Document 3NgoM9ZZ2oO5QLj37Mb2Q6X96

FILE NAME Kent KNT DATE 1951 May DOC KNT122 DOCUMENT DESCRIPTION Bulletin of the New York Academy of Medicine - Primary Cancer of the Lung with Special Consideration of its Etiology THE ACADEMY HENRY ALSOP RILEY ording Secretary CANDER T. MARTIN LAROLD R. MIXSELL WILLIAM Barclay PansONS BENJAMIN P. Watson JARIN S. WIGHTMAN The Trustees eding Secretary nmittees brarian Emeritus CHIBALD MALLOCH ecutive Secretary Education AHLON ASHFORD Legal Counsel x W. Davis Esq HILIP VAN INGEN RD Secretary JOHN ASHFORD KIDD ROBERT F. Loer BULLETIN OF THE NEW YORK ACADEMY OF MEDICINE VOL 27 NO 5 MAY 1951 : : me a i at PRIMARY CANCER OF THE LUNG WITH SPECIAL CONSIDERATION OF ITS ETIOLOGY . ; . EVARTS AMBROSE GRAHAM , Bixby Professor of Surgery Washington University School of Medicine St. Louis Missouri es : i Sages : . Rpesesesesesey . high APPRECIATE very much the honor which you have you inviting give this Ewing accorded me in inviting me to give this fifth James Ewing I Memorial Lecture Many years ago when Dr. Ewing first published his Neoplastic Diseases I was greatly 82525252525253 82525252525253 stimulated by it I wish sincerely that he was still alive to help solve some of the pathological problems concerned with the subject about which I am going to speak to you tonight Bronchiogenic carcinoma differs from other cancers in two import- ant respects ) it has shown an enormous increase in the last thirty years and 2 there has been a progressively larger incidence in the male sex cm There can no longer be any reasonable doubt that the ~ very great increase in the incidence of bronchiogenic carcinoma is real and not merely apparent Kennaway and Kennaway in a study of death certi- Ewing Memorial Lecture delivered at The New York Academy of Medicine * May Fifth James 3 the Department of Surgery Washington University Medical School and the Barnes Hospital From St. Louis 26 THE BULLETIN = : ees i ficates in England and Wales found evidence of a great increase from 1928 to 1945 and more recently Doll and Hillquote a British government report which shows that for the twenty year period from 1922 to 1947 the incidence of the condition found in autopsics in Eng- if land and Wales increased fifteen times over what it had been previously during Actual figures on the increased incidence in the United States the same period are not available but it is noteworthy that although Adler in 1912 could collect only 374 cases from the world's literature individual experiences in this country greatly exceed that total of re- Hospital ported cases from the whole world For example at the Barnes we have had 1375 proven cases in the last thirty years or nearly four times as many as Adler could collect from the world's literature In the United States statistical studies at the Charity Hospital of New Orleans by Ochsner and DeBakey at the St. Louis City Hospital by Whecler and at the Hines Veterans Hospital by Ariel Avery et al have all shown that in recent years bronchiogenic carcinoma has become the most frequent visceral cancer of the male patient Cancer of the stomach which formerly occupied first place has been relegated at least in those institutions to second place No one can deny that there were excellent pathologists in the last century who certainly knew cancer when they saw it It seems hardly likely that those of the caliber of VirchowVirchow Cohnheim and Rokitansky could have missed recognizing the condition at autopsy as frequently as would have been necessary to account for the pronounced difference in | incidence then as compared with now Moreover the argument ad- # vanced by some that the increase is only apparent because more people are reaching the cancer age now loses value when one realizes that not only is the number of cases increasing but more striking striking this cancer has changed its relative position in frequency The fac that more people | are now reaching the cancer age would not explain how it has happened | that bronchiogenic carcinoma has advanced to a position of first place ; in men from one of about eighth place in frequency this all within | , the last thirty or forty years Along with the increased incidence of the condition there has also been a progressive distribution in favor of the male sex For example ; when Adler compiled his statistics the ratio of males to females was iif about three to one In contrast in our last 150 cases the ratio was 18.5 of a great increase from 2 quote a British govern- five year period from und in autopsies in Engat it had been previously he United States during teworthy that although m the world's literature exceed that total of re- le at the Barnes Hospital rty years or nearly four world's literature In the Hospital of New Orlcans ty Hospital by Wheeler Wheeler 1 Avery et al have all rcinoma has become the nt Cancer of the stomach relegated at least in those at pathologists in the last y saw it It seems