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FILE NAME Kent KNT DATE 1940 DOC KNT107 DOCUMENT DESCRIPTION Journal Article - Does Chronic Irritation Cause Primary Carcinoma of the Human Lung - Archives of Pathology CCT YT ea DR SESE ET IEICE TERE ATT EO MATE TT ge ett Seg Hee 942- 43 942--43 942-43 942-43 942--43 942-43 942-43 942-43 942-43 TEE |g ARCHIVES OF PATHOLOGY ad 5 , f 5 EDITORIAL BOARD : ! LUDVIG HEKTOEN HEKTOEN Chicago Chief Editor : JAMES EWING New York OSCAR T. SCULETZ Evanston Ill he S. B. WOLBACH Boston GEORGE H. WHIPPLE WHIPPLE Hochester N. ' FRANK R. MENNE Portland Ore 1 i ae Volume 30 Volume 30 Volume 1940 - .% Ws wile} 338087 WAY 338087 KP PUBLISHERS AMERICAN MEDICAL ASSOCIATION CHICAGO ILL OOM OOM IEICE Fs EOE TL esS e E50R 9 ENE Ae Critical Reviews DOES CHRONIC CARCINOMA CARCINOMA IRRITATION CAUSE PRIMARY OF THE HUMAN LUNG MADGE THURLOW THURLOW AND MACKLIN ALD CHARLES C. MACKLIN M.D. LONDON LONDON ONTARIO ONTARIO CANADA Primary cancer of the hung in common with other forms of growth is almost universally believed to malignant chronic irritation which originate through soune form of in the bronchial usually sets up a chronic inflammatory process : view mucosa The literature contains many examples of this ; Thus Davidson stated Numerous theories mostly relating to the factor of have been advanced irritation in some form or another of the respiratory tract to account for this phenomenon fourteen causes found chronic irritation - Simons who listed of the bronchial bronchial mucosa a factor common to all of them and concluded that this cominon factor is the cause of pulmonary cancer Fried 3 said that irritation is - . it is beyond doubt as necessary a predisposing factor in the causation of cancer of the lungs as it is in cancer of other : the commentators it organs In the minds of seems to make but little difference what the irritant is so long as it is an irritant and there are various mechanical chemical thermal bacterial electrical types such as more than and radioactive Often one type is at work on a given region as when an of the tongue's surface is area ' persistently scratched by a sharp stump of a tooth mechanical with erosion of the epithelium and tected tissues to irritants of bacterial exposure of the unpro- and chemical types The sine qua : non seems to be that the irritant shall act over a long period There is constantly or at short intervals is no agreement as to the length of time that required in any given case to produce a cancer is conceded that this factor is a variable one and operates in such association with other variables as age anatomic site and predisposition The irritant too must From the University of Western Ontario 1. Davidson M Cancer of Medical School England John Wright & Sons I.tthde. L1u9n3g0 and Other Other Intrathoracic 2. Simons E. .: Primary Carcinoma of the Publishers Inc. 1937 Lung Chicago Tumors Bristol The Year Book 3. Fried R. M Primary Carcinoma of the Wilkins Company 1932 Lung Baltimore Williams & 924 mato have per s phen rable canc mult the c path 1 the i mate MAC MACKK LIN MACL KLIN PI RIMN ARY CARCINOALI OF LUNG 925 act sufficiently strongly to produce an effect in the tissue but not so strongly as to cause total necrosis of the tissue It seems certain also that in most if not all cases inflammation super- venes in the region undergoing exposure to the irritant The inflamma- tion is a reaction on the part of the tissues to the injury occasioned by the irritant It may theoretically at least be regarded as protective in nature though the means sometimes defeats the end as in silicosis Since chronic inflammation is well nigh inevitable and universal concomitant of chronic irritation the one term has often been used as synonymous with the other and thus it is that chronic inflammation is regarded as the etiologic agent in primary cancer of the lung without any distinetion being made between the fundamental irritating agent and the tissue responses following its chronic action So widespread is this usage with regard to chronic inflammation indeed that we find it convenient in the following pages to discuss the alleged causes of primary cancer of the lung under headings of the pathologic conditions geuerally inflammatory in nature rather than of the specific irritants Commentators have found it difficult too to distinguish between chronic inflammation per se and the chronic reparative process and it would seem that the two phenomena are so involved one with the other as to be practically inseparable Thus if we were accurate we should ascribe the growth of the cancer to the hyperactive repair process with its urge to increased cell multiplication reserving to chronic inflammation or to some other factor the carcinogenic influence which first sets a cell or cells on the cancerous path It is our purpose in this review to bring forward data indicating that the thesis that primary carcinoma of the lung is due to chronic inflam- inflammatory changes in the lung is unproved We do not feel justified as yet in denying outright that chronic inflammation causes pulmonary cancer but we affirm that on the whole the evidence now available does not warrant such an assumption Even the carefully selected called positive evidence that is commonly regarded as supporting the thesis is by no means equivocal That chrone inflammation should have been implicated as the cause of cancer is not surprising for the two are often present in the same region the lung changes changes We would point out however that because primary cancer of is not infrequently found associated with chronic inflammatory in is no reason for assuming that it necessarily is due these Indeed this association no more justifies the conclusion that the cancer is so caused than does the circumstance of mau being ford near the scene of a crime establish beyond doubt that it was he who com- mitted the fortuitous crime His presence at the scene may have been merely It seems quite possible that chronic inflammation often stands relation to primary cancer of the lung as does the immocent man at the 926 ARCHIPES OF PATHOLOGY site of the crime Indeed in many cases the inflammatory changes are neither the cause nor a chance associate of the cancer but are its result Moreover even if at some inture time adequate proof should be forthcoming to show that in some cases chronic inflammation or irrita- tion is the extrinsie only in mass data cause of pulmonary cancer such proof can be not in individual cases There are persons used who present no ^'vidence whatever of chronic inflammatory disease of the lungs who nevertheless show development of cancer of the lung and on the other hand there are persons who despite having suffered from inflammatory diseaseosf the lungs for years never have cancer of the long It is impossible to say of any one case that had the chronic inflammatory change not existed cancer of the hung would not have developed ENVIRONMENT ENVIRONMENT AND HEREDITY IN THE ETIOLOGY CANCER Op THE LUNG OF PRIMARY with all other cancers the problem of the origin of primary cancer of the lung naturally divides itself into two aspects concerned with 1 supposed productive factors acting from outside the body and 2 constitutional factors inherent in the body and varying with the patient and particularly with the strain or line of descent These agencies are characterized as environmental and hereditary respectively The environmental factors may be subdivided into two categories 1 those that would be encountered in the course of ordinary living which are the various chronic irritants commonly used to explain human cancer and 2 those which have been discovered by inducing cancers in animals through the experimental use of specific chemical agents called carcinogens As man is not used in the experimental production of cancer all malignant growths arising in him must come under the heading of 1 tumors induced by the chronic irritations of ordinary life or 2 tumors arising on account of constitution These may be considered as primary poles or extremes useful in our mental processes in the study of the causes of cancer Actually the constitutional factor enters into - every production of tumor and the only point which needs to be determined with reference to is the extent to which it is participating in any given case So if the environmental factor is admitted all tumors are of dual origin We shall now review briefly the sources of called chronic irritation to determine what proof has been brought forward to sustain the thesis that chronic irritation causes pulmonary cancer man A large number of citations from the literature might be made in support of the idea that chronic irritation especially in the form of chronic inflammatory change is responsible for the genesis of primary cancer of the lung MACKLIN MACKLIN MACKLIN MACKLIN PRIMARY CARCINOALA OF LENG 927 These would be in practically all cases merely opinions without any valid basis of proof They might be encountered with an equally large number of statements questioning the role of chronic irritation in the causation of primary cancer of the lung These again would be opinions for the most part with no proof to sustain them They would show two things however first that the theory of chronic irritation has not been accepted without question and second that the burden of proof should rest on those who assert that primary cancer of the lung in man is caused by chronic irritation or inflammation ALLEGED ENVIRONMENTAL CAUSES OP PRIMARY OF THE HUMAN LUNG CANCER Simons listed a number of supposed general causes of primary pulmonary carcinoma in man and in them he finds a common factor namely chronic irritation These alleged causes should be divided into two sections 1 those capable of being produced by pulmonary cancer these are often found associated with such cancer because they are sometimes the results of the presence of the cancer either alone or in combination with other influences 2 those which are not capable of being produced by cancer of the lung but which might be found associated with in the same patient in varying percentage of cases With regard to group 1 it might well be that in some instances these conditions conditions have been present before the cancer ever started although they are are not nucessarily the cause of the cancer while in others these conditions have not been present until after the cancer started and are a direct result of the growth of the tumor We shall now discuss the conditions which belong to group 1. They are chronic bronchitis pulmonary abscess asthma bronchiectasis pleurisy emphysema and conditions simulating pneumonia and influenza The conditions listed in group 2 by Simons * are trauma tuberculosis pueumonoconiosis chalicosis syphilis roentgen iqadiations inhalation of dust especially from tarred roads smoke especially if bearing chemical irritants as in certain of the industries motor exhaust fumes and war gas various industrial and occupational hazards involving the breathing of hot air especially if bearing chemical fumes tobacco smoke or the air of certain mines such as those of Schneeberg Bohemia which contain not only irritant dusts but radio- active substances substances as well It will be found that as industry ends and new chemicals are encountered this second list of conditions which are supposed either rightly or wrongly to cause cancer of the lung will increase