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at BRONCHIOGENIC CARCINOMA the incidences being 40% and 25%, respectively. This suggest that metaplasia of the bronchial mucosa following [uenza is no Factor in the increased incidence of carcinoma. 139 autopsies studied by Simpson in patients with pulmonary only 5 of the patients had influenza preceding the lung Hueper is also of the opinion that there is no significant p betnceen influenza'and bronchiogenic carcinoma. An apparently plausible theory concerning the cause o£ bron- carcinoma is inhalation of irritating +oases such as ha~t gas of combustion motors and gases emanating Prom tarred roads. Kawahata observed 21 cases of carcinoma of the lung in years among workmen employed in an illuminating g-as gen- erator and consequently exposed to dust and hot gases containing tar. Hampeln stated the belief that there is a definite relation to the increased production of smoke and dust in large cities in that these substances by constant inhalation produce a chronic irrita- tion of the bronchial and pulmonary epittxelium, increasing the f-requency o[ caxcinoma of the lung. Staehelin also stated the opinion that the inhalation of dust containing chemical sub- stances which possess a specific carcinogenic agent is responsible for pulmonary carcinoma. An increased incidence .of.carcinoma of the lung among open air workers exposed to road dusts was ob- served by Kermaway and Kennaway. This is not substantiated by our experience because in our 58 patients subjected to pneumon- ectomy, 32 (55.2%) had indoor occupations and 26 (44.8%) worked out of doors .(Fig. 8). Whereas it is possible to produce malignant lesions experimen,tally by the application of tar to epi- thelial sure;aces, it is difl~cult~to ima~ne how either the inhalation . 0f exhaust gases of combustion motors or the inhalation of gases from tarred roads can account for the increased incidence of bronchiog~.nic malignancies. Campbell demonstrated experimen- tally that exposure ot~ mice-to exhaust gases Prom combustion en~-:4nes had little effect on the incidence of primary brdnchio- genic carcinoma when compared with the controls. Davydofl~ and Uspensky observed a definite increase in the incidence of bron- chiogenic_.carcinoma in Russia in the-past ten years, although therewer~ few_.a, utomobiles and practically.no tar/ed roads in that country.:~ Similar observations have been made by Boyd in~ Can-.

OCHSNER, DIXON, AND D~BAKEY ada and by Husted and Biilmann in Denmark. Holmes state that the increased incidence of noma be~n in Great Britain before roads were tarred. and Franke state that the incidence of bronchiogenic increasing in the city, of Ri~, even though there is no the tarring of roads or in the number of automobiles. cIusions are drawn by Lehmann and Probst, who believe inhalation of gases fi-om tarred roads has little to do with creased incidence of bronchiogenic carcinoma. .~ FI~ 8--Graphic representation of o~:upation in authors' • 58 pneumonectomies. _ We have repeatedly emphasized the probable relationship tween smoking and the increased incidence of bronchiogenic cinoma. The chronic irritation resulting from the "- ~ , cigarette smoke over long periods of time is well known and chronic,bronchitis in smokers is so common that their cougtt~ consid~ed inconsequential and o[ no significance. Whereas longed chronic irritation o[th~, bronctiial mucosaas a . , :inhalation of smoke can in itself be a'factor in the- .. neoplastic disease just as any prolonged and continued .. can produce such a lesion, it is probabld ttmt smoking, ex. _e~. _= ;..- . .additional and more"active, influence. than ~ ..... :ii i:::-) alone, . ,¢_-x_ perimentalIy.. : it_ has .beeri~ demoustrated

hip ~ic don .~ don ~ BRONCHIOGENIC CARCINOMA a carcinogenic effect (Wacker and Schminke, Leitch, Phil- Lickint, Roffo, Lu-Fu-hua, Morpurgo, and Boehncke). is some contr6versy concerning which component of to- is responsible for the epithelial proliferation and the" effect. In addition to nicotine, there are other sub- in tobacco, such as pyridine bases, phenolic bodies, am- and certain hygroscopic agents, which are irritants. Stoe- • and ~Vacker produced epithelial proliferation in animals with Hamilton stated that pyridine •produces lesions on the skin similar to those observed in patients handling tarry sub- i~nces. McNally states that in addition to nicotine the tarry material separated from tobacco smoke has a significant irritating He demonstrated that from 6.5 to 11.5% o[ this residue could be absorbed or retained in the body. Hygroscopic agents which are added to cig-arette tobacco for the purpose o[ assuring satisfactory moisture content are usually irritating. Glycerin and diethylene glycol are commonly used. Of ~eat ~igTdficance are the investigations of Roffo, who demonstrated that tobacco does exert a carcinogenic effect and that the c~rcinogenic effect of tobacco tar varies considerably with different types o[ tobacco. He found that tar obtained from. black Kentucky' tobacco.when applied to the skin o[ rabbit~ produced epithelial tumors- as read- ily as coal tar. In both a tumor developed in 100%. On the basis o~ his clinical observations on 78,000 patients treated at the Uni- versity Institute for Experimental Medicine and for the Study of the Treatment of Cancer in Buenos Aires, Roffo cond'udes that tobacco is the most i~i..'portant factor in determining the localization of cancer. Hoffanan on the b~sis of his statistical analyses of the incidence of cancer states, "Stnoking habits unquestionably increase the Iiabili~ to cancer of the mouth, the throat, the esoph%mas, the larynx, and the lung. The_ change in the cancer death rate dur- ing recent years has not, however, been at all dispropor- tionate to the enormous increase in-.the dgarette smoking - ~.: habit which has replaced the older method of smoking, ~ unquestionably more injurious than Smoking of dgars.-- .. The in~reas~ o~ .caiacer.3f the lung observed in this and. " tent directly traceable .to the commdn/practiceo[ cigarette:-5~

