·Publication Number 187
AMERICAN LECTURE SERIES
A Monograph in
The BANNERSTONE DIVISION of
AMERICAN LECTURES IN CHEST DISEASES
Edued by
J ARTHUR MYERS, MD, PRD, FACP.
Professor of Medicine and Preventive Medicine and Public Ilealth
Unitcrsity of Minnesota Medical School
Minneapolis, Minnesota

·By
Lung
SEYVOUR M FARBER, VID
Cancer
Associate Clinical Professor of Medicine
University of California Medical School
Lecturer in Diseases of the Chest
University of California School of
Public Health
1:1)
.
CHARLES C THOMAS PUBLISHER
Springfield • Illinois · USA

·CHARLES C THOTAS PUBLISHER
BAYNEASTOVE HOUSE
301-327 East Lawrence Avenue, Springfield, Illinois, U.SA
Published simultaneously in the British Commonwealth of Notlons by
BLACKWELL SCIENTIFIC PUBLICATIONS, LTD, OXFORD, ENCLAND
Published simultancously in Canada by
THE FYEASON PRESS, TORONTO
This monograph is protected by copynght No
part of it may be reproduced in any manner
without written permission from the publisher
Copyright 1954, by CHARLES C THOMAS · PUBLISHER
Library of Congress Catalog Card Number. 53-8643
Printed in the United States of America

·Dedicated to
LeRoy H Briggs
distinguished physician,
teacher, and friend

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·Introduction Ву I ARTHUR MYERS THE RECENT phenomenal increase in knowledge of prevalence, diagnosis and treatment of cancer of the lungs has made imperative the preparation of a concise and practical volume containing all available facts concerning this disease His long, intensive study of pulmonary malignancy, his extensive clinical experience, his investigative spirit, and his vision of the solution of the problem have admirably qualified Seymour Farber for the preparation of such a volume This monograph is the result of 10 years of constant study and observation in the field of bronchogenic carcinoma Such a period is almost nothing in the observation of persons with a lifetime disease like tuberculosis, but with cancer, which moves with such swiftness and usually kills with such promptness, a decade of observation is adequate to justify conclusions The procedures here recommended and the conclusions drawn were based upon 1,070 autopsies which were carefully studied both chnically and pathologically These necropsies were performed in 19 California hospitals of all types, each employing a registered pathologist This insured broad and basic material In addition, 3,000 per sons suspected of having lung cancer were admitted for cytological studies of sputum and bronchial secretions, along with other differential diagnostic procedures, in the laboratory of the University of California Hospital (via 1 - ·LUNG CANCER One of the most important sources of material was the authors private practice, which provided an oppor tunity to study general practitioners' problems and view points, as well as unique experiences in diagnosis and treatment of cancer He first presents a broad pattern of etiology, histopathology, roentgenology, diagnostic aids and treatment for all cincer and then focuses on that of the lung This book is rightly directed to those in general practice, who compose the oven helming majority of physi cians throughout the world It is they who most often have the opportunity to make the first examination of the individuni who is developing cancer Therefore, general practitioners are and must continue to be in the front line in the fight against this diserse In order to hold that line they must be adequately equipped with the latest tech mics un diagnosis and treatment, as well as the best general information available General practitioners in turn, are the ideal group to transmit information concerning cancer to the public This they do personally through the families of their clients, and through cancer control organizations Without full cooperation of the public, further progress in the control of this condition will be slow With a relatively long silent period in its early evolu tion and with its host usually becoming aware of the presence of illness only after metastases have occurred people everywhere should learn that cancer must be found before there are manifestations of illness of its victims are to be treated successfully The most serious handicap in the entire control more ment is lack of a specific test to indicate the presence of the disease while the lesions are still microscopic such as we now have in the tuberculin test for tuberculo sis Learning through such a test that cancer is present somewhere in a given individuals body, the physician ·INTRODUCTION could make oft repeated evamınations of those parts most frequented by this disease and locate the lesions as soon as they attain sufficient size to be detected Thus one might expect to locate and remove most cancers before they have metastasized While awaiting such a test for cancer, much can be done to improve the present situation Although he recognizes that the only successful treatment of cancer today is surgical extirpation, the author, like many other workers in this field, has a deep convic tion that the future treatment of pulmonary cancer will be with drugs Therefore he has outlined this complex field in such a way as to make all physicians more sensi tuc to developments in chemotherapy in the future It is heartening to see emphasis placed upon the responsibility of physicians caring for persons who have inoperable or recurrent carcinomas At present, this constitutes at least 90 per cent of all who have cancer of the Jungs It has been estimated that there are some 30,000 inoperable cases of bronchogenic carcinoma puust m the United States The author says, "A real challenge to the physician's art is a patient who is inoperable at diagnosis or has post-operative recurrence" He then proceeds to present step by step the physician's armamentarium in coping with this situation Dr Farber's extensive and long experience in the front line of the fight against cancer of the lungs, along with his constant teachung of formal medical school courses, lecturing before medical societies, presenting postgraduate courses for both specialists and physicians in general practice, and personal conversation with many practicing physicians have enabled him to grasp the needs of a physicians He has met these needs simply, concisely, and yet so completely that it is a priuilege to speed this volume on its way to physicians everywhere