hardly Cohnheim and Rokitansky t autopsy as frequently as pronounced difference in eover the argument ad- rent because more people when one realizes that not re striking this cancer has he fact that more people plain how it has happened o a position of first place uency this all within e condition there has also e male sex For example of males to females was o cases the ratio was 18.5 es collected by Lindskog Primary Cancer of the Lung = 263 between 1938 and 1943 he found the ratio 4.5 to 1 but in another series in 1947 and 1948 it had become twenty to on^' The preponderance of incidence in males raises the question of immunity whether sexual factors play a role in conferring a relative upon the female sex In other words does the state of femininityfemininity make it less possible to develop a bronchiogenic carcinoma To gain information on this question Kemler and the writers used Greene's method of transplantation of small fragments of hunan bron- chiogenic carcinoma from a male subject into the anterior chamber of guinea pigs eyes Our experiments showed that the transplantation was equally successful in both female and male animals Likewise Gum- bronchiogenic breck in assaying the male sex hormones in ten cases of carcinoma in men found that there was no essential difference between the cancer subjects and normal controls of the same ages Therefore it seems that the state of masculinity or femininity has no inherent quality that is responsible for the marked preponderance of incidence of bron- chiogenic carcinoma in men From all of this it seems reasonable to assume that there has been something in our culture or methods of living in the last thirty or forty years which has been responsible for the remarkable increase of this cancer and that men have been more exposed to this carcinogenic influence than women Occupational factors would seem to be relatively unimportant since all economic classes and men engaged in all kinds of occupations seem to be affected The butcher the baker and candle- stick maker all are prone to have the condition Moreover both urban and rural dwellers seem to be subject to it about equally When one speculates on what factors we are exposed to now different from those in existence formerly various possibilities suggest themselves One of these of course is the great increase in the use of petroleum products since this is the automobile age Preliminary observa- tions on this point however fail to show that oil field workers garage mechanics and others particularly exposed to petroleum products or to inhalation of exhaust fumes from automobiles have a significantly greater . incidence of the disease than others Without mentioning other possi- bilities for which there is no striking incriminating evidence at the prcs. ent time we can take up for consideration immediately one factor which seems to be very important That factor is tobacco smoking especially the use of cigarettes 204 THE BULLETIN CASES 60.0 OF PERCNTAGE 40.0 NONE LIGHT MODERATELY HEAVY HEAVY AMOUNT OF SMOKING EXCESSIVE LEGEND ETRITED MM GENERAL HOSPITAL POPULATION 780 CASES MALES LUNG CANCER 605 CASES MALES CHAIN Fig 1 In this chart a comparison is made between the amount of smoking done by 605 male patients with bronchiogenic carcinoma and men without lung cancer of approximately the same age groups economic status and percentage of urban and rural residence Light smokers have used from 1 to 9 cigarettes per day for more than 20 years Moderately heavy indicates 10 to 15 cigarettes per day for more than 20 years Heavy smokers are those who have used from 16 to 20 cigarettes per day for more than 20 years By excessive is indicated the use of from 21 to 34 cigarettes per day for 20 years and by chain smokers is meant those who have used 35 cigarettes or more per day for at least 20 years The idea that smoking may be an important factor in the etiology of bronchiogenic carcinoma has been suggested by many writers Adler made such a suggestion in his monogragh Tylecote Hoffman McNally Lickint Arkin and Wagner Roffo,,and M^...llerwere additional workers who prior to 1940 thought that smoking especially of cigarettes was important in this respect In 1941 Ochsner and DeBakey18 called attention to the similarity of the curve of increased sales of cigarettes in this country to the greater prevalence of primary cancer of the lung Recently Wynder and the writer19 made the largest statistical study of this question reported up to that time A survey of the smoking habits was made in 684 proven cases of bronchiogenic carcinoma The information was obtained by means of a personal interview with each patient EXCESSIVE CHAIN le between the patients with without lung ups economic ural residence cigarettes per y heavy indimore than 20 ave used from than 20 years from 21 to 34 chain smokers rettes or more S nt factor in the ctiology 1 by many writers Adler lecote Hoffman Mc- 6 and M^...ller17were addi- at