Let us review first the course of development of a cancer of the lung so that we may see why the conditions in group 1 are so often found associated with this malady HOTTIE TET EEE CIEE ML ae eae ARCHIVES OF PATHOLOGY COURSE OF DEVELOPMENT OF TYPICAL CANCER OF THE LUNG Although no one has followed the course of a cancer of the lung from its onset to its full expression the following outline is regarded regarded as probably accurate The epithelium in some local region of the bronchus undergoes a change which makes it malignant to the rest of the body At this point we are not discussing what the nature of the change is or whether this change is occasioned by forces inherent in the cells or is by extrinsic brought about influences The cells whose ability to differ- entiate into normal cells and to organize into normal tissue has been wholly or partly lost still retain their ability to grow and do grow The growth at first is probably slow This is the beginning of the tumor In thue the tumor causes a narrowing of the bronchus so that au obstruction to airflow ensues together with a handicap to the normal bronchial eliminative mechanism This impairment of function is followed by degenerative changes in the part of the ling served by the involved bronchus The irritation produces a congh often nonproductive at first of chronic character which simulates that of chronic bronchitis Inflammatory changes in the mucous membrane follow the damming back of the excretions normally wafted away by the cilia or removed by the peristaltoid action of the broncinus or by coughing The cough grows worse and streaked sputuu is produced When the obstruction to the bronchus is complete either through blocking of the lumen by the growth within or by pressure on the bronchus by the encircling growth without there is atelectasis in the lung beyond the point of obstruction This is followed by bronchiectasis of the bronchi in the collapse area which dilate to make up for lost volume of lung Another effect of the diminution in volume of lung is compensatory emphysema in the alveoli of the surrounding lung tissue These become more dilated with coughing An asthmatic wheeze may develop in the narrowed bronchus before it is completely obstructed If the center of the tumor becomes infected and undergoes necrosis the patient may show an abscess of the lung with drainage of the pus through the bronchus If the tumor grows extensively toward the periphery of the lung before it breaks down the pleura becomes inflamed and pleural effusion results The pus may rupture into the pleural cavity and the patient may be operated on for empyema without the cancer of the Jung being recognized The onset of the symptoms may be acute and simulate influenza or pneumonia or the onset may be gradual and tuberculosis may be diagnosed In any of these steps an erroneous diagnosis may be made and the patient may later when the cancer is discovered asume assume that the " chronic bronchitis " influenza asthma or tuberculosis which he was supposed to have was the cause of the cancer The physician sometimes accepts at face value statements to Sree AE ea wea te MACKLIN PRIMARY CARCINOMA OF LING 929 the effect that the patient had chronic bronchitis for some time before the cancer was recognized and that the one was therefore the cause of the other The course of bronchogenic cancer as is probably true for all other cancers can be divided into three periods First there is a silent period which lasts from the moment of the initial change of normal cells into cancer cells up to the time when symptoms of such severity begin that the patient associates them with the onset of his illness This stage is apparently the longest and is completely silent as far as the localized activities are concerned though symptoms may be produced from a metastasis in some other region but may give rise to vague general symptoms The second or symptomatic period is characterized by the onset of symptoms which progress up to the time of the diagnosis of cancer of the lung or until death if the diagnosis is not made This period may be relatively brief only a few months or at the most it may be a few years The third period is the diagnosed stage and is usually the briefest it is nonexistent if the diaguosis is not made In most cases it lasts from death for relatively few for a brief time the time patients of diagnosis of cancer of the long have been operated on and cured until even It is evident then that because of the initial silent period there is trouble in ascertaining whether any particular chronic inflammatory disease preceded the onset of the cancer of the lung Thus bronchitis coming before the diagnosed period is thought to antedate the cancer although the cancer existed in the silent period before the onset of the chitis The symptomatic period before cancer of the lung is recognized during which the patient may have various pulmonary symptoms helps to confuse cause and effect of cancer of the lung and to make patient and physician alike interpret the symptoms produced by the cancer as symptoms of conditions giving rise to the growth SPECIFIC CALLED CAUSATIVE FACTORS OF CANTER Of THE LUNG GROGP 1 Chronic Bronchitis bronchitis has been looked on by some writers as of importance in the etiology of cancer of the lung because bronchial mucosa 1 it produces chronic inflammation of the and 2 it is found with some frequency in the histories of patients with cancer of the hung What evidence is there to support or to deny the assertion that chronic bronchitis plays a causative role in pulmonary cancer One of the first arguments that will occur to any one is that bronchitis may be generalized in distribution while cancer of the lung is localized The inflammatory changes of bronchitis are widespread and peripheral as well as central while cancer of the fute is localized and is usually bilar JOJOJUJEJ JUJEJO IR JE je ||||||||| atatakataka atatakataka Pescagar 930 ARCHIVES OF PATHOLOGY If chronic inflammatory changes induce the cancer why does not the cancer originate diffusely over the hing Chronic bronchitis has no special predilection for the male sex but cancer of the lung occurs about four times as often in males as in females It would seem if chronic bronchitis is a major cause of cancer of the lung that meu should be minch greater sufferers from bronchitis ihan are women yet no such preponderance has been mentioned in the texts ou discases of the lungs and mortality statistics do not show more bronchitis in males than in females Although might be assumed that the regeneration of the bronchial epithelium in chronic bronchitis would lead to cancer of the lung we must ask if there is proof that it does so First is bronchitis followed more uten by cancer of the lung than not Second how many patients with cancer of the lung give a history of chronic bronchitis that is of such long duration that it can legitimately be looked on as baving antedated even the silent period of the cancer's growth There are no adequate answers to either of these questions because we do not know how many persons in the population lave chronic bronchitis and we have little idea of how long the silent period can be Since most takers of clinical histories content themselves with stating that the patient had complained of chronic bronchitis failing to give the time during which the bronchitis existed we cannot place much reliance on reports in which is merely stated that a certain percentage of patients with cancer of the ling have had bronchitis First we should have to exclude all those in whom bronchitis probably followed instead of antedated the silent period of the pulmonary cancer Since we know that cancer in general is slow growing and that in men who have worked in the Schneeberg mines cancer of the lung may develop from ten to twenty years after they have been pensioned off from work the mines we should probably have to allow a minimum of at least ten years before the cancer was diaguosed as the period during which it was probably present in the silent stage Therefore all patients with cancer of the lung in whom chronic bronchitis started within the last ten years before the diagnosis of cancer of the hung was made should be excluded as most probably being patients in whom the cough was either the result of the tumor or coexistent with it though not actually caused by it Those who had a history of cough for more than ten years might possibly be looked on as patients in whom the cough antedated the cancer although this would not inevitably be so Second we should then compare the latter group of patients with the general population in regard to the incidence of chronic bronchitis If 10 per cent the population past 40 have a history of chronic bronchitis we need not be surprised if 10 per cent of patients with cancer of the lung UTTAR AP IET AL ee pee that thiscondi- WY condi- MIP Waray 2S [Poysey remembered remembered that this condi- AYHOSPHPEN par LfToasuyy observations observations are cited show that Bo aphpse op Ysnona aBsc] agent agent pulmonary pulmonary cancer have for- ev ocupoave Cavuouynd saop wey the lung lung causes chronic chronic bronchitis bronchitis ot], yO foun udraoq g waste explains certain certain percentage percentage percentage the cases cases ayl Yo asayo ayy jou st pie found and that unless unless chronic chronic bron- Agent Jo sasna ogy jo 9duyI. found more often patients patients patients with cancer ey punop oq ased wogipuoes population population the same age and as JO MOIsHpaG Aq Pasnvs SisupapTE patients patients cancer of the lung how- Jo datosaid ayp JO YNsar v Moreover Moreover chronic chronic chronic bronchitis bronchitis includ- AUOAYA DYY [om SIPPY Popespsuourry an average average from numerous series nogonpoe? ayy ib NONn duposndd Dp , stpysitasg diMoedy) fo apor mg WY daolasarpy pus vonyNdod pussuad ayy bronchitis bronchitis bronchitis is no means universally universally punoy ApuoNtos alout st Suny ayy with cancer of lung that when is WLSTUL TOC PR SHUG sO the tronsor has caused caused the bronchitis bronchitis fsasra oy JO Jaqronte aduny vo ui there is way of showing that that QxwoSsaad ayZ asnv2eq st I punoy conceivably conceivacboncleivyably have antedated antedated the tumor of stoned yo soioysay ayy. UL puny patients with cancer cancer of lung SHOPS Jug AVS UTD OAL STILT, as Ou] UL paytodar soso yo of pulmonary carcinoina carcinoina has not been Soylis ato I squanud oyl yo yuaa dx] Gg qhoqu UG dFO1 UE ano TOU SANp saaotT Aq pasnys yey Aut bronchitis bronchitis bronchiectasis frequently frequently PUROTPTULIS JOU St GRaad IA9 primary cancer of the lung following following arp ur Soaanbary syr spuotuad so] a bronchus bronchus by tumor tumor Hence Hence prisuad ayy ur ueyy sunyp ayy jo clinically or autopsy autopsy a large per- t AWOL ouy suqepoyue SEM cancer the lung it is caused by aay SuOIpPUOS OAsy aD YouyAs ut in the majority majority Zacher Zacher ) Os puv SUIQOLA SH fo JUIOS Us lasts over much longer period period period yey CP) rsprp Ong vonod benign tumor can almost always grow aauusnus Te st SHitpuorqd outed bronchus before killing killing the patient ThereA-L SIOTLIAL OU} To IsopY 2ouRa Quart poss Ae 24:29 1935 st iavp ou dounos<Tkurpaaaxe sr uot Wehnschr 967 1931 24:29 SEV TOUS UShoyyE (Csesuo QOL) sean, 7Z Wehnschr 967 ayp Wt paramos Yop SUP WOT ITUOIYS SEM MOT (puod WOposayU JSAUOUNTTOD 9p, PoPeEUlaL , UOS[OYIEN PUR [PEMxeyy