OCHSNER, DIXON, AND-DEBAKEy smoking and inhalation of cigarette smoke. The factors unquestionably increase the danger of cancer velopm.ent." As early as 1923 Fahr stated that he believed the " bronchiogenic carcinoma was due to the increased inci cigarette smoking. Lickint also believes that digarette is an etiologic factor in the production of bronchiogenic noma and that many case~ can be prevented by the h-ore smoking, particularly in patients belonging to known to have a high incidence of cancer. Harnett found in a g-roup of 69 men with bronchiogenic carcinoma, were non-smokers, 26.1% were moderate smokers, 40.,5% excessive smokers; and in 29% it was not stated whether smoked or not. Anderson quotes Kramer as stating that a 5 cigar yields 200 rag. of tobacco tar, whereas an eight-hour behind an automobile resulted in the collection of only I ~ of a similar tar. M~Nally found that the tarry residue in cigarettes varies h:om 4.84% to 15.29% with an average of Recently Black suggested that commercial lead may be inciting factor "in bronchiogenic carcinoma and that the lead tobacco may bE the [actor, in the causation of the lesion in ers. Wallace and Ja "ckson surest that the small amount in tobacco may be responsible for the carcinogenic effect bronchial mucosa. In an attempt to determine the causal donship between inhalation of-exhaust gases, cigarette and bronchiogenic carcinoma we ga'aphed the incidence of bronchial lesion aga.inst the sale of cigarettes and the sale automobile tags in the United States (Fig. 9). As seen by g'raph there was no parallelism between the sale of automobile- licenses and the incidence of bron..chiogenlc carcinom,'~ but is a distinct parallelism between the sale of cigaxettes and the • incidence, of the bronchial lesions, . .,: . - Barnard compares the development of_ bronchiogeni~ noma with the development of. basal cell garcinomd of the Skin and believes that chronic irritation ofthe bronchiis the/esult of- repeated infection and other inqtations which are [actors in stimu- _ gating, the fftowth of cardr/oma~.. He mainl~ tha~-bronchial. " mucosais a tissue in which carcinoma.is likely "

BRONCHIOGENIC CARCINOMA and Dible on the basis of the silica content and the histologic of pneumonoconiosis in 70 patients with and 50 without carcinoma concluded that silicosis plays an impor- etiologic role. Klotz reported that of 50 patients with sill- coming tO autopsy 8% had bronchiogenic carcinoma whereas iin 4,500 neeropsies in which there was no silicosis, only 1.18% ishowed bronchiogenic carcinoma. Dick found that in a series of 1131 casesof bronchiogenic carcinoma, in 44 there was evidence of silicotic nodules, whereas in 11 others there was fibrosis ~ith suggestive silicosis although no "~ao~Iules could be demonstrated. According to Hamett, silicosis :plays a definite etiologic role in bronchiogenic carcinoma. He found that metal gTinders were • likely to develop.fibrosis of the lung from silica dust and that they developed bronchiogenic cardn0ma two and one-fourth times more frequently than other individualL - ,-- Other- specific and non:Specific pulmonary /rffecdons have been suggested as responsible etiologic factors in the production- of bronchiogenic carcinoma. Of these, tuberculosis is probably the most trequ_emly mentioned. According to ~.wing, the tubercle badllns, becatis~, it is an-irritating agent, is one of the most f re- - 1201