smoking especially of I Ochsner and DeBakey18 of increased sales of cigarof primary cancer of the he largest statistical study vey of the smoking habits aic carcinoma The infor- terview with each patient Primary Cancer of the Lung 265 265 A standard questionnaire was used and most of the interviews were made by two medical women who were ignorant of the diagnosis at the time they questioned the patients The subjects of the interviews were EF from all social and economic classes and from widely scattered parts of the country It was found that of 605 males with bronchiogenic car- cinoma other than adenocarcinoma 96.5 per cent had smoked more than a half pack of cigarettes daily for more than twenty twenty years as compared with 73.7 per cent of 780 males without lung cancer who had smoked as much and who were of a comparable age group Even more pressive was the fact that among the lung cancer group 51.2 per cent had smoked more than a pack a day for at least twenty years as compared with only 19.1 per cent who had smoked that much in the group without lung cancer In only 2 per cent of these cases did the patient not smoke at all or less than half pack of cigarettes daily The most striking features revealed from the study were that in the correlation which seems to exist between cigarette smoking and bronchiogenic car- cinoma apparently it is necessary that the man be a heavy smoker at least a half pack of cigarettes per day and that he has smoked for a long period of time usually twenty years or more Fig ) ' The commonly held belief that women smoke as much as men and that therefore they should show as great an incidence of bronchiogenic carcinoma as men is not borne out by a statistical study In order to investigate this point two groups of hospital patients without lung cancer were interviewed All of them were more than thirty years of age and they were comparable as regards economic status One of these groups consisted of 552 women and the other of 780 men Of the wo- men it was found that 79.6 per cent were nonsmokers and only 1.2 per cent had smoked more than a pack of cigarettes a day for at least twenty Bad years By contrast this percentage of 1.2 is to be compared with one of ae 19.1 found in the males who did not have lung cancer It is an interesting coincidence that this ratio of 19.1 to 1.2 compares closely with the sex ratio of incidence of bronchiogenic carcinoma which was 18 males to 1 female in our last 150 cases It is chiefly the girls and young women who are the female heavy smokers and they have not yet had time to smoke for twenty years or more Perhaps in another decade or so there will appear a marked increase in the incidence of bronchiogenic carcinoma in the female At present and presumably during the time that the disease has been showing its great increase it seems clear that men have been 266 THE BULLETIN 100.0 1 80.0 CASES 600 OF PERCNTAGE J 40.0 5.6 20.0 LIGHT MODERATELY HEAVY AMOUNT OF HEAVY SMOKING EXCESSIVE LEGEND OO FES GENERAL HOSPITAL POPULATION 780 CASES MALES GENERAL HOSPITAL POPULATION 352 CASES FEMALES CHAIN 2 Chart which shows the error in the belief that w Fiogmen in the cancer age more than 40 years old have smoked as much for as long 20 years as men of the same age group The designations light moderately heavy heavy excessive and chain have the same meanings as in Fig 1 much more exposed to the consequences of smoking than have women Thus the greater preponderance of lung cancer in men may perhaps be explained Fig ) Of importance in considering a possible relationship between eigar- ette smoking and bronchiogenic carcinoma is the interesting article of Dungal the Professor of Pathology at the University of Iceland He t finds that in that country primary cancer of the lung is still a compara- tively rare disease being ninth in frequency among carcinomas of various organs At the same time the amount of cigarette smoking is very much less than in other countries For example in 1932 the per capita consumption of cigarettes in Iceland was only eighth of that in the United Kingdom Since World War II however the amount of cigar- ette smoking has greatly increased but presumably an insufficient period of time has clapsed to have an effect on the incidence of bronchiogenic carcinomia The evidence therefore secins at least suggestive that excessive cigar- ette smoking carried out for a long period of time twenty or years more has been a factor in causing the remarkably increased frequency of bronc is lacking cancer e cigarette carcinog containe in the p tobacco Anoth is that if may have that the s ment of menon is mentally and the aj Of co only etiol had never ~ has been of a bron what risk excessive s The c which has type In 1 type Mai + pathologis mentioned carcinoma of assumin arrangeme reveal mo M of have - of the i erately e same than have women en may perhaps be hip between cigarteresting article of ity of Iceland He is still a