iq uonypidopdose-ayppalt stp) UL SOTSUOIY SIUO.LYDS JO AUSPINUT aly HO PPP AQUI OM Jou Op aay MpyeuNptopyy rou ayy, sof ayqistiudsas an suv Lb Stag sp yoy yaoi 8 AIG ANY} JO FOMOUE Iso1sua 917} SUIMpyWL SHLpUEIE OMOIP pLTp vavtp OF Pepoadxs aq Avur Ftp oy Jo WII YA syuoned jo quo Jod gg SHjuosq OTTO perp savy Tory -ndlod petouad ap jo yuas sad QO JP Oav7OUT Woaasqjog diysuoneper pay pe asnus AUY TM ALI} WROITAS SLUMPING MUOATD Jo SEOYSUT UPAR 6 PNA FO PIONLOMED RTO AMPA ON TIN OF WONTINISEE SOHC IOIEIO TOI UIE TEESE EOS Er oe ea eae ema nee ARCHIVES OF PATHOLOGY fore bronchiectasis is always an accompaniment of a benign tumor of the lung of any duration according to Wessler and Robin It may be of course that a patient who has had bronchiectasis to some other cause may subsequently have cancer of the lung due In such a case the bronchiectasis preceded but did not necessarily cause the cancer Many patients have bronchiectasis who never have cancer of the lung indeed Graham Singer and Ballon stated that in patients in primary lesion is bronchiectasis it is striking that there but few examples of carcinoma which have developed in a bron- chiectatic dilatation Until the proponents of the idea that the chronic inflammation caused by brouchiectasis induces cancer of the lung can show that bronchiectasis which preceded the onset of the cancer is followed by cancer in the inflammatory zone of the wall of the bronchiectatic cavity in a percentage of cases which is significantly higher than the percentage of cases of cancer of the lung in the population of the same age and sex distribution which is without bronchiectatic cavities we may conclude that no relation has been demonstrated between the chronic inflammatory changes occurring in bronchiectasis and pulmonary cancer Asthma Asthma although not primarily inflammatory in nature may induce chronic thickening of the mucosa as well as of the muscle coats It has been advanced by some authors as one of the causative agents in cancer of the lung As in the case of the two conditions just discussed asthmatic symptoms may result from the presence of a pulmonary cancer and so a history of asthma preceding the diagnosis of the cancer cannot be accepted as evidence that asthma caused the cancer On the other hand true asthma of long duration may be found in persons in whom cancer of the lung later develops and again this need not imply a causal relation between the two conditions unless cancer of the lung can be found in persons with chronic asthma in far greater proportion than in the general population Again we have no idea of the true incidence of asthma which antedates cancer of the lung in patients with this form of cancer since publications based on the clinical histories give for the most part merely a statement that asthma occurred in certain percentage of cases of cancer of the lung without giving any idea of the length of time during which the asthma had existed before the cancer was diagnosed From cases reported in the literature it seems that on the average about 7 per cent of patients with cancer of the lung had a history of asthma Therefore even if asthma is looked on as contributing to the 6. Wessler H. and Robin C. B. Am M. Sc 183 164 1932 7. Graham E. .; Singer J. and Balton H. .: Surgical Discases of the : Chest Philadelphia Lea & Fehiger 1935 p 815 TOUTE Tere Caer Terre large alveolar alveolar spaces other other "LL A sareesees 6 associated with regen- VS OE Tg epithelium and reasonably looked on Fey {1094} ayy UTEPSAS of the . Emphysemn Emphysemn Emphysemn the compensatory compensatory Jo sasus Jo saris accompaniment acompaniment cancer cancer of lung in the later stages sucMIpdor asauy Wod.M oq atelectasis ensued and then result result cause SE TL suypoosqayy ur incidence this this condition the the general population population population oq Aue uoisugra peanayd incidence incidence conconddition icotndiitoionn antedating cancer cancer SHTYyoHOIG therefore can reliable reliable deductions deductions Suravoyoy oq} puy alveolar emphysema emphysema plays in causing cancer cancer the the Lene poaudosorsuing wuatdua 1 Abscess.This Abscess.This may associated associated with cucer of the uTaCditt 10; Ayqeocins breakdown breakdown of center the growth so vy, payeys y SIPS pur such history should be recorded recorded frequently SUIpuy OF ATA TIA of the lung Funk Funk that pulmonary pulmonary pulmonary ayy st Suny ay] in man past should should make one one suspect suspect that yuorped YoyAs present presenats Sep ay sty Aq anhorur Jou pae Suny ayy jo sauna involvement involvement of the pleura in form of dry peamopd v ASTIN effusion or empyema empyema may be found in patients with7 PANT symptom st ypord Wmutipeur 2 complains One the methods diagnosis diagnosis diagnosis cancer cancer of osNUD aiNdsqo JO ssaosqe centrifuging aspirated aspirated from sediment pleural effusion effusion aaouua TTT sjuonud 103 cancer cells the sediment Baker Baker Bates Bates poozszapun ATISUO SI patient with pulmonary pulmonary cancer cancer may treated oY) Jo Mya uv se Suny for some time without the underlying underlying cause of Cannot group cases JOU setp opor U yng unl Summing up evidence evidence this group cases we youpar apo.t ayy oy conclusions conclusionemphyssema justifiabljusetifable justifiable abscess Because Because chronic fuamony Sunt ayz jo asthma emphysema emphysema abscess presence SB tumor SIL ST TOT ALOU, JOU SI found result of the presence association association association ay, sasNTD3} To inevitable inevitable inevitable and cancer that certain certain degree degree found association any JaTe cancer the lung lung will found proved proved un wavy ayy jo aq Sar a4 cancer The crucial point conditions actually actually goons jo aavyonpoad sv these chronic chronic inflan~-natory inflan~-natory conditions actually penpsuoiq ayy jo vores| M. 1879 1930 asuryo Saojrumuryur ue spams you st snitis and Ellis R. Lancet 1935 , says padyys-pasinq e yas ad ANNIOtOp OP Joo wruasdydtra avpooap owotuyu | ato Mey BUMUOMPAOJLOU St Jnasaud ye Joord US Sop oy, jo Jaonvo Joo TM syuoned ue sey ye ey Suny alt 30 AWOUED UTE Spode cf CaO AOUL ALP Poco seip JOLIN] Aavtouynd 2 Jo WSHO sy UOTsonb puosog Suyepayre vuayyse ana wy adcoid wes ano [YU TPE PE OSMUa BOSE LP VOUOPTAI OU SLIT ATO PUL OOHLDINS 10 OSTA [UNL B stort ott Aq st yp foouna Areuotuynd oF vomsodsrpord- PPO ONE AO PINGOR LIME AME NINATES IEN N T TINTOEN EG ADOPCJLAPALAPA DOJENJEH EJC10 DOJENJEHEHEJC10 DOJENJEHEHEJC10 Initierenesbat Initierenesbat 934 ARCHIVES OF PATHOLOGY PATHOLOGY predispose to cancer of the lang is that their presence actually antedating the probable time of onset of the tumor is found in significantly higher percentages of patients with cancer of the lung than of those without cancer of the lung when the two groups are kept comparable as 10 age sex and industrial occupation where there is the slightest sus- picion that such occupation might be a cause of pulmonary cancer We have shown that such evidence has not been advanced for any one of the aforementioned conditions because there has been little attempt to separate the patients with cancer of the lung into two groups those in whom the pulmonary conditions were a result of the presence of the tumor or at least were initiated after the tumor had started to grow and those in whom the conditions might legitimately be interpreted as having antedated the cancer There also has been little attempt on the part of those who affirm that these conditions predispose to cancer of the hung to ascertain the incidence of these conditions in the general population of the same age and sex as the group with cancer of the lung The opinions advanced by the supporters of the idea that these chronic pulmonary conditions cause cancer of the hung have largely been based on the finding of these conditions in an appreciable number of patients with cancer of the lung without regard to their incidence in the general population We have shown that no single one of has been proved to be the cause of cancer of the hung these conditions The addition of a number of uncertainties may make a larger number but it does not add to the accuracy cause cancer of the to cause cancer of of the result If none of these has been shown to hung the sum total of them has not been shown the lung nor has the common factor resident in them chronic irritation been shown to be conducive to the formation of tumors of the lung GROUP 11 We now turn to the second group of called chronic irritations listed by Simons which are looked on as causing cancer of but which are not symptoms of the disease itself although the hang in some instances they may simulate some of these conditions Influensa a search for previous infections of the lung which might explain the origin of primary pulmonary cauicer and especially its apparently great increase since 1920 workers have suggested that influenza might be a major factor Askanazy Winternitz Wason and McNamara and others found metaplasia in the bronchial epithelium following influenza which in some cases was almost indistinguishable from malignant growth There is no proof that the epithelial metaplasia 10. Askanazy .: Centralbl f allg Path u path Anat 443 1919 11. Winternitz M. .; Wason J. M. and McNamara F. .: of Influenza New Haven Conn Yale University Press 1920 The Pathology follow the 1 had and inci died tion to 1 can give infl be : wit and MACKLIN MACK MACKLIN L @ PRI IMAN RY CARCINOMA CARCINOMA OF LUNG 935 following influenza went on to cancer formation since carcinoma of the lung bas developed in only a very small part of the population who had influenza in 1918 ani recovered In patients who had influenza and who have since died of some other disease there has been no higher incidence of cancerous change in the lungs than in patients who have died without having had influenza Thus if 50 per cent of the population now at the ages of 40 to 50 had influenza in the period from 1918 to 1920 one would expect to find that 50 per cent of the patients with cancer of the lung who are now between the ages of 40 and 50 would give a history of having had influenza Before one may attribute to influenza a part in the causation of caucer of the hung it will have to be shown that influenza has occurred in far greater number of persons with cancer of the lung than in persons not having cancer of the lung and even then there would be no conclusive proof that a short attack of influenza lasting but a few weeks could produce such lasting changes as to initiate a pulmonary cancer Even with specific carcinogenic agents whose effect has been definitely demonstrated a single applica tion or repeated applications for a short time do not usually result in cancer to be effective they must be applied frequently and over a long period or must be introduced into the body in such a way that their effect is continuous Other arguments against the role of influenza in causing cancer of the lung are as follows Influenza is generalized cancer of the lung is localized Jufluenza affects both sexes equally cancer of the lung predominates in the male sex The increase in cancer of the lung began to be noted in some countries before the 1918 epidemic of influenza Finally it must be remembered that cancer of the hug may begin its symtomatic period as an attack simulating influenza from which the patient does not completely recover There is fever lassitude cough