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·Acknowledgments BECAUSE successful treatment of bronchogenic carcinoma as radical, and because of the complexity of the subject generally, it is sometimes assumed that the disease is a problem for specialists It is, of course, a problem concerning many kinds of specialists, but it is also a clinical problem of great magnitude, the immediate concern of all engaging in the practice of medicine The typical patient with lung cancer does not present himself at a cancer clinic, or a university hospital when symptoms first become apparent, he comes to medical attention routinely This book has been written from the point of view, then, of the chnician, upon whose judgment other members of the medical profession must depend It is impossible to acknowledge all the obligations that are represented in a book of this kind Every professional man with whom I have discussed the subject in the last 10 years has, in one way or another, contributed to this study But there are special contributions which cannot be neglected Drs Mortimer A Benioff, E Fred Alston, Milton Rosenthal, James G Tobias, Allen K McGrath, Jr, Lloyd W Espen, Walter H Buel, Judith D Smith, Jesselene H Thomas, and Richard F Barquist are, or have been, my colleagues in this study They constitute the group without which this book could not have been written Dr Cameron Ward has generously given of his time in reading the manuscript William Brandt, of the University of California English Department, has been assiduous in lus numerous and » aluable suggestions in) ·X11 LUNG CANCER for shaping the prose style toward muximum clarity and conciseness, and Miss Eleanor Little has checked the en tire manuscript for conformity with established medical usage The aid of Dr Irving Reingold in securing photo micrographs' is gratefully acknowledged Lastly, I should like to express my gratitude for the devotion displayed by my secretaries, Sadie Kaye and Jean Mulcahy Mistakes of one kind or another there must be in a book, but the co operation I have received has been of immense help in reducing such errors SMT ·Contents INTRODUCTIOV BY) ARTIIUR MYERS V11 ACKNOWLEDGMENTS 8 9 CHAPTER I ETIOLOGY Infection Tuberculosis Chrome infections Chemical Irritants Schneeberg Jachymoy radiation Chromium Silicosis Other No 12 12 16 16 17 17 18 22 28 33 35 UNE Petroleum products Metabolism and Heredity Heredity KAPTER 2 ILISTOPATHOLOGY Pathologic Classification Microscopic appearance-squamous cell carcinoma Adenocarcinoma Undiferentiated carcinoma Early Aspects of Malignancy Squamous cell carcinoma Adenocarcinoma Undifferentiated carcinoma The Significance of Pathologie Classt fication Associated Pathology [x] 36 36 36 40 47 49 ·XIV LUNG CANCER 52 CHAPTER 3 CLINICAL FEATURES Respiratory symptoms Cough and sputum Chest pain 55 56 58 59 60 60 61 61 62 63 63 61 64 65 65 66 Dyspnea Hemoptysis General symptoms Fever and sepsis Loss of strength Metastatic findings Physical Examination Wheeze Emphysema Atelectasis Clubbing of the extremities Tracheal deviation Metastasis CHAPTER 4 ROENTGENOLOCY Fluoroscopy Parenchymal tumors Hilar lesions Bronchial Block Emphysema Atelectasis Secondary Infections Supplementary Roentgenologic Tech niques Bronchography Tomography Angiocardiography CHAPTER 5 FURTILER DIAGNOSTIC STUDIES Bronchoscopy Cytologic Diagnosis Cell size Nuclear irregularity Hyperchromatism Mitoses Nucleolar aberrations Cell grouping 67 68 71 76 77 77 80 80 83 83 84 85 87 89 93 97 97 97 99 99 100

·22
CONTENTS
ху
105
CHAPTER 6 SURGERY
Care of the inoperable cancer pa
tient
CHAPTER 7 No SURCICAL TECHNIQUES
Hormonal therapy
Specific chemotherapeutic agents
Cell poisons
Folic acid antagonists
Irradiation therapy
CHAPTER 8 CONCLUSION
BOLIOCRAPHY
INDEX
116
121
121
123
124
129
132
134
137
147

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·Etiology 7 THE MODERN physician is of necessity a practical man If he has the inclination to master the complex theory Caracteristic of the advanced fields of medical research he has not generally the time His professional life us primuly concerned with people not theory and what ever view the scientist puts forward the physicians inter est in disease remais a therapeutic one an interest in muns amictions this questions are always specyfic Math each patient his first question must be What alliction? and his second What can be done about it? The theory underlying a particular diagnosis and remedy is of sec ondary concern But all virtue to excess is nice and the pricticality of the physician can become imprictical A disease is not after all a collection of signs and symptoms responding uniformly to specific procedures a disease is an abnormal process a dynamic process brought about by exterior interference with normal