compara- | carcinomas of vari- te smoking is very 932 the per capita ghth of that in the e amount of cigarinsufficient period e of bronchiogenic hat excessive cigar- : twenty years or ncreased frequency | Primary Cancer of the Lung Ey ee 267 of bronchiogenic carcinoma during the last thirty years The proof is lacking and will remain absent until it becomes possible to produce cancer experimentally from some or all of the products contained in cigarette sinoke Various possibilities as to the source and nature of the carcinogenic substances come to mind Of importance could be tars contained in the smoke and inhaled into the lungs substances contained in the paper such as arsensic insecticides used in the growth of the tobacco etc. Another point brought out by the study of Wynder and the writer " is that if a man was an excessive smoker a few years ago the fact that he may have stopped smoking recently does not preclude the possibility that the smoking may still have been an important factor in the development of his recently acquired bronchiogenic carcinoma This phenomenon is analogous to the lag which is well known to occur experimentally in the mouse between the application of a carcinogenic agent and the appearance of the tumor Of course it is realized that excessive cigarette smoking is not the patients only etiological factor After all in 2 per cent of our cases the had never smoked Similarly it is well known that not every man who , has been even a chain smoker for many years develops a primary cancer of a bronchus There are no data available at present to indicate just what risk of developing such a cancer a man takes when he indulges in excessive smoking over a long period of time The common variety of bronchiogenic carcinoma and the one which has shown the remarkable increase is the epidermoid or squamous type In many others the pathological diagnosis is undifferentiated type Many histological varieties have been described by differen _ pathologists The most common designated types other than those jus mentioned are the adenocarcinoma the round cell and the oat cell carcinoma There is considerable doubt however about the correctness of assuming that these called morphological differences noted in cell arrangements and types really represent different varieties of cancer In many cases an examination of different parts of the same tumor will reveal morphological variations which could casily lead to different diagnoses if one should adhere too closely to rigid classifications For example if one recognizes a round cell or an oat cell carcinoma as a distinct type from an adenocarcinoma he may have difficulty in supporting his case if he will examine other parts of the same tumor In general . - 7 . " 2 . - : we 268 THE BULLETIN P however it seems to the writer that perhaps two common types occur either the ducts or the of which one is the epidermoid or squamous variety and the other the bronchial glands to be adenocarcinoma Most of those tumors which are designated as undif- .5 subject of adenomatou ferentiated seem to be less differentiated variants of the epidermoid type propose that the epith The importance of considering the morphological varieties here is trachea and bronchi 1 Moye that perhaps one can think of the epidermoid carcinoma of the bronchus the called bronchia fusha as being a fundamentally different disease from the adenocarcinoma at * called mixed tumor least in so far as its etiology and pathogenesis are concerned At any rate of them There is no that is a concept which the writer would like to suggest with the full realization of the danger of placing too much reliance on morphological classification To some pathologistsit may seem an error even to recog nize the existence of adenocarcinoma of the bronchus Yet unquestion- ably there are bronchial carcinomas which present microscopically an these hypotheses Non by Womack and the v noma is derived from a The only disagreement theory many of the va adenoid arrangement of the cells suggestive of an attempt to form bryonic bronchial buds glands In our experience one finds such tumors about equally distributed authors just quoted ap between the two sexes and they are far less cominon than the epidermoi,d and fully formed glar Te a or squamous variety whichis the ordinary tumor occurring predomi- fetuses and newly bor Sea nantlyin males structures especially th According eat Se to the suggested concept one can think of the epidermoid and peritracheal lymph Se es or squamous carcinoma as being caused by a transmutation or metaplasia chial adenoma Since of adult bronchial epithelium due to the action of carcinogenic influences glands occurred not of which cigarette smoking seems to be an important one On the other hand there is some evidence that the group of tumors commonly called by various names such as bronchial adenoma cylindroma carcinoid oat between the cartilagin found not only peribr of bronchi and trachea