and then a dragged partial recovery The patient says that be had an attack of influenza but what actually happened was that his pulmonary cancer began to show itself with respiratory symptoms that simulated an influenzal attack Therefore before deciding that a history of influenza in a patient with cancer of the lung is indicative that influenza is a causative agent one must be sure as with the other diseases discussed that the disease was true influenza and that it ante- dated or probably antedated the onset of the cancer i there should have been a period of at least ten years between the influenza and the diagnosis of cancer Even that might be too short a time but anything under that is almost certain to be too brief an interval An average derived from mumerous series of cases of cancer of the lung reported in the literature shows that in 12.4 per cent the patient gave a history of previous attacks of influenza some of which may have SO UOTE API OP ETAT ATO IEICE Meee 930- ARCHIVES OF PATHOLOGY been results of the presence of the cancer rather than the cause 12 Kerley found that although the influenza epidemic had been particularly severe in Iceland there had been no great increase in the incidence of pul- monary tumor there Boyd Hill and Maxwell and Nicholson among others have felt that influenza probably does not play any role in cancer of the lung Until can be shown that true influenza ante- dating the dinghisis cancer of the lung by ten years or more occurs in the history of patients with pulmonary cancer more often than in the history of patients without pulmonary cancer one cannot accept influenza as having been proved to be an agent in producing primary pulmonary carcinoma | Tuberculosis If chronic inflammatory changes are looked on as a possible or even a probable source of cancer of the lung it is natural that tuberculosis should have been regarded as an etiologic agent because in of its chronicity Ewing felt that tuberculosis was associated with cancer of the lung unduly frequently but practically all other workers have felt that there was a very infrequent association between the two conditions Unless tuberculosis and cancer of the lung are mutually exclusive one should find about the same proportion of pulmonary cancers in persons dying of tuberculosis provided of course that the two groups compared are kept constant in regard to age and sex as one finds in population not dying of tuberculosis The necessity of the proviso is at once apparent since the highest absolute number of deaths from tuberculosis is usually among the young and among females One finds for example in Canadian data for 1936 that 1 of every 8 men who died between the ages of 40 and 44 died of pulmonary tuberculosis Let assume that all of these had tuberculosis and that none had a cancer of the lung erroneously diagnosed Also 1 of every 100 men who died at the same age died of recognized cancer of the lung One would expect without any significance being attached to the finding that 1 of every 8 men dying of pulmonary cancer between the ages of 40 and 41 would also have active tuberculosis and that 1 of every 100 men dying between the ages of 40 and 44 with tuberculosis would also have cancer of the lung Chiari stated that from 3 to 12 per cent of patients with cancer of the lung have active tuberculosis These figures deal with men of all ages dying of tumor of the lung Again illustrating from Canadian data and taking only men dying after the age of 40 since pulmonary tumor 12. Kerley P. .: Brit J. Radiol 333 1925 13. Boyd W Canad M. A. J. 210 1930 14. Hill R. .: Edinburgh M. J. 320 1934 15. Ewing .: Neoplastic Diseases ed 3 Philadelphia W. B. Saunders Com- pany 1928 16. Chiari IL Klin Wchnschr 183 1938 MACKLIN MACKLIN MACKLIN PRIMIKY PRIMIKY CARCINT OF LUNG -fl is relatively uncommon before that age we find that approximately 3.3 per cent of men dying in 1936 in Canada died of what as mary tuberculosis This was diagnosed probably represents the minimal esti- mate of men dying with active tuberculosis in Canada in that bas's we should that year On of cancer of expect approximately 3.3 per cent of males dying the lung after 40 to show in addition to the " tuberculosis a figure agreeing with Chiari's data cancer active In countries in which there is far more tuberculosis than in Canada the patients dying of cancer of the proportion of addition will be far lung who have active tuberculosis in higher than 3.3 per cent in countries in which the tuberculosis rate is lower the proportion will be under 3.3 It is found on per cent examining the records of those persons with pulmo- nary cancer who showed active tuberculosis of the the caucer did not lungs at autopsy that grow in the wall of the tuberculons cavity where the inflammatory changes were taking place in the The tuberculosis was majority of instances more often found in the lung opposite to the in which the cancer developed than in the one from the reports in which the sites same hung if one can judge of the two diseases were given in the autopsy protocol Or if the disease was was not in the present in the same lung it same lobe Even if the two same par of the lung which is processes are found in the might be due to apparently rarely the case this still Maxwell and chance association Most authors including Nicholson Chiari Funk Hill Husted Boyd mann and others have and Beil- expressed the opinion that there cannot be demonstrated any causative influence on the part of tuberculosis in ducing cancer of the lung Fried ** said pro- It is of interest that the occurrence of tuberculosis and of cancer in the same organ is rarely seen at necropsy same person or in the This observation taken together with the frequency of tuberculosis in the general to conclude that tuberculosis does population leads one not predispose to cancer of the lung Puctimonia onset of cancer of the lung may simulate monia so that the patient may give a history of phet- thinks was the cause of the puctumonia which he pulmonary tumor On the other hand the patient may have had true or pneumonia either antedating the silent period antedating the symptomatic period of the cancer without there being any association between the two Since pnetanon^>a is by no means iancommon disease one would many expect to find a great an fif the fation who have had popu- puetumonia and recovered therefore expect to find an equal percentage of one would who have had patients with cancer of the lung pneumonia without there being any significance in the Hustel and Belfmarin G Acta path et microbiol Scandiumx 14:14 ) Fried' py 17 SOTO AE AU AU ICSU TSU IE DEAE MEME ot th at se se see esteseemeetee en ARCHIVEARCS HIVES OF PATHOLOGY fact Thuis in Canada 5 per cent of the men dying after the age of 40 in 1936 died of pneumonia ably 3 men who recovered was at that time about 25 For every man that died there were probsince the mortality rate in pneumonia is or per cent Therefore we can assume that another 15 per cent of men dying at that age had had the disease at some carlier date lait had recovered and died of something else There- fore we should not be surprised to find that about 15 per cent of patients with pulm^-^ ngcancer give a history of having had true pneumonia The pneumonia have occurred in the same lobe in which the cancer was to develop or had already developed or it may have occurred in different lobe or on the apposite side as was the case with the patient reported by Graham and Singer As the incidence of the history of pneumonia in cases of cancer of the lung we find the following data Parish found this history in of 32 cases Matz in 15.2 per cent of 138 cases Hill in 10 of 107 cases Maxwell and Nicholson in 7 of 100 cases These are the figures wee should expect if pucumonia has no relation sehatever to the produc- tion of cancer of the lung Har GassinIgt is not to be wondered at that war gassing has been suggested as possible cause of pulmonary cancer in some cases There would seem to be only two possible ways in which war gas might cause caucer of the lung 1 by a direct carcinogenic effect in which case it would probably have to be applied repeatedly in small doses over a long period sivce a few exposures would probably not induce ; cancer 21 by the production of a chronic inflammatory condition in the lung that would be carcinogenic The first assumption carries little weight because it has not been shown that war gases have a specific carcinogenic effect and because there is no history of numeros repeated applications of them the second reason is also without much value since we have found that none of the chronic inflammatory or degenerative conditions which war gases caused such as chronic bronchitis emphysema asthma activated pulmonary tuberculosis and pulmonary fibrosis can reasonably be linked with the development of cancer of the lung From data supplied by Malz and by Stein and => Joslin on United States Veterans of the World War we see that of 164 men with cancer of the lung 8 or 4.8 per cent gave a history of having been gassed in the war 75 to 80 Maxwell in the age and $ Nicholson found 4 men from among about range of World War veterans who had historics of having been gassed in the war and who also had pulmonary cancer 19. Graham A. and Singer L. .; A. M. A. 301 1371 1933 20. Parish T. .: Practitioner 125 1930 21. Matz P. A. M. A. 2086 1938 22. Stein F. and Joslin H. .: 0 Song Gynec & Obst 902 1938 MACKLIN MACKLIN AL PRIMARY CZ OF They held that war gassing has un In order to evaluate adequately the role in causing possible role of cancer of the lung war gassing in the ? of cancer of the lung we need to know the following facts Wprhoadtuctisiotnhe number of World War veterans living at the present time What percentage of these were gassed in the war In what number of World War veteraus has cancer of the lung developed up to the present What percentage of these were gassed in the war Is the percentage of gassed men significantly higher in the group with caucer of the lung than in the group without cancer of the lung To these questions we have no exact answers but we have the following data Approximately 4,750,000 men were accepted by local draft boards Of these 740,000 were rejected at camps because of physical and mental defects About 87,000 d'ed of war injuries and disease leaving approximately 3,923,000 men who survived the war Of these about 75,000 had been gassed and had survived These figures are taken from the Military Surgeon of October 1936,2" and from Matz's about 1.9 per cent of the enlisted men the deati rate in the ensuing years has article on war were gassed and been about equal gases Thus survived H in the gassed and nongassed groups we should expect that about 1.9 per cent of the surviving veterans have been gassed If the death rate has been differ-difer- ential in the two groups that figure will be higher if the gassed veterans have not died in such great mumbers and lower if they have died in larger mumbers than the rest of the veterans Stein and " Joslin reported that of 164 veterans with cancer of the 4.3 cent gave a history of having been gassed This would lapupnegar to pbeer two and a half times the proportion of gassed men in the veterans group in general But if we calculate what departure from the average percentage of gassed men one might expect in so small a sample of veterans as a group of 164 we find that on the one band no gassed