 69 3 19 1 1 W jftJ>- oj the lauiiogittii cell y/vr ofh:-s cv,zcr in atbtsios -a&kerx 301 LalySJS.. The k\n in Table 1 malc.cascs. yrcof lung lie ce)l-l>pe liiuo'uld be |cncy in ihe *c severely cncy of. the . compared I and severe .. v here'there " [»y die type jicnnal and I ere adenoabestojis k. However, fica.1t. Ihe fumour Centrally or ^her with Iphy, brooIthere was a {«%) of Vrat w d 32 \ r appeared 175 of the . judgment ripheral in }OJi) were •7%) of the losis panel f- was taken I aspects of l**r Teud P f » 7 3 0 11 M 2« tt 69 * 1» TABLE 5 SOME FEATURES OF PATIENTS WITH TUMOURS OF DIFFERENT CFLI, TYPES CtUupe AdtcocarcinotTH Other Age a '/•til txpciue Aft a: dts:h Ltirtit prrUx, LfK?:h aftxpi.i*rc No. Meo* Ac. Mca* he. Mum St. IT 21 2J 14 2M 29-6 3<?| 2*3 19 23 30 16 «-7 J7-6 3?-* 56-3 17 2! 27 14 3J« 29-3 IS-7 27-9 II 23 » 14 ' Uraa tS-9 21-2 21-9 22-9 t .Smoking habits The smoking habits of 69 of the SS disease, is felly representative of lung cancer in those, men in the scries had been recorded (Table 4). All wii'n certified asbestosis as i: is the usual practice for the men had smoked cigarettes, though three hid coroners in England and ine pneumoconiosis panels given up the habit over 20 vears before death and is Scotland to arrange a necropsy, and this applies eight others had given up more reeer.tiy. whether the patients die in hesphai or n their Though the numbers are small they do not suggest homes. The scries clearly does not con'.ain all subthat the heavier cigaretie smokers were liable to any jects having certified asbestcsis and lung cancer who particular cell-type of lung cancer. Sixty-seven per died in the United Kingdom in the period surveyed, cent of the patients with squamous and cat-cell but those not included must have been emitted ooly carcinomas were moderate or heavy smokers, v.hiie because of administrative errors in net notifying the corresponding figures for those with adeno- cases to the authorities at death, not holcing necropcarcinomas and for the other cancers were 64% ar.d sies, losing records, or because pathologists took inadequate histological sections. Ncr.ejof these errors is likely to ha^e occurred more often with any ; Age at first exposure In the different groups the particular cell-type of tumour. mean age sifirstexposure varied only between 28 and We consider thai 8S cases form a large enoogh 31 yeais. A quarter of the men in the series had serbs to provide a reasonable assessr.-.en: cf the started to work with asbestos between the aces of 14 carcinoma cell-type frequencies occurring in certiand 18. but nearly onc-nfih had no; been exposed fied asbcsiosis. Many patients with certified ssbestountil over the sge of 40 (Table S). sis have severe lung tiisccse and it may be that iung cancers in early ari siight cases of asbcitcsis are not Age at death This was known for ail patients, and adequate!}' represented, so any carcinoma cell-type the mean age at death for the different cell-types is relationship with ?.sbe»!osis is likely to be exagalso shown in Table 5. The figures are very similar gerated jr. this seri-.-s. lo these found in cases of ncn-asbesics lung cancer; The real difficulty lies in finding a comparable patients with ozl-ce'A carcinoma usually die about series of non-astestos b-t presumably cigarettefive years younger than those with squamous car- induced Jung canc-trs for comparison, and this seems to be insuperable. Most reported large scries of lung cinoma. cancers contain a hii> proportion cf cases where the Latent period This has been cakriated as the histological diagnosis i; based upon bronchiai biopsy irsean cumber of years between first exposure and sp:>cimens, so that they rcf.ecl the high incidence of death, end in the different groups varied between squamous and oal-cc!l tur=:ours in the larger accesi:b!e brcr.chi but igr.orc the rnor« inaccessible 27-3 and 33-2 years (Table 5). peripheral adenocarcinomas Tnis can be seen ir. the Duration of exposure Apart from three m»n with papers by Wyr.der and Gral-am ('$50) arid by Doll squamous-ccll tumours -whose period of exposure and Hill (1964) referred to lai.tr. On the other hand, was recorded as less lh3n two years, all hid been scries based upon surgically resected specimens exposed for rr.ore than 10 years. The mean duration i.