OCHSNER, DIXON, AND DEBAKEY quent etiologic factors in bronchiogenic carcinoma. Bah'on .Cherry suggest that tuberculosis plays an etiologic role in the duction of these neoplasia. Of 31 patients reported by had tuberculosis. Fried reported 13 cases in which and bronchiogenic carcinoma coexisted. On the other Rokitansky long ago emphasized the rare occurrence of losis and cancer in the same person at necropsy..These dons were subsequendy made by others (Albrecht; Kramer; L6izag~a and Vivoli; L~abarsch, and Reinhardt). and Monserrat report that whereas the incidence of F tuberculosis is high in the Philippines, bronchiogenic " is encountered in£requendy. In a series of 24~ cases of genic c~rcinoma, Kikuth found only 22 with tuberculosis. comparison of 886 persons with active tuberculosis and a ~oup without tuberculous involvement, Pearl found the dence of malig~aant tumors in.. the former to be 1.2% and in latter, 9.3~o. He concludes that the rarity of the two lesions the same person "is apparently due to a significant tween the two patholo~c phenomena which disappears when if the tuberculous process retrogres~ or heals, particularly by fibrotic route.'" Similar Observations have been made by Carlson and Bell. L6izaga and Vivoli found only one cas~ of of the lung in 2,400 autopsies on tuberculous patients. Simpson and Ziemssen have suggested that syphilis may an etiolo~c factor. Letulle observed evidence of syphilis in 11 cases of bronchiogenic carcinoma. The coexistence of and bronchiogenic carcinoma has been observed by Bonnamour, Brouardel, Martin and Colmt, Popper, Rouslacroix and There is, however, not su~icient evidence to suggest that syphi~ is a factor in the production of bronchiogenic carcinoma. Non.sl~ecific,-chronic inflammato~ lesions of the bronchi been suggested as possible etiologic factors. Frommel found chronic bronchitis, bronchiectasis, and emphysema were in ~9 of 41-cases of bronchiogenic ~-cinoma. Klotz observed case in which a malignancy developed in a bronchiectatic in a patient who had suffered from bronchiectasis for fifteer~, Simpson, L~scke, Fried a~id Hunt:have observed the .... _ of chronic lesi0 in ci~ br~ br b~ p1 p1 s~ pl 6'. d, r~ a t, t I t

)If, ,nch In BRONCHIOGENIC CARCINOMA cinoma. Relatively recently Stewart and Allison reported a case in which a microscopic focus of oat cell carcinoma was found in a bronchiectatic cavity of a pulmonary lobe which was removed for bronchiectasis. Blake reports an inoperable case of bronchiogenic carcinoma which developed at the site of a retained metallic for- eig-n body which had been aspirated 6 years previously. It has been suggested by Bonner, Goltz, and Siegmund that the meta- plastic changes consequent to the injury of the ePithelium in these chronic inflammatory lesions are responsible for the neo- plastic change. It has long been known that the inhalation of radioactive sub- stances is responsible for the development of bronchiogenic neo- plasia. This is demonstrated conclusively by a high incidence of carcinoma among the workers in the Schneeberg mines, first em- phasized by Anastein. Rostosk], Saupe, and SchmorI found that 62% of workers in the Schneeberg mines who were followed until death died of primary bronchiogenic carcinoma. A more recent report of studies on the Schneeberg miners conducted by the gov- ernment committee for the prevention of cancer states that these mali~nant tumors are considered to be due to radioactive emana- tions. D6hnert kept 48 mice in the Schneeberg mines ~or" periods rang-ing from two hundred to three hundred and seventy days, and of 26 submitted to microscopic examination, 7 were found to have neoplasms, 2 of which were in the lung. He concluded that these tumors were caused by the radium contained in the air. In addition to being radioactive, the dust contains a high con- tent of arsenic and cobalt (Schmorl and Uhlig). Similar observatiohs were, made by Pirchan and Sikl, who stud- ied the pitdablende mines bf Joachimsthal, which is across, the mountains ~om Schneeberg. The latter authors found that ra- dium emanation in the air of J~ichymo.v pits is as high as 50 mach6 units. Peller-fotmd that during the years 1929 to. 19~8, 89 Joa- chimsthal miners ch-ed, 6 of whom were ekamined postmortem. Of these, 47 (52.8%) died of cancer, 42. of whom had primary br~nchiogeni.c carcinoma,. Peller is of the opinion that. the high incidence of bronchioger~ic carcinoma among these-miners is due to the radi_'oactive factor in the mines: Although the presertcd of dust alone~migl_a_t be responsible for the development of bronchio-