men might be found and on the other as many as 4.1 per cent might have been gassed without there being any causal relation between the gassing and the cancer Therefore the 4.8 per cent found is not far removed from the 4.1 per cent expected owing to variations in samples of veterans and we can conclude that the difference is not enough to suggest that the gassing played any part in the production of cancer Moreover even if gassing were conceded to have induced cancer 25.2 per of the lung in some veterans it would be obvious that most developed in veterans without previous gassing also that in most of the men who were gassed cancer of such cancers cent and the hung has not develope-d c this lesion has appeared in only several hundred among a possible seventy thousand 23. Grifith C. .: Mil Surgeon 251 1936 OIA EE IPOOOeseAT EIT ITO 9411 ARCHIVES OF PATHOLOGY Occupations in Relation to Primary Cancer of the Although many attempts been made to link the occupation of the patient with his pulmonary cancer these attempts have been unsuccessful with the sole exception of the pulmonary cancer which occurs in the miners of Schneeberg and Joachimsthal in Bohemia the incidence of which is so high in comparison with that of cancer of the lung in other places in comparison and so high with the incidence among the neighbors who are not working the mines that there seems to be little doubt that this occupation is strongly productive of cancer of the lung It is still a disputed point as to what the carcinogenic agent is in these mines Arsenic radioactive emanations and borne molds present in the mines have been implicated Outdoor occupations in which dust is inhaled have been thought in he represented unduly among the patients with pulmonary cancer Duguid ** indoor occupations have been found to be represented in undue numbers Bonser Industrial hazards Schachter 20 labor- ing jobs Brockbank 27 chromium dust Alwens Banke and Jonas ** iron oxide in silica dust rather than the silica itself Campbell 2"silica dust Anderson and exposure to coal gas Dibic Dible Klotz metal grinding in the air or to coal tar on the skin and the preparation and sale of tobacco the Kennaways have all been ) brought forward as possible causes of cancer of the lung instances the occupation given at the time the diagnosis made may not have been the occupation of the patient at In all such of cancer is the time bis cancer developed perhaps twentoyr twenty years before More- over one must always take into consideration the district from which the data were drawn Thus in an agricultural district practically all the pulmonary cancers will be found in farmers just as will most of the gastric cancers and most of the chronic nephritis In district where mining is the sole occupation most of the pulmonary caneers will be in miners in districts where every one is working in tobacco all the pulmonary cancers will be in tobacco workers and so on For any one district the effect of occupation must be determined by finding the percentage of males of certain ages working in that occupation who 24. Duguid J. Lancet 111 1927 25. Bonser G. M J. Hyg 340 1929 218 1934 26. Schachter J. de m^'d de Paris 700 1932 abstracted Am J. Cancer 165 1933 27. Brockbank W Quart J. Med 1:32 1932 28. Alwens W Bauke E. E. and Jonas W Klin Wehnschr 1854 1936 29. Campbell A Brit M. J. 755 1938 39. Anderson C. S. and Dible J. .: J. Hyg 185 1938 31. Dible .: Lancet 982 1934 32. Klotz M Am J. Cancer 35:38 1939 33. Kennaway N. and Kennaway E. J. Hyg 236 1936 MACKMACL KLIN PI RIMN ARY CARCINOMLA OF have pulmonary cancers as compared with the percentage of males of the same ages not in that industry who have such cancers One must not compare the incidence of cancer of the hungin middle males work- ing in mines with the incidence of cancer of the lung all the rest of the villagers males and females of all ages One must try to keep the two populations populations compared as constant as possible with respect to all factors with one exception namely the factor being investigated Thus if one is attempting to ascertain the possible effect of dusty occupations on the incidence of pulmonary cancer one must be sure that one deals with all those exposed to the same type of dust on the one hand and with those who do not meet that dust on the other Also the distri- butions of the groups compared must be the same as to age and sex Third those exposed to the dust must not be moef eting factor which might also theoretically theoretically be productive some other pulmonary pulmonary cancer for example tobacco smoke Even these simple rules are seldom followed lung in ascertaining the role of any occupation in determining the onset of cancer of the a Silicosis Because of the fibrosis which occurs in the kings of persons affected with silicosis it has been suggested that this may silicosis have a role induced by to play in producing cancer of the lung The changes are the connective tissue rather than in the epithelium of the bronchus and so it is not probable that silica will prove to be carcinogenic Silicosis was carefully looked for by Berblinger in 50 cases of pulmonary cancer and no evidence of it was found although silicosis is very common in his district Jena Germany That list clause changes the whole aspect of the finding Had silicosis been rare in his district his failure to find it would have given no indication of any possible lack of relation between the two Till found no relation in between silicosis and cancer of the lung his cases or in reviewing reviewing the literature If the cases of pulmonary cancer are in a district where there is a high incidence of silicosis we should find the two occurring together with some frequency; if the cases are in district where there is little silicosis we should expect the two conditions to be associated seldom if they are not causally related That the conclusions drawn from the incilence of these two diseases must be carefully caftrolled statistically is pointed out an editorial in the British Medical Journal in discussion of the cases of Anderson and Dible These authors found a high silica content in 12 of their 70 cases of pulmonary cancer as compared with 48 cases used as controls The editorial points out 34. Berblinger W 839. 1932 Med Klim 1337 1931 abstracted Am J. Cancer 16 35. Silicosis und Pulmonary Carcinoma editorial Brit M. 411 1938 OOOO SEAL ATA TALI IEE IED CHC se80 se see seoneanmenen sat ee seminal oe oe 942 ARCHIVES OF PATHOLOGY that even if their conclusion is correct that sifica plays a role in causing pulmonary cancer the conclusion is not justified by the material they bad It goes on say that such a conclusion would be justified only if there were a series of almost 3,000 controls this figure being based on the incidence of primary cancer of the lung in the general population Klotzfound Klotzfound pulmonary cancer in 8 per cent of his series of 50 cases of silicosis as contrasted with 1.17 per cent of 4,500 unselected unselected autopsies which he used as controls The latter group of autopsies were apparently on patients of 15 years and upward as it did not include the autopsies of the pediatric service The objection to conclusions based on such material is this In using unselected autopsies perhaps to obtain a called random sample the control material was most dissimilar from the cases of silicosis under review Among the subjects of unselected autopsies would be a large number of females while the patients with silicosis Cancer of the lung is would be entirely or almost entirely most frequent in males therefore one males would to find more cases of cancer of the lung among patients with expect silicosis than among the subjects of autopsies in general merely on on the basis of unequal sex distribution Again the patients with silicosis are for the most part in the middle age group or old age group for it takes years for silicosis to develop Cancer of the lung is most frequent after 40. The subjects of unselected autopsies will include many patients in age groups well below 40 an age at which cancer of the lung is infrequent On the basis of age distribution we should expect to find more cases of cancer of the lung among patients with silicosis than among unselected subjects of autopsies Finally there will be variations in the percentage of cases of pulmonary cancer from group to group of autopsy cases even when these groups are standardized for age and sex these variations are attributable merely to the difference in samples of the population in each case may be that Klotz's # conclusions are correct and that pulmonary cancer is more frequent among patients with silicosis than among a group similar in age and sex but his conclusions as unsound mutil without silicosis he has compared But we must reject his silicotic patients with a group of men of the same age distribution as the patients with silicosis and made due allowance for possible variations between different samples of the population b Asbestosis Few cases of asbestosis associated cancer of the lung have been reported Egbert and Geiger Here again we should expect to find the two conditions the same person in some cases on chance distribution with primary Hornig * associated in alone Since 336.6. Egbert D. S. and Geiger A. .: Am Rev. Tuberc 143 1936 37. Hornig .: Ztschr f Krebsforsch 281 1938 Hen ae aarae te ising they : ly if . n the i 50 sted were lude -ons -ons haps most jects the sales could could with a the are takes quent dients ng is find mong mong mong n the Topsy these f the imary ga ga reject tients with ferent imary Since MACKLIN MACK MACKLIN L PRI I MAN RY CIRCINOGLA OF LUNG 943 asbestosis occurs in ten of middle age cancer of the lung may be found in these patients in a higher percentage than in the general population bu we have no proof that is found in greater percentage when a group of men of similar age from the general population is used as the standard The criticism that was made with respect to Klotz's data on silicosis may be made also of the data of Lynch and Smiths Lynch and Smith have reported that in 2.343 consecutive necropsies over a period of twelve years cancer of the lung was found seven times an incidence of 0.3 per cent In the 35 cases of asbestosis in some of which the lesions were very mild cancer of the lung was found twier an incidence of 5.7 per cent Are these values significant they asked or is the sample of cases too small Before such figures can be of any value they must select from their 2.343 consecutive necropsy records orly those on males since their 35 cases of abestosis doubtless all relate males They must then select from these records on males only those on males in the age range of the males with asbestosis When this is done it will be easier to decide whether the incidence of pulmonary cancer is higher among patients with asbestosis than it among those without asbestosis c Pneumonoconiosis Odier dusts besides silica are said to cause cancer of the lung There may be much or little dust depending on the occupations of the patients with cancer of the lung and on the district in which they live rural patients will have little coal pigment while residents of industrial cities like Pittsburgh will all have a great deal South Africau miners have a high incidence of pneumunoconiosis but a low incidence of cancer of the lung Vorwald and Karr examined the records of 15,587 persons who had long been