function or by a specific physio logic disturbance It has a cause or coordmate causes To approach disease from any less comprehensive point of view is to risk serious error There are of course certun diseases such 18 lobar pneumons? in which a well marked classic" appearance can be anticipated with some confidence in such instances dngnosis ein with some safety be a more or less routine evalantion of signs (31 ·LUNG CANCER and symptoms Few of the major diseases of the thoracic cage, however, are so regular in their progress that such a routine approrch to diagnosis is possible Disease is conflict, and the symptoms and appearances that result are seldom specific enough to add up regularly and me chanically to the correct answer Consequently, the serious afflictions to which man is subject are very likely to be approached by a system of trial and error, a process of elimination which the patient does not always survive The record of the medical profession in the diagnosis of bronchogenic carcinoma is regarded as unsatisfactory Our own findings are in conformity with published studies We have surveyed 1,070 cases of bronchogenic carcinoma, morphologically proven, collected from 19 hospitals in California. In bl per cent of these cases, no positive diagnosis was made prior to autopsy Compared year by year, it apparently took as long to make a correct dingnosis of the disease in 1949 as it had in 1935 (Fig ure 7) Most of this difficulty arises from the absence of any kind of "classic" case of bronchogenic carcinoma, its most common characteristic being its protean manifesta tions Thus, there is no available model form of the disease to serve as an accurate measure for diagnosis of the indı vidual instance Surely in these 1,070 cases the possibility of bronchogenic carcinoma frequently occurred to the examining physician soon after the patient required medı cal attention, only to be rejected as unlikely on the basis The cooperation and help of the pathologists and staff of the onl no vlarged Birmingham VA Hos nt Hospital French IIospital ngeles County IJospital Let Mt Zion Hospital Oakland VA Hospital Permanente Hospital San Francisco City and County Hospital San Joaquin County Hospital Santa Clara County Slospital Stanford University Hospital St Luke's Hospital Unrersity of Cali fornia Hospital and Wadsworth VA Hospital 11 L 1 Hof 11 ·ETIOLOGY 5 of madequate signs and symptoms As a consequence diagnosis of the disease too often depended upon a pro tracted course of evaluation by elimination or other drag nostic possibilities Barring an inovation in diagnostic technique any sub stantial improvement in the current diagnostic record requires a sounder approach to the disease Diagnosis requires an understanding of the disease process which underlies and gives rise to clinical appearances rather than a check Irst of signs and symptoms Such a basic approach can produce a much higher percentage of early diagnoses than are now obtained This approach requires some knowledge of and interest in the actual course of a disease beyond that which is visible to the eye and mea surable by diagnostic techniques The research workers interest is centered in etiology and pathology for improvement of techniques for con trolling the disease the practicing physician must concern himself with the same subjects primarily for their service to diagnosis The problem of bronchogenic carcinoma honever cannot be isolated from the problems of malignancy in general and the whole subject is dependent upon our knowledge of normal physiologic behavior As has been pomted out many times the problem of cancer is ult. mately a problem in tissue gronth and the difficulties which arise when a coherent and comprehensixe theory of cancer ctiology is attempted reflect the complexity of normal cell development Although there are still large gaps in our knowledge of the latter subject the general outlines of the process seem to be clerr enough Vost important to an under standing of malignancy is the well established fact that ? normal fissionahle cell (with which cancer research is especially concemed) does not hhe 1 single principle of ·6 LUNG CANCER development and control Its course is governed by two distinct control mechanisms Basically, such a cell is limited in its potential de clopment by its inherent structurc which is determined ultimately by an enzyme or enzymes An undifferentiated cell may mature into one of several mature cell types, but the range is limited As an instance, the undifferentiated, basal cells of the bronchi mas de clop into cited epithelial cells, non ciliated epithelial cells or goblet cells in the presence of a mechinical or infectious irritation, such cells may approach squamous stratified cpithelium But thus completes the range of normal possibilities Every tindifferentiated cell according to the "territory” in which it arises, has a similar selection of mature forms mto which it ay develop Such a dev clopment is irrei ersible, and a mnture cell cannot atsclf divade Upon these individual cells, already limited by their enzyme structure, the requirements of the whole organism are imposed the operation of this second iry control scems at times to be mechanical, but more important to such control is the complicated system of hormones and related substances which direct and integrate all bodily processes By this means the mature form that a particu- Iar cell will assume is determined Likewise, the needs of the organisin as a whole determines the rate of production of undifferentiated cells, by fission, and the rate of maturation Both in