cell round cell or adenocarcinoma in many instances may arise from@ fetal bronchial buds which have remained dormant until adult life The tumors arising from suc extend into the bronch evidence for this idea will be presented later Here however it may be 4 known fact that adeno stated that if this concept is true those tumors just mentioned which are either potentially or actually malignant may be thought of as a conver- refers to the article by tumors in children one sion of embryonic epithelium rather than adult epithelium into cancer states that his observa cells This group of cancers then should be regarded as representing an ideas of Womack and t entirely different condition from the ordinary common variety of epi- One reason for reg dermoid or squamous bronchiogenic carcinoma as adenocarcinoma as \ Fried in 1934 proposed that the bronchial adenoma originates in Wessler the bronchial mucous glands Previously Reisnerin 1928 and Wessler and carcinoid as essenti squamous cancer of the and Rabin in 1932 had postulated more specifically that the origin was the epithelium of the ducts of the mucous glands In 1941 Goldman and evidence that cigarette duction of the former Stephens considered that the tumor can come from the epithelium of carcinoma occurs in a " common types occur riety and the other the re designated as undif- of the epidermoid type logical varieties here is cinoma of the bronchus the adenocarcinoma at concerned At any rate to suggest with the full liance on morphological an error even to recog- onchus Yet unquestionsent microscopically an of an attempt to form about equally distributed non than the epidermoid nor occurring predomi- i think of the epidermoid .nsmutation or metaplasia of carcinogenic influences . ortant one On the other umors commonly called vlindroma carcinoid oat instances may arise from nant until adult life The Here however it may be ust mentioned which are - e thought of as a converIt epithelium into cancer garded as representing an * common variety of epi- 1 ial adenoma originates in ner in 1928 and Wessler ifically that the origin was ids In 1941 Goldman and 5 my ne from the epithelium of Primary Cancer of the Lung 269 either the ducts or the glands Stout25 likewise in 1943 considered the bronchial glands to be the origin In 1950 in an excellent review of the subject of adenomatous tumors of the bronchi Goldman and Conner propose that the epithelial cells of the scrous and mucous glands of the trachea and bronchi or the ducts of these glands form the origin of the called bronchial adenomas the cylindromas the carcinoids the called mixed tumors and the carcinomas which may arise from any of them There is no good reason to doubt the correctness of any of these hypotheses None of them really is opposed to the idea advanced by Womack and the writer in 1938 that the called bronchial ade- noma is derived from a fetal bronchial bud which has remained dormant The only disagreement that can be said to exist is that according to our theory many of the varieties of tumor just mentioned arise in latent cmbryonic bronchial buds which contain the bronchial glands whereas the authors just quoted apparently assume that the tumors arise from adult and fully formed glands and ducts Harris after a study of human fetuses and newly borns points out the similarity of infantile types of structures especially the bronchial mucous glands and the peribronchial and peritracheal lymphadenoid tissue to the histologic findings in bron- chial adenoma Since in the material studied the bronchial mucous glands occurred not only just beneath the mucosa but more deeply between the cartilaginous rings and since the lymphadenoid tissue was found not only peribronchially and peritracheally but within the walls of bronchi and trachea as well Harris states that it can be deduced that tumors arising from such tissues may be intramural or extramural or may extend into the bronchial or tracheal lumen He also mentions the well- known fact that adenomatous tumors have been found in childhood and refers to the article by himself and Schattenberg in which several such tumors in children one only seven days old were reported Finally he states that his observations are compatible with the observations and . ideas of Womack and the writer One reason for regarding the group of tumors commonly designated as adenocarcinoma as well as oat cell round cell carcinoma cylindroma and carcinoid as essentially a different condition from the epidermoid or squamous cancer of the bronchus is the fact that there is no convincing evidence that cigarette smoking has any etiological influence in the production of the former group of cancers In fact when a bronchiogenic carcinoma occurs in a patient male or female who has never been a 270 THE BULLETIN il smoker it is more likely to be one which is diagnosed as an adenocarci- noma or one of its variants oat cell round cell carcinoma etc. than as an