exposed to dusty atmospheres and found that only 3 of them had caucer of the lung He stated that the dust must be carcinogenie before its presence will induce cancer of the lung Arkin and Wagner and ** Berblinger both found pneumonoconiosis rare in their series of cases of pulmonary carcinoma d Tarred Roads Dusts and emanations from tarred roads have bean said to be responsible for the increase of pulmonary cancer noted in the last two decades Campbel" l but workers in Russia where tarred roads are few have noted the same increase in cancer of the lung as has occurred in other countries Husted.17 in Denmark found that patients with primary cancer of the Cammin about the same proportion from areas where there were no tarred roads as from areas 38. Lynch K. M. and Smith W. .: Am J. Cancer 567 1939 39. Vorwald A. and Karr J. W Am J. Path 14:49 1938 40. Arkin A. and Wagner D. .; J. A. M. A. 106 1936 41. Campbell J. A Lancet 233 1934 J. Indust Byg & Toxicol 449 SOI TL IEAL reared 944 ARCHIPEARS CHIPES OF OGY where tarring had been carried out Boyd found no evidence that tarring had played any role in his 14 12 the conclusions which cases Valade pointed out that of Campbell " reached as to the efficacy of this type dust in causing cancer of the lung were based the which produce high number of on reactions of mice that what might be spontaneous pulmonary cancers and carcinogenic for mice need not he so for men We may conclude that there is no demonstrable proof at that form of dust has any role in present any producing cancer of the lung for it has not been demonstrated that pneumonoconiosis is present in the lungs of with patients pulmonary cancer in any higher proportion than in group corresponding of the general population habit Other agents such as roentgen rays tobacco smoke and motor exhaust fumes have been that suggested as possible causes The suggestion roentgen rays are a cause is almost absurd for the are that only a small of probabilities has percentage those in whom cancer of the lungs developed ever had their chest under for diagnosis of their roentgen rays before they came where there is cancer Motor mechanics working in garages an abundance of exhaust fumes are said to show incidence of pulmonary cancer than the no higher bellstated bellstated that exhaust gases from general population and Campinternal combustion engines do not increase pulmonary cancer in mice Tobacco factor in the increase of smoke might be one pulmonary cancer The is one which permits long continued application of the smoke to the bronchiai mucosa it is or at least was a habit more prevalent among men there are two possible agents which might prove to be namely heat and the derivatives of cancer producing tobacco There are those who point out that the increase in the increase in the consumption of tobacco parallels the incidence of pulmonary cancer This have significance If tobacco is may or may not a factor it must be proved that deriva- tives of tobacco are carcinogenic or that the repeated application of heated smoke is conducive to in cigaret smoke cancer McNally stated that the tar contains enough chemical irritants to increase in cancer of the lung Koffo ' found account for the cancerous women 42 who exhibited among a group of 5,000 cancer in what he called the smoke stream namely the lips these women were heavy tongue jaws larynx and smokers He found pharynx All of burnt tobacco that the products of produced carcinoma when painted on rabbit he feels that there ears and are probably many aromatic substances in tobacco that are carcinogenic His findings are suggestive But the increase 42. Valade M. P. cited in 521 1939 Carcinogenesis in the Lung Annotations Lancet 43. Campbell A McNally W. 45. Roffe V. FL Brit J. Exper Path 146 1936 Am J. Cancer 1502 1932 Dentsche med Wehnsehr 1267 1937 jen thats eR hte MACKLIN MACKLIN MICKLIN MARY MARY CARCINOMA OF LENG 945 in cancer of the lung should be much greater among females than among males since smoking has increased among women far more the last two decades than it has rapidly in among men Data published by the Metropolitan Life Insurance Company * show that the incidence is not policyholders greater among females The rates among the industrial of 45 74 years of age show that in 1917 the rate for cancer among females was 2.5 pulmonary per hundred thousand This rose to 8 per hundred thousand in 1938 an increase of 220 cent The rate for cancer of the lung in males rose in the same period from 3.2 to almost 23 per hundred thousand an increase of more than 600 per cent Their conclusion is that it appears doubtful that smoking is factor in cancer of the lung causing Controlled observations over a longer period are to settle this point Tovestigators must not necessary rest content with finding that a high percentage of patients with pulmonary cancer are tobacco smokers ; they must find that the percentage of smokers in this group is sig- nificantly higher than that in the general population of a similar and sex distribution age When we review all the theories on the cause of pulmonary cancer we find that not one supposed cause has been proved to he a real cause and that none of the alleged causes has been investigated with suffi- cient statistical accuracy to enable the observer to ing any weight No one cause no suru of pass an opinion carry- causes no common factor in them namely chronic irritation through inflammation of the bron- chial mucosa has been demonstrated to occur with in patients with cancer of the any greater frequency lung than in group from the general population of comparable age and sex distribution at a time sufficiently long before the onset of the cancer that it may be interpreted as ante- dating this rather than following it Naturally any condition which is a sequela of cancer of the lung may be found patients with pulmonary cancer than in more frequently in persons not affected with this type of cancer Such a condition when obviously the result of cancer of the lung must be excluded from a discussion of the latter's causes e Schneeberg Miners the miners of the The high frequency of cancer of the lung among Schneeberg and Joachimsthal valleys has been recognized for many years It seems that this occupation is one which does enhance the incidence of pulmonary cancer beyond that known elsewhere and apparently beyond that of the neighbors of The who do not work in the mines Thus valleys Pirchan and Sikl stated that 12 of 19 Schneeberg miners dying in 1929-1930 had cancer of the lung at autopsy Of 12 miners dying in 1932 9 had a clinical diagnosis of 46. Cancer of the Lung a Ins Co. 20 1930 47. Pirchan A. and Sikl Growing Health Problem Statist .: Am J. Cancer 681 1932 Bull _ Metrop Life He 946 ARCHIES OF PATHO pulmonary cancer Siklreported Siklreported Siklreported similar figures for the miners of Joachimsthal Of 15 miners dying in eighteen months autopsies were carried out on 10 of these 8 had carcinoma of the lung The age of these men was 49 and the lung average , average period of exposure in the mines was seventeen years years This incidence of cancer of the lung has not been equaled anywhere else in the world The cobalt the arsenic the dust the radioactive emanations all have been incriminated Sikl * stated thngechnical analysis of the lungs showed no trace of important foreign elements The test for radioactivity was negative although although he felt that radioactive emanations in the mines may have a part in producing pulmonary cancer Maisin " quoted de Laet as saying that in Belgium pulmonary cancer has not developed in workers workers in radium although they wear no masks and are covered with and breathe the dust of the works all the time However the plant had been in operation only twelve years at the time of de Laet's report Of interest in this connection are Martland's 5" findings findings in workers with radium paint The girls who died of osteogenic osteogenic sarcoma were exhal- ing radioactive air as shown by tests yet none none of them presented cancer of the lung A whole series of questions to which we have as yet no answers and may never have arise If the radioactive emanations in the air in the Schneeberg mines are responsible for cancer of the why did the radium paint workers in the United States die of bonelaunndg ? not lung tumors especially as it was shown that the lungs were exposed to radioactive emanations May it be that there is an inherited factor for cancer of the lung in the Schneeberg miners which has been increased through continued inbreeding in these rather isolated mountain valleys with a small population and that the carcinogenic agent in the mines whatever it may he enhances an already present tendency toward pulmonary cancer Is it possible that taken in small doses the radioactive substance induces pulmonary cancer which may have a long latent period whereas radium taken in presumably larger quantities as is the case when radium paint is swallowed may induce bone tumors with a shorter latent period of development Thus these victims would die of osteogenic sarcoma before they had time to develop pulmonary cancers Certain that although the miners have a very high incidence of cancer of the hung they do not have a high incidence of those chronic pulmonary conditions which are supposed to the lung Thus Pirchan and Sikl # said that predispose to of the 9 men cancer of with clin- ically diagnosed cancer of the lung not one had a history of chronic pulmonary disease that was not directly related to to the onset of the cancer 48. Sik IL Ztschr f Krebsforsch 609 1930 49. Maisin .; Cancer Bruxelles 111 1934 abstracted Am J. Cancer 28 - 164 1936 , 50. Martland H. .: Am J. Cancer 2435 1931 MACKLIN MICKLIN PRIMARY CARCINOMACARCINOMA OF LUNG 947 Throughout this discussion we have repeatedly emphasized that it makes no difference how great is the percentage of patients with cancer of the lung who point to any particular disease in their past history provided that a similarly great percentage of the general population bas had the same disease in which the whole Thus if the cancerous patients come from a region population has had measles every patient with cancer of the lung` will give a history of measles Il 90 per cent of the population past 40 have had tuberculosis 90 per cent of with cancer of the lung will probably give a history of If the main occupation in the district is farming most of with cancer of the lung will be farmers but if mining the patients tuberculosis the patients is the main industry most of the patients with cancer of the lung will be miners This fact has been little appreciated by those who argue that because 25 or 50 or 75 per cent of patients with cancer of the lung give a history of particular disease that disease must be carcinogenic hence we shall try to present this matter more in detail at this point In the accompanying chart the first rectangle represents a theoretic population One fourteenth of them black bar at the top is charac terized by having a certain disease X. The subsequent rectangles represent those portions of the population which have had some other condition condition Thus in rectangle 2 we might indicate those who had had for example chronic bronchitis in 3 those who had had influenza in 4 those with arteriosclerosis and so on We will assume that none of these groups overlap Now it will be seen that one fourteenth of the population in rectangle 2 also