clinical work and experiments with animals, it has proven virtually impossible to detect the precise nature of this hormonal activity It is an open question whether an adimunistered hormone operates by direct operation in all instances or by the suppression of other and native substances Hosei er, there is reason to belicic that tlie behavior of undifferentiated cells is gen crally determined by the total balance which is main ·7 ETIOLOGY tained between several hormone type substances rather than by the operation of a single such substance The development of malignancy requires that a cell or a group of cells escape to some extent the limits im posed by the needs of the organism and its normal en vironment Interest at the present time is chiefly centered upon the alteration of the cell itself This alteration is probably in the nature of a mutation The structure of a cell is composed of enzymes which convert body fluds to the needs of the particular cell and through which the cell performs its service to the organism as a whole For 1 cell to become malignant it is necessary that this basic enzyme pattern be altered without destruction of the cell In bronchogenic carcinoma as in cancer generally the malignant tissue often closely resembles normal tissue of the aren in structure and the microscopic appearance of the individual cells It is obvious that the alteration of the cell enzyme structure is a very limited one Something has been added or removed or altered so that the indi vidual cell retains most of its properties perhaps er en all of its properties except its self limiting one Little is known about the details of the process by wluch the malignant transformation takes place Several investigators have confirmed the experimental supposition that the significant alteration takes place in the cytoplasm of the cell rather than in the nucleus Experimentally it has been found that a particular enzyme can be lost gradu ally in the course of several cell divisions However in most instances the transformation is presumably accom plished by the immediate effect of 1 substance exterior to the cell upon the particular enzymes responsible for cell growth The action of such a substance upon the en zyme is perhaps is specific as that of antibody upon micro orgmism Cancer producing substances are not only spe ·8 LUNG CANCER cific for certain laboratory animals, and strains within the genus, but are very often actie only in a particular organ of the affected animals Cancer arises as a result of an interaction between the specific tissue of the host and the carcinogenic agent In human malignancy, cases are occasionally met in which one or the other of these two elements in cancer genesis clearly predominates Very often, however, it is difficult or impossible to make such a judgment So far as bronchogenic carcinoma is concerned, it is apparent that both elements share largely in the origins of the growth The pronounced age and ser predilections of broncho genic carcinoma suggest just as clearly the importance of hormonal factors Perhaps the relaticly equal importance of these two elements is partly responsible for the fact that specific findings concerning the etiology of bronchogenic carcinoma are not always easy to relate to one another it must also be recognized that there is no reason to suppose that we will discover a single etiologic agent or etrological situation for the disease It must be anticipated that more and more etiologic agents for lung cancer will be demon strated as time goes on, and it is possible that such agents will be found to operate toward the same end by radically different means As a consequence, the etiology of bronchogenic carcinoma can best be organized by relating specific facts to the etiological theory to which they most clearly relate The first such theory is that bronchogenic carcinoma is in one way or another the result of an infection More widely held, at least in this country, is the theory that lung cancer arises as the result of chemical action upon cell structure These theories are not necessarily mutually exclusive, but each must be examined in its own right Quite distinct is the third problem of whether or not there ·9 ETIOLOGY is such a chemical etiologic agent widespread in the environment, since this inyoles the question of rising incidence All of these theories and problems are related in some way to what must be the fourth consideration, the constitution of the individual upon which etiologic agents operate INFECTION A theory of infection for malignancy has always had the attraction of simplifying medical concepts, it brings cancer in line with other disease processes The theory had its secure beginning in the work of Rous, who isolated from chicken sarcoma a cell free filtrate with which he was able to transmit the disease it is generally assumed that the agent in the filtrate was a vinis, although this has been disputed A similar filtrate has been demon strated for a rabbit tumor by Shoup in 1931 The agent in this instance was almost certainly a virus, since the tumor was found to be epidemic among wild rabbits, it was obviously contagious Among wild rabbits, the result ant tumor was a benign papillom?, but when Shoup trans mitted the virus by an acellular filtrate to laboratory anı mals, the tumor was malignant in a large percentage of instances This is the only instance so far uncovered of tumor contagion occurring in nature Perhaps of more relei ance to the concept of cancer genesis among human beings was the discovery of the muk factor" This agent was found accidentally during