epidermoid carcinoma Moreover there is no evidence that the adeno- carcinoma has participated in the striking increase in bronchiogenic car- cinoma general Although apparently there are actually more cases of adenocarcinoma found than formerly the small increase in this type in contradistinction to the large number of cases of epidermoid carcin- oma can probably be accounted for by such factors as the greater num- ber of people in the cancer age nowadays better means of recognition 11 etc. li According to the concept mentioned above it seems tempting to fo assume that those carcinomas designated as adenocarcinoma oat cell and fi round cell carcinoma arise from an embryonic bronchial bud which has failed to develop into normal tissue and has remained dormant for many Ww years before being transformed into a carcinoma The fact is of course is well established that in the growth of the embryo the lungs are formed c by a process of budding from the trachea which in turn is formed from ce foregut the embryonic SO In developing this concept the called bronchial adenoma furnished gr the first suggestion Often the microscopic appearance of this rumor ca resembles fetal lung so closely that it is practically impossible to dis- th tinguish it from the lung of for example a 16 weeks old human embryo So far as I know the first one to note this similarity was Bremerof the ca Department of Anatomy at Harvard who reported it to Churchil.31 For ch the most part the cells contain very little cytoplasm so that they give the tis appearance of consisting chiefly of nuclei Moreover they are usually on round or oat shaped of The next point to establish was whether or not these called adeno- siz mas ever become malignant by developing into carcinomas Whenin Tu 1938 Womack and 12 offered evidence that this tumor is potentially malignant as demonstrated by the invasion of neighboring lymph glands tur we found no supporters of the idea For example in 1941 Carter sio of the Brompton Hospital London from a study of twenty cases WO stated that he had found no evidence of malignancy except perhaps slight to i invasion of the bronchial wall in a few instances Strangely also in 1944 tun Engelbreth of the University Institute of Pathological Anatomy bro of Copenhagen in in an article which carried the title of Benign Bronchial Alb Adenomas concluded that there was little evidence that those tumors live is an adenocarcima etc. than as e that the adeno- onchiogenic carually more cases case in this type idermoid carcinthe greater num- as of recognition ems tempting to oma oat cell and al bud which has ormant for many fact is of course lungs are formed is formed from lenoma furnished ce of this tumor mpossible to disd human embryo is Bremerof the Churchill.31 For that they give the they are usually e called adenonomas When in nor is potentially ing lymph glands 41 Carter wenty cases . ept perhaps slight gely also in 1944 ological Anatomy Benign Bronchial that those tumors Primary Cancer of the Lung 27 ever become malignant although in all of his twelvetwelve cases he reported there was marked invasive growth Now however many cases of un- doubted malignancy have been reported in which metastases were found at autopsy not only in the regional lymph glands but in the liver and other distant organs as well See for example Adams Steiner and Bloch Anderson Stowell Bigger Alexanderand Chamberlain and Gordon In 1945 Womack and 10 in a paper presented to the American Association for Thoracic Surgery reported two cases in which autopsy was performed after bronchoscopic biopsies had established the diagnosis of called adenoma In both cases metastases were found in the liver In one case the bronchoscopic biopsy had been made four years prior to the death of the patient In the carcinomas which arise in the called adenomas the cellular structure corresponds closely with that of the latter tumors In other words words the prevailing type of cell is one which has very little cytoplasm cytoplasm and therefore seems to consist chiefly of nucleus It has the morphological characteristics of the cat cell or round cell seen in some pathologists by those groups which are strongly those carcinomas which are designated by names Often also the cells are arranged in suggestive of an adenoid structure and be- cause of that arrangement many pathologists would use for the tumor the name of adenocarcinoma Criticism against the concept that the called adenoma and the carcinoma which is derived from it may represent an embryonic bronchial bud which has remained dormant without forming normal lung tissue has been made on the ground that if this conception is correct then one should expect often to find such buds during the routine examination of lungs It should be understood however that they are of microscopic size unless they have become enlarged sufficiently to be recognized as tumors expres- In 1904 Albrecht coined the term hamartoma for