has disease X. the same proportion as was present in the general population This is true of the groups represented in rectangles 2 to The group in 7 shows a much higher concentration of X patients than do the other groups while the group in 8 has fewer X patients than has the general population From such diagram one would be justified in looking on the group in 7 as probably peculiarly susceptible to disease X while those in 8 would be considered relatively immume that all the groups are comparable ficant factors are concerned We are assuming this example as far as sex age and other signi- signi- forteth Now let us arrange these same data in rectangle 9 which represents the population affected with X which is one forteth of the total population Here we see that three groups each have a fourth of the patients with group 5 one X patients discase X. These are 2 3 and 7. Group 4 has an eighth sixteenth and groups 6 and 8 each a thirty second of all If we looked at this column without viewing the data in columns to 8 we should be very likely to conclude that groups 2 3 and 7 are equally susceptible to X and that groups and 8 are the most immune to this disease The latter conclusions would of course he wrong as the data in the rest of the diagram clearly show ARCHIVES OF PATHOLOGY It is in the latter form that the data dicaling with the cause of pul- monary cancer are usually presented We are told that a certain percentage of patients with cancer of the lung give a history of chronic bronchitis or of influenza or of some other coudition and if this per- centage is high it is assumed that the disease named is an important 4 68 g | read fae ined 1. The general population is represented in rectangle 1. Those with a history of a disease which we will call X are shown by the black bar at the top This is one fourteenth of the total area of rectangle All percentages percentages in this figure are of course theardie and are used merely for purposes of demonstration ; 2. This rectangle represents per cent which has bad chronic also larve X. the proportion of the bronchitis Note that total population namely 25 one fourteenth of this group 3. This rectangle represents those in the paquilation namely 25 per cent who have bad infinenza One fourteenth of them have X. This rectangle represents those in the population manely 12.5 cent One fourteenth of them have X. 5. This represents the part of the population which per cent One fourteenth of them have X. who has have arteriosclerosis asthma namely 6.25 proportion namely 6. This represents the part of the population with a history of war gassing namely 3.12 per cent One teenth of them have X. Because X has developed in the five groups 2 to 6 in the same proportion as in the general population we cannot assign a specific role to any of these conditions in the production of discase X. 7. This is the part of the population who are miners of radioactive 3.12 per cent ores n^uely Here the incidence of X is eight times as great as that found in the general population or in the five preceding groups of the population It that some factor associated with mining of these ores is productive of Xa.ppeBaurts - because not all miners have X and because many who are not miners do have X other factors besides the mining of these ores enter into the canse of X. 8. This is the part of the population which has a history of tuberculosis 25 per cent The incidence of X is much lower here than in the if some factor inhibiting the development of X was present in gtehinsergarlopuoppulation as 9. This rectangle shows the part of the population in which X fourth of these have had develops ; One bronchitis another fourth influenza another fourth exposure to radioactive ores One eighth have arteriosclerosis one sixteenth have asthma one second have had tuberculosis and one second have been gassed Data in the latter form are usually used to determine the importance of any specific disease as a cause of cancer of the long It is assumed that all the groups in the rectangles 1 to 9 are of the same age and sex distribution and that no group in any rectangle overlaps that in any other . MACKLIN CARCINOMLA OF LUNG 949 causative factor in producing carcinoma of the lung If the percentage is low it is assumed that the disease has no significance in the causation of cancer of the lung The diagram in figure 1 shows that it is only when the disease in question is found in much higher percentage of the group with pulmonary cancer than of the general population that one can consider that it has an etiologic role in producing pulmonary cancer But even this is not enough It is necessary that the group in the general population which we are using as a control for the pulmonary cancer population be comparable to the latter in all respects except that the general group does not have cancer of the lung otherwise one might find that the group with cancer of the hang had the condition in question in higher percentage than had the general population without there being any significance in that fact For example some of the veterans of the World War are asking for compensation for cancer of the lung which they claim was brought on by the chronic pulmonary diseases which they contracted through expostire encountered during military service Now how might one go about settling the justice of such a claim One might say The incidence of pulmonary cancer among war veterans much higher than among the general population therefore it must have been the hardships of military service which caused this increase We are assuming for the sake of the argument that it is more frequent among war veterans But the war veterans are all males and the general population holds more females than males Hence an adjustment for sex would have to be made as to make both groups comparable Next the average age of the war veterans lies between 45 and 60 while the age of the general population will range all the way from birth to 100 years The two groups must be made comparable as far as age is concerned Then one might argue that although the hardships of military service did not actually cause pulmonary cancers they caused these lesions to develop much earlier because the age at which the cancers were developing in the veterans was much younger than that of the patients with such cancers in the general papniation But again the age distributions in the two groups are different the ages of the veterans being concentrated in the range from 45 to 60 while the general population has those under 45 among whom pulmonary cancer is not frequent and those from 60 on among whom is frequent Hence only those among the voters who were destined to get cancer of the lung at younger ages would be included in the veteran group Those in whom it will develop after 00 are not included since the veterans have not yet reached 60 years and over In this way the average age at which pulmonary cancer developed in the veterans would be less than that at which it develops in the general population Hot aun 950 ARCHIE OF PATHOLOGY SUPPOSED ENVIRONMENTAL FACTORS A GENERAL DISCUSSION The introduction of consideration of experimental work into a discussion of carcinoma of the human lung may seem irrelevant but it is not really so For a few decades the experimental production cinoma by called chronic irritants leut strong confirmation idea that chronic irritation was the sine qua non of all cancer of carto tlie Thus when no evident chronic irritaut was found it was assumed that it was present anyway as witness the citations at the beginning of the paper The evident irritants were mechanical thermal chemical and bacterio- logic agents Sometimes it was stated that it was not the irritant but the chronic inflammatory changes set up by it that produced the cancer In recent times however we have come to look on carcinogens as involving more specific agents Certain viruses such as that of Rous have been shown to be the cause of certain definite animal tumors Specific chemical bodies such as dibenzanthracene and the estrogens have been shown to produce carcinoma on repeated application Much depends apparently on the chemical formula comparatively minor alterations in the structure of the compound ntean wide alterations in the carcinogenic power A large literature has grown up around these carcinogens Cook Andervont * and others It has been found duce cancer and that experimentally that not all chronic irritants prosome of the highly carcinogenic agents are not irritating that what may be carcinogenic for one animal need not be for another animal or even in another strain of the same animal and finally that what is carcinogenic for one organ in an animal need not be productive of cancer in auother organ of the same animal Let us illustrate these points briefly Some marked irritants such as mustard gas are not cancer producing although they cause intense inflammatory reactions Visser and ten Seldam ) Again some highly carcinogenic chemicals are nonirritating when applied to the skin Andervont . Tar painted on the skin of rats did not produce cancer of the skin while if painted on mice or rabbits it did cause such cancer The same tar painted on mice differing in their genetic susceptibility produced cancer of the skin in highly susceptible mice and failed to produce cancer in highly resistant mice Kreyberg ) It is of interest 51. Cook W Proc 52 Andervont H. .: Tumors in A Symposium Press 1938 p 54 54 Roy Soc London s 111 485 1932 Effect of Bacterial Products on Growth of on Cancer Madison Wis University of Malignant Wisconsin 53. Visser J. and ten Seldam E. .: 3092 1937 Geneesk tijdschr v Nederl 54. Kreyberg .: GeneticGenetic and Constitutional Aspects of Spontaneous and Induced Tumors in A Symposium on Cancer Madison Wis University of Wisconsin Press 1938 p 183 th st e St vi lele P F ... ' | " t . c U ] | f i | i ALACKLIN MACKLIN PREALARY CARCINOMACARCINOMA OF LUNG 951 that cotton mule spinners suffer from entatieous cancer due to the coustant spraying of the skin with liquid petrolatum whereas they do not exhibit cancer of the lung in any increased percentage although they con- stantly inhale air in which the same oil is present in the form of tine spray Simpson Chimney sweepers had a high percentage of cancer of the skin yet the constaut inhalation of an atmosphere containing the same carbon particles as caused cutaneous cancer did not lead to cancer of the hung Injections of estrogens are productive of cancer of the breast and of the uterus in mice but not of cancer of the gastrointestinal tract or of the lung Therefore it can be stated that before any condition such as chronic pulmonary disease can be regarded as producing cancer it must be proved beyond doubt that 1 the condition is capable of producing _ cancer apart from any ability to cause chronic inflammatory change 2 that it is capable of producing cancer in the animal under discussion and 3 that is capable of producing cancer in the specific organ in question Merely to show that a condition induces chronic inflammatory changes in an organ is no longer sufficient for it is known that chronic inflammatory changes can exist for long periods without producing cancer and also that cancer van occur with no reasonable evidence of preceding inflammation for instance in retinal blastoma shortly after birth PROBABLE KOLE OF HEREDITY IN PULMONARY CANCER Although specific carcinogens can produce cancerous