-.clude a high proportion cf squamous tumours, of exposure varied between 17S years for those with because they are more likely to tx. resectable, and a squimoiis-cclicarcinomato2)-9yeirsior those wish low proportion of cil-ccll carcinomas and acenoadenocarcinoma. The difference was not statistically corci.-.orms beca-jse these are mere jftcn found to be inoperable. Ail postmortem series from scuic hospisigniiicant. tals are influenced by the facts that patients with known inoperable cancer lend iO be discharged home or to a chronic sick hospital. aRd hcsoital Discussion necropsies are often held only when the clir.ical This sciit?, unlike most postmortem studies of the - «*-- . * - v » - v h 3iil .. WwrfAVi. k . - t . L " - > i F. li'/J/K-f//, MurUlL. Xwteuse, crj DSu-x A'. Ikimru TABLE 6 CELL TYPES IK MALE LUNG CANCER. BROADGRKN HOSPITAL, LIVERPOOL. 1950-60. IN THHEE SERIES Crtl Ijrpe SMjuimou* Oai-ctll ., ' £ « * . - » / bsf?n ttr'.ct So. 379 IS 167 41 lttiel1 0?rte:.v. spc.'^n */ A<s. 41-1 3JT 2-0 18-1 32 107 77 142 24 923 Keeropty strits So. 17 38 29 12 7 37-J 131 94 17-4 29 *I5 t*-5 36-9 27-2 61 101 *1 •1 •When optratioa* fo.:o»ed broainsat biopty ihe cue is ss&idei only u*. Ihe optniiir. series. diagnosis is uncertain. For these rcasor.i a lung cancer necropsy series includes few of the more . .easily diagnosable proximal bronchiai tumours such as squamojs carcinomas, b-il it contains a high proportion of adenocarcinomas, which are less easily diagnosed and ofl:.. r reseni first with symptoms from their metastases. Thesepoip.tsarede.T!orjstr3:edin Tab*e6, which has been prepared after removal of female cases from material already published (Whitwcll, 1561 b) on cases occurring in the Liverpool area in one hospital. The tabic shows the frequency of adenocarcinoma ia the biopsy series to be 2%. in the opera tier, series. 9-5%, and in the postmortem series 23%. These cases \xere probably mainly cigarette-induced carcinomas and in nor.e was asbciiosis fou::d, but Liverpool-is anarea where I0%ofcdu]ima'.esshc.¥pleufa! piaq-jes at necropsy, ar.d where pleural mesotheliomas are relatively common (Whitwell and Ra'vcliife, 1971), so it is probable that if these Liverpool cases are used as a control series they may well underestimate differences between asbestos-exposed ar.i nor.-asbestos-expesed populations. There is r.o i r « indication of the overall frequency of adenocarcinoma i.i an unseiected population but probably the figure lies between 15 and 2u%, which is about ha^f the frequency ue hate found in mare severe asbes- among 17 male asbestos carcinomas, or about 35%, On the other har.d, Kannerstein and Churg (1972), in a study cf 50 lung cancers in asbestos workers, found a frequency of 22%, which was « r y similar to their control series. Hosvtver, iheir series was a mixture of cases diagnosed by bron-chial biopsy, secondary deposit biopsy, operation specimens, and postmortem tissues, ar.d it is difficult to assess the significance of fir.dings based upon such variable material. Our study has emphasized the important factor of cigarette smoking in the development of asbestos lur.j cancer, supporting the viem-s of Sslikoff ei al (196S). Retrospective studies rely upon clinical notes made leng ago in case-records, and though routine notes concerning smcking habits can be misleading they usually tend to underestimate the smoking habits of patients. In the present series (here were no patients who had i.'