a peculiar tumor of the liver By this term he meant to imply that it was an sion of an abnormal growth of the normal structures of the organ The word is derived from the Greek word hamartia which means failure to reach the goal The idea of Womack and the writer that some of the tumors of the bronchi and lungs result from the failure of embryonic bronchial buds to develop into normal adult structures is in line with Albrecht's conception of hamartoma concerning his tumor of the _ liver and in our article of 193827 we called attention to the similarity IE ONT AE, 272 THE BULLETIN Te ee TP IN of our own conception of the origin of these tumors to that of Albrecht Black AMM for the tumor of the liver described by him Probably also of a similar Fuchs nature are the carcinomas which we reported arising in congenital tion cystic disease of the lung and in association with other developmental abnormalitics of the lung Although some of the recent writers have applied the term hamartoma to the tumors which seem to us to arise in fetal bronchial buds most authors still designate them as bronchial exam Acker Ai ary c adenomas Perhaps it is fair enough to state that even the use of the term hamartoma implies that the tumor has arisen in an embryonic rest Those who use that term therefore seem unconsciously to agree with our con- been 1 the m nomat ception of its origin In our first article in 1938 Womack and 127 noted a resemblance of these tumors to the mixed tumors of the salivary glands and therefore proposed the name of mixed tumors of the bronchus The reason for this suggestion was that in some of the cases we found cartilage and even bone and in some there was an adenoid arrangement of the epithelium like that often seen in the salivary gland tumors Names however arc tures ( tumor lobe o - ently has be the m to the of little importance Of passing interest is the possibility that some of the tumors of the bronchus other than those of predominantly epithelial type so may arise from embryonic buds For example a chondroma a fibroma or a lipoma may have such an origin The embryonic bud is composed not only of endoderm but of course of mesoderm as well The latter is destined to form connective tissue smooth muscle bronchial cartilage and appare except by Oss well fi within three 1 ent is any other tissue of mesoblastic origin If therefore the mesoblastic tissue reacts abnormally to some unknown growth stimulus a tumor may arise in which mesoblastic tissue will predominate The chondroma fibroma and lipoma could perhaps be explained on that basis Although those tumors are rare we have had several examples of each kind Possibly a bit of additional evidence that such tumors arise from bronchial buds perfori The secretio patient case re Others is the fact that epithelial elements have been reported in chondroma of the bronchus by McDonald Harrington and Clagett a finding which we have confirmed in some of our own cases Since the buds contain Laipply Ar both endodermal and mesoblastic elements it might be expected that tumors arising from them would be composed of both elements Just as the epithelial elements may give rise to a carcinoma so malignant tumors may also arise from the mesoblastic components Thus a fibrosarcoma may develop Examples of that tumor have been reported recently by seems t as its cli This na been aj discase ors to that of Albrecht bably also of a similar arising in congenital 1 other developmental e recent writers have ich seem to us to arise ate them as bronchial ven the use of the term embryonic rest Those Those To agree with our con- noted a resemblance of glands and therefore nchus The reason for und cartilage and even ment of the epithelium . Names however are me of the tumors of ly epithelial type also ondroma a fibroma or ic bud is composed not well The latter is des- ronchial cartilage and c the mesoblastic tissue ulus a tunior may arise e chondroma fibroma basis Although those each kind Possibly a e from bronchial buds orted in chondroma of agett a finding which Since the buds contain night be expected that both elements Just as na so malignant tumors cs Thus a fibrosarcoma in reported recently by Primary Cancer of the Lung 273 Black from our clinic by Carswell and Kraeft,,and by Curry and Fuchs Even more striking however is the occurrence of a combina- tion of sarcoma and carcinoma in the same tumor We have had two examples of the latter combination which will be reported by Bergman Ackerman and Kemler.47 Although not arising in a bronchus there is another variety of primary carcinoma of the lung which should be mentioned briefly It has been recognized only recently It has been given various names of which the most commonly used are perhaps alveolar carcinoma multiple multiple adenomatosis and carcinoma mucocellulare One of the most striking features of the condition is that it has a multiple origin However when the tumor is first recognized the multiple