changes are the conditions mentioned earlier in the paper shown to be carcinogenie? It has been assumed that they may be because one has no other explain nation of pulmonary cancer if one insists on the presence of extrinsic factors as the sole causative agents of all cancers But cancer is a problem of failure of differentiation of organization and of growth differentiation organization and growth are problems of the inherent makeup of the cell itself and of its ability to utilize certain chemicals in its metabolic processes Therefore one should not overlook the fact that idiopathie alterations in the inherent makeup of the cell may be responsible for cancerous changes without the intervention of any carcinogenic agent In other words the cancer may arise through hereditary causes It is known that under the inuer of hereditary determiners descendant cells of the original zygote differentiate into cells with quite widely differing potentialities Absence or alteration of these determiners for normal differentiation may also be hereditary Thus the alterations necessary for changing a normal cell into a cancer may be under the aegis of determiners locateidn the germ plas~-n 55. Simpson S. .: Quart J. Med 413 1929 952 ARCHIVES OF PATHOLOGY PATHOLOGY that This alteration sui generis may come about mechanisms One may through two different he a somatic mutation i c a sudden departure from the normal line of cells from which the altered cell sprang which departure then becomes hereditary for all cells descended from . original mutating cell That such a mutation should occur would be wholly unexpected since there was no factor in the germ cell from which the individual came which playedorirgoinlael ifnertdieltiezre-d mining accurrence of the mutation The patient with cancer of the ; hung in this case would not have come from a strain in which factors cancer of the lung were inherited nor would he be able to have more offspring in whom cancer of the lung would develop than a without cancer of the lung person The second mechanism would be one in which the into a tendency to alter cancerous cell would have been inherited being due to factors resident in the fertilized germ cell Just as there are inherited factors which guide the destiny of the entodermal cells which form bile duct then liver so that this gut then development proceeds noraially in an orderly fashion at definite times the life of the embryo the times differing depending on whether the cabryn comes from or a human a mouse a dog ovtum and just as there are inherited factors which cartilaginous development at the permit the luniau epiphysial lines for so many years in humerus but for a different number of years in the femur before the cartilage cells cease proliferating and allow boue cease so there may be inherited factors growth to location at which permit cells in a specific a specific time in the life history of the individual to alter and become cancer cells What proof bave we that these last two mechanisms are possible and that not all cancer nor indeed all pulmonary cancer needs be inter- preted as arising through the agency of extrinsic First with the single exception of the pulmonary ccaanrcceirnoogfentihce fScahcnteoer-s berg and Joachimsthal miners we have of the lung in man is no adequate proof that cancer evidence but caused by extrinsic factors This is negative it should be of value in forcing us to hunt for other causes of human pulmonary cancer before cancer as being due to external we accept all pulmonary agents For the idea that sporadie somatic mutations or hereditary alterations are of the human frequently the cause of cancer lung we have the following indirect additional evidence The vast majority of such cancers in man appear to rise from one point of origin as would be expected were a somatic mutation the cause whereas if external agents acting on the lung were we should expect that the responsible tumors would be multiple and over both lungs Thus tumors induced in mice by hydrocarbons chiogenic as in man but are not bron- subpleural and may be multiple rather than ; MLICKLIN MAC MACKLIN MACKK LIN MACKL LIN PI RIMN ARY CARCINOMA OF LENG 953 single and may be bilateral in the germ cells and that Second we know that mutations do occur the cells with such mutations are then propagated as a new line of individuals There is no reason to suppose that matations are limited to germ cells alone and that such mutations could not occur in any somatic cell in the body Have we any evidence that definite hereditary factors may be present in the germ cell which cause cancer of the lung to appear at definite time in the life cycle of the individual As far as cancer of the lung is concerned we have no human pedigrees that would prove it to be inherited and again the evidence must be indirect Cancerous altera- tions of cells have been found to be inherited in strains of mammals in which experimentation is possible The type of cancer produced by the strain is more or less constant Thus there are strains with a high incidence of pulmonary tumors Lynch 50 others with a high incidence of mammary tumors and others with a high incidence of hepatic tumors There are strains of mice in which several types of tumors may be capable of developing but which tend to die of the type developing first thus obscuring the other cancerous potentialities Since man biologically is much more closely identified with other mammals than he is differentiated from them it would be reasonable to suppose that if cancer shows dependence on hereditary factors in mice the same will be true for man although the actual mode of inheritance may differ widely in the two species In rectal gastric evidence that related mammary and members of a uterine cancer family tend to in man we see good resemble each other more closely in the production of these tumors at a definite time in recog- their life than do unrelated members of This suggests that hereditary factors play not in all of these tumors Cancer of a community Macklin Macklin Macklin ) a predominant role in many the lung was seldom recog- nized before 1900. Hence even if it were inherited and transmitted according to a simple scheme so that one would familial cases we should not have many records frequently of familial encounter instances owing to the fact that pulmonary cancers in the preceding generations remained undiagnosed Finally we may use the evidence furnished by tumors in twins Macklin ) True we have no records of pulmonary cancers in twins since of but since cancer of the lung is like is like all occurs in the lungs instead of elsewhere much when we use tumors in twins to xcept " other cancers it that it we may not be assuming too show that cancer and heuce pulmonary cancer may be inherited If one examines records of can- 56 Lunch C. J. J. Exper Med 747 1931 57. Macklin M. T . a Familial Incidence of Cancer Cancer Madison Wis University of Wisconsin Press 1938 p 277 1940 in 32 Symposium on B Heredity Om atibL 954 ARCHIVES OF PATHOLOGY cers in monozygotic and dizygotic twins one finds the following facts Monozygotic twins with an identical inheritance resemble each other far more often in and at about the have with respect This is true even having a caneer and having it in the same organ same time of life than do dizygotic twins who may to cancer either an identical or a different heredity when the dizygotic twins studied are all of the same sex thus eliminating differences in environment due to occupation which are present when the twius are of the opposite sex This would indicate that fog somatic mutations may he responsible for some cancers they are probably not responsible for all for it would be very rave for identical twins to have an identical somatic mutation in the same organ at about the same age were that mutation not under the guiding influence of heredity To sum up then it would seem that the called chronic irritants supposed to be responsible for cancer of the lung have not been proved to be causes of such cancer since 1 many have cancer of the lung who are not exposed to these chronic irritants while 2 many exposed to them never have cancer of the lung Until such proof is forthcoming investigators are closing their minds to other perhaps fruitful passibilities by insisting that because specific carcinogens are responsible for cancer of the lung in some instances they must be in all Such an atti- inde is no more reasonable than to state that because diabetes develops an animal from which the pancreas has been removed all diabetics are without a pancreas Sporadic mutations and hereditary influences may and most probably do play a large role in causing pulmonary cancers as well as other types of malignant growth SUMMARY Tu conclusion then we may say that none of the specific diseases or conditions causing chronic inflammation of the lungs can be said to have been proved to be causes of cancer of the lung They have not been shown to be suore common in patients with pulmonary cancer than in group of the general population of similar age and sex and until those nary a significant difference can be be found between their incidence in with pulmonary cancer as compared with those without cancer their causal relation to this type of cancer will pulmo- remain purely speculative This of course refers to chronic inflammatory discases which have antedated the cancer by a suflicient number of years so that they can be excluded from being interpreted as the result not the cause of the cancer Chronic irritation especially disease as a cause of pulmonarypulmonary in the form of chronic inflammatory cancer has been assumed the idea has been copied from text to text repeated from author to author with MAR KLIN MACKLIN MACKLIN MACMKALCIKNLIN PRIMARY CIRCINOMET CIRCINOMET OF LENLGENG 935 little critical analysis of its possible role Sonaie Sonaie tary factors must be matations and heredi considered and their probable role in cancer of the lung recognized Trne causing carcinogenic carcinogenic duction of cancer of the hung will no doubt be found aagsenmtosdefronr tinhdeustprro- p yro- expands its use of chemicals But But as industry develop some types of cancer will will one seventh of meu over 40 and since about one fifth of all cers in males are in the lungs can- lungs one thirty fifth or about 3 all men over 40 will die of this per cent of increase in the type of cancer cancer There may be an increase the maximal incidence of cancer of the lung in any industry beyond rate for caucer of the lung in the general one can never state that population but lung had he any patient would not have had cancer of the not beeu in that occupation Thus of even with the presence carcinogenic agents admitted their role in cannot be proved in in in any individual causing cancer of the lung lung 100 case nor can they be said to be per cent effective effective since a certain to the carcinogenic percentage of persons exposed without this agents would have had pulmonary pulmonary carcinoma even exposure The effectiveness of producing carcinoma of the any carcinogenic agent in of increase of lung can be judged only by the increntent increntent incidence carcinoma of the lung in large groups not by its total It is therefore impossible impossible to an absolute role in carcinogenesis carcinogenesis in any assign to any extrinsic factor carcinogenesis in any individual case F tee encom ermem IIE UAT IL ag