-i smoked cigarettes at some time, and 64% had been moderate or heavy smokers all their lives. There was no significant difference in the smoking habits of patients with different ceiitypes of lung cancer. It is wideiy held that squamous and oal-celi caretnomas of the lung are th; types caustd by cigarette smoking, while adenocarcinomas are unrelated to this habit, an opinion largely derived from lOSiS, the studies cf Wynier and Graham (1950), De'l and Comparison of the present ^testes cancer series Hill (1954), and Kreyberg (1552, 196$). Among with the earlier Liverpool series has the advantage Wynder and Grahams* series of 644 male carcinomas that the same diagnostic criteria and classification there were only 39 adenocarcinomas, and the authors ha-ve been used, and interpretation has been by the considered that they had not seen a suffici nt number same pathologist of adenocarcinomas io decide whether they conOur finding of an overall frequency of 34% of tained a higher proportion of chain-smokers than adenocarcinomas in the lung cancer of certified was seen in the control patients. Dcil and Hill found asbeslosis, ar.d of 3S% in the severely affected lungs 33 adenocarcinomas in their series of 916 lung (Table 3) is higher than in most scries that have been cancers and there was no statistical difference in the published. Hueper (!S66) fou.-.d 39% of adenocarci- amounts smoked by patients with tumours of differnomas among 104 published cases and compared ent histological grGuns, but they though: that the this with 9-5% in ms'e controls. Kourihar.e and number of adenocarcinomas was too small to conMcCaughey {1966} four.d six adenocarcinomas clude that no diiTercnce existed. In 1964 these authors l U M j a « I ^ . . I I H J J I • • • y ^ n ^ m m m m ' m .i'iig» A study oj //«• hhiolfi reported a prospective study of lung cancer in British doctors, from which they concluJcd thct there was n o marked cssoci-ition of sneckinc with adenocarcinomas, but this scries included on!y 13 adenocarcinomas, Krcybcrg (1962; I96S) censiders that JURE cancels due to external carcinocens such as cigarette smoke and asbestos dust are -mainly squamous and oat-ccll tumours, end thai adenocarcinomas are endosonous growths which have no: risen greatly in their frequency in this century. His opinion is partly based upon re-cxaminjtion and re"classif.ratidn "of rnaisriai already studied by Do!and Hill, but in his later work (Kreyberg, 196S) he admits a threefold increase :rt the incidence of adenocarcinoma in cigarette srr.ofcerv compared with nonSmokers. The Opposite view has been given by Ashley and Davfes (1967) in a study of lung cancer in men from south Water. Among 442 cases for which smoking histories were available there were 50 adenocarcinomas, and cigarette smoking was foynd to be associated wish adenocarcinoma as ofter. as with ether types of iurtc cancer. They concluded that the h i s t o r i c a l t)pe cf tumour depended entirely upon which part of the respiratory tract was affected. It is probable that ciga-ette stroking can exert a carcinogenic effect upon different parts of the bronchial tree, usually producing squamous or oatcell jurjiaurs when the m e r e proximai areas are affected, ar.d adenocarcinonias when distal parts are involved. As the concentration of carci.-.cgen is likely to be higher in the more proximal parts of the bronchial tree it is t o be expected that sc.uarr.ous ar.d oat-cell tumours wili be most common with cigarette-induced carcinoma. However, when asbestos dust, which reaches the distal parts of the bronchial tree, acts as a co-carcinogen with c»°axetie> smoke, it is not surprising t o And that the maximum carcinogenic effect, probably a multiplicative one, produces adenocarcinoma in the distal part of the respira'ory tract. We uish to (hank Dr. Waikins Pitchfo.-d, Dr. R. M. McCoMii). >ne doctcrs of the pnsun-.occn-c^'5. panels, and Dr. W. Buchanan of the Department ofET.pIojroent for their assistance and co-operation, ar.d Dr. J. C . Gilicr. and Professor R. S. F . Schilling for (heir interest and advice. References Aifitcy, D. J. ar.d Davics. H. D. (3967). Ca^re.- cf the Jun: histology and biological behaviour. Ceectr, 20, J65J74. s celt lyjvs oflur.z cancer U uibnipt workers 203 Berr;-. G.. 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