OCHSNER, DIxoN, AND DEBAKEY genic carcinoma, the investigative work of Willis and would tend to disprove this, as would the fact that bronchi. carcinoma is not as ~equently found in other miners who. pneumonoconiosis as do those in the Schneeberg mines. and Brutsaert were able to produce tumor-like structures lun~ of guinea pigs exposed to silica dust, but there was dence of carcinoma developing. ~ Trauma has been blamed for the development of genic carcinoma but ~ually plays little or no role since the pulmonary lesion existed before the trauma was Isolated instances have been reported in which trauma ably played a role in thd development of the bronchiogenic (Aufrecht; Georgi; Gomez; Hand:ford; Hedinger; Luckow, Sch6ppler; Scott and Forman; and ~Vells and PATHOLOGY Carcinoma involving the lung is almost entirely a the bronchi, although rarely it may begin in the alveolL right side is involved more frequently than the left. In a of .4,732 cas~ which we previously collected from the there were 2,761 (58.3%) tumors involvihg the right lung 1,97I (41.6%) involving the le~t lung. In Fischer's series of cases of pulmonary carcinoma the right lung was involved in 53' the left in 45% and in 2% the lesion was bilateral. In the cases which Fischer reported ixt which the location was according to the bronchus involved, the findings were as right main stem bronchus, 142; left main stem bronchus, II bronchus of the right upper lobe, 148; bronchus of the left lobe~ 130; bronchus of the right lower lobe, 120; bronchus of left lower lobe,. 105; bronchus of the right middle lobe, 15. In the 190 cases which we have observed, .the right lung involved in.98 (51.6%); the left lung in 87 (45.8%), and in:-i (2.6%) both lungs were involved (Fig. I0).. Ix~ the 58 cases which we have done-a pneumonect0my [or p,rimar~ genic carcinoma, the right lung was involved in 34 (58.5%) the left lung in 24(41.4%) (Fig. 11). The involvement lobes 2 lobe lower in the neopla~ high to us Knox's high, heir 'were o~ dJJ~se, 80% o~ b: near the the perip bronchi~ ~-' Most hye of" mors axis with its

BRONCHIOGENIC CARCINOMA ~be 2 (3A%), right lower lobe 14 (24.1%), right upper and mid- lobes 2 (3.4%), right middle and lower lobes 2 (3.4%), left lobe 13 (17.2%), left lower lobe 7 (12.1%), and le[t upper lower lobes 4 (8.9%). Most bronchiogenic neoplasms are lo- ated in the region of the hilum. According to Boyd, 90% of these neoplasms are in this area. This incidence seems somewhat high to us since in our series it is not quite so high. In Frissel and Knox's series the incidence o[ hil~ carcinoma also was not so high. being only 49.7%;. 17.8% involved the parenchyma and were of/.he nodular variety; 6.5% were peripheral; 23.9% were disuse, and 2.1% were bilateralm'.fliary. According to Edwards, 80% o[ bronchiogenic carcinomas 6¢cur in the larger brondfi or near the origin o[ the secondar~ bronchi and only 20% occur in- the peripheral bronchioles. According to Betts~ in 62 cases of bronchiogenic carcinoma, 46 were located in the re,on o[ the. hilum and 16 peripherally, Most bronchio.genic carcinbmas probably be~--, in the basal layer o[ the bronchial mucosa. According to Bamard, these tu- mors arise most f~equenfly at @e junction o£ the bronchial branch ~th its parent stem and that early in the growth of the lesion the ~ ~ 1205 " " "

OCHSNER., DIXON, AND DEBAKEY mucosa overlying the neoplasm is intact, but shows color, particularly that of a whitish ~ay or whitish pink. have been many classifications of bronchiogenic gested and the one most frequently described has been ferentiation between squamous cell carcinoma, small differentiated cell carcinoma (oat cell carcinoma), and carcinoma. There has been litde uniformity of cerning this classification, however, and for this reason it most logical to us that the classification proposed by the most logical one. This classification is based on the ment of cells lining the bronchi and. explains adec histologic structure of all primary" bronchJogenic Normally the ceils lining the mucous membrane of the tree represent varying degrees of differentiation an& don of the ori~al endodermal cells. "Apparently the undifferentiated, end~lermal ancestor is capable of developing into ciliated cylindrical lium, goblet cells, cuboidal cells, arranged into acinar tubular structures producing a serous or mucous indifferent cells, lining the ducts of these glands, and another kind of cuboidaI or low cuboidaI ceils cilia which line partsof the terminal bronchioles. In tion to the variety of cells, just enumerated there are, neath the ciliated cylindrical-and goblet ceils, g number of bther epithelial cells whk:h, like the basal in the epidermi~, are lined up along the border toward tunica propria. They are the cells from which the layer o.f ciliated cylindrical and goblet cells is replenishecL~- These cells, which may be called 'reserve ceLts,' are the ent cells of the ciliated~ cylindrical, and goblet cells. In addition they. naturally also possess the qualitie~ .of ~ ancestor cells in that they may differentiate into any _ of epithelium that an endoderrfiaI ceilis capable of i Halpert is of theopinion that it is" from these- reserve cells bfonchiogenic carcinomas originate by a pi-ocess liferatiOn:. He, therefore, dassifie~ .brdnchiogenic r three types depending-apoh the embryo!ogic direction of • :-..; .~/ tende: genic c carcinc cell car AIt~ ered b~ to the ff that and me bronchi dence Neely, bronckic and fxeq is distan~ fast man in by determi~