origins may all be confined to one lobe or one lung The tumor arises in the parenchyma of the lung apparently in the cells lining the alveoli The name multiple adenomatosis has been applied to the condition because sometimes one can recognize the multiple sites of origin as several nodules The few cases which up to the present have been reported have either been uniformly fatal or apparently on the way to becoming so with perhaps one exception That exception is a case designated as a carcinoma mucocellulare and reported by Osserman and Neuhof.48 After a lobectomy the patient was alive and well five years later In three cases of my own one of the patients died within three years after lobectomy and another one slightly more than three years after a pneumonectomy In the third case although the patient is still living less than a year has clapsed since a lobectomy was performed The condition is sometimes but not always characterized by the secretion of a large amount of mucus which may be coughed up by the patient and apparent also in the specimen of the tumor itself Several case reports will be found in an article by Delarue and the writer.49 Others will be found in articles by Drymnalski Thompson and Sweany by Wood and Pierson by Stephens and Shipman by Swan and by Laipply and Fisher.54 ' A remarkable fact about this recently discovered tumor is that it seems to be identical in both gross and microscopic appearance as well as its clinical course to a disease of sheep known generally as jagziekte This name a South African word which means driving sickness has Africa been applied to the condition because it was in South that the disease was first recognized and carefully studied It is now prevalent in 274 THE BULLETIN many parts of the world In Iceland it occurs in epidemic form and is responsible for enormous losses of sheep In recent years it has been recognized in the Western part of the United States There seems to be rather general consent among pathologists who have studied this disease in the sheep that it is due to a virus which has not yet been found Cowdry was one of the pioneers in the investigation of the cisease SUMMARY Bronchiogenic carcinoma has shown an amazingly increased incidence within the last thirty years and the increase seems to be progressive At the present time it is overwhelmingly a male disorder More and more evidence has been accumulated that excessive cigar- ette smoking is an important etiologic factor although not the only one The great preponderance of the disease in the male sex is not duc 5 to any special immunity of females Rather it seems due to the fact that contrary to popular belief many fewer women of the cancer age smoke than do men A statistical study of this question demonstrates the truth of this statement The marked increase in bronchiogenic carcinoma has been in the 7 type usually designated as epidermoid or squamous or a variant recog- nized as a undifferentiated type A corresponding increase has not been noted in the adenocarcinoma $ or in those types which some pathologists call round cell or oat cell carcinoma Evidence is presented which scems to indicate that cpidermoid car- oy Se cinoma of the bronchus presents an entirely different etiology from that of adenocarcinoma oat cell or round cell carcinoma The suggestion is ipA made that the former type of cancer is due to the metaplasia of adult to ny carcinomatous epithelium under the influence of one or more carcino- Wenie genic agents but that the adenocarcinoma including the oat cell and round cell carcinoma arises in a latent embryonic bronchial bud The recently recognized alveolar carcinoma sometimes called multi- ple adenomatosis which closely resembles the discase of sheep known as jagziekte is briefly discussed 14 ns REFERENCES ON FOLLOWING PAGE in epidemic form and is recent years it has been States There seems to be have studied this disease has not yet been found tigation of the disease nazingly increased inci- he increase seems to be g nale disorder ted that excessive cigarhough not the only one the male sex is not due ems due to the fact that of the cancer age smoke demonstrates the truth cinoma has been in the ious or a variant recog- d in the adenocarcinoma 1 round cell or oat cell ate that epidermoid carerentetiology from that noma The suggestion is he metaplasia of adult to of one or more carcino- cluding the oat cell and onic bronchial bud . sometimes called multi- isease of sheep known as AGE Primary Cancer of the Lung 275 REFERENCES 1. 1. 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Cardiac Catheteriz The introduction into the venous syst sampling blood in t auricle the right ven subject maintained in of mixed venous bl chambers and vessels of these sided : side of the heart i.c. t The The work reported here wi port of the Life Insurance From the Department of and the Pulmonary versity Division Bellevue Given 19 January 1951 i Academy of Medicine