experiments which were primarily concerned with heredi tary factors in experimenting with two strains of mice, one strain with a high incidence of mammary carcinoma among mature females, and another with a very low inci dence, it was found by exchanging neu bom females that the critical factor was not heredity but some filterable agent transmitted by the mother s milk The low incidence ·SIS 10 LUNG CANCER female mice which had been nursed by females of the high incidence strain developed mammary cancer when mature, as did their descendants Again, this was pre sumed to be a virus l'urther experimentation with “mill fictor” carcinoma comphcated the original findings by demonstrating that the hormone folliculin was also required for cancer gene Female mice whose ovaries were removed before maturity did not deselop mammary carcinoma even though they had been pursed by females of the strains carrying the milk factors On the other hand, male mice nursed by milk factor females developed mammary cor. cinoma of the hormone were administered It is assumed that the factor transmitting the disease passes mto the bloodstream of the young animals and collects in the vicinity of the mimmary glands, where it may rem un in active indefinitely, unless folliculin in some way prepares the ground for the development of a malignancy This whole series of experiments proudes an excellent illustration of the problems involved in the etiologic theory of cancer Does the virus require the hormone for activity? Or does the hormone act directly upon the potentially malignant cells and only indirectly upon the virus? We do not know A great deal of experimentation has been directed to ward the possibility of virus induced malignancses, but the three groups of experiments previously cited consta tute the bulk of the evidence for the theory At the pres ent time, most miestigators seem inclined to regard the Rous chicken sarcoma, the rabbit papilloma, and the milk factor mammary carcinoma as exceptional situations having no parallel in human malignancy It is casier to assume that there erists in nature three erceptional viruses able to produce cell mutation in certain circumstances, than it is to adapt our experience with human malignancy to a theory of virus origin ·ETIOLOCY These is, of course, no evidence that pulmonary carcimonia is of viral origin where an etiologic agent has been indicated with reasonable certainty, it has been chemical if a viral agent were isolated on pulmonary carcinoma, it would probably be so ubiqmtous as to lose much of its significance Tuberculosis. All the evidence for a viral etiology for malignancy has been experimental, on the other hand, the possible importance of tuberculosis in the etiology of bron chogenic carcinoma depends entirely upon chnical olser vations The theory that there is a real connection between the two diseases is an old one, and it has suffered manı vicissitudes Ewing at one time helieved that tuberculosis would eventually prove to be the most important single ctrologic agent in bronchogenic carcinoma When large scale autopsy studies made it apparent that tuberculosis could not possibly fill this role, it was often somewhat hastily assumed that it had no significance to malignancy studies at all An opposing theory was even advanced which suggested that there was some kind of antagonism betueen the two diseases, so that the tuberculous patient could at least be given the doubtful assurance that he had acquired some kind of immunity agamst lung cancer Statistical studies are inconclusie De la Fuente found only 34 cases of coexistent tuberculosis and carcinoms in 2,500 autopsies at Sea View Hospital On the other hand, some miestigators have forind impressie percentages of coeustence Fried found 34 cases of vo existent tuberculosis in 319 antopsies where the primary diagnosis was lung cancer It is sery difficult to determine the relationshup between tuo such processes in Indnadual instances, and it may be that the high percentage of cooristence that Fried found is to be accounted for by reactna tion of old thberculous lesions So long as malignancy was regarded as a kind of catastropluc destruction or alteration of a cellular enzyme pattern, the elfect of a chronic conda- ·12 LUNG CANCER tion such as tuberculosis was of dubious importance Re cent studies in cell physiology suggest however that permanent alterntion cın be achieved gradually that an enzyme may be eliminated through a series of cell dist sions perlıyps when such division is excessive If this is the case the local imbalance resulting from pulmonary tuberculosis may occasionally result in malignancy lic do not have sufficient eudence for accepting or rejecting the possibility In any case coexistence of tuberculosis and cancer is ? diagnostic problem of importance There has been a sharp increase in the proportion of the tuberculous popula tion who are over 40 years of age as this trend develops the problem of cocxistence will become increasingly So long as we routinely check for tuberculosis and not for carcinoma there will remain the tendency to treat a patient for the former while he is dying of cancer Chronic infections The rationale for proposing any chronic lung infection is an etiologic agent in broncho genic carcinoma is much the same as the rationale for proposing tuberculosis although each infection must be established or disproved in its own right There is of course almost invariably some kind of infection second zry to a lung tumor Where carcinoma is discovered during the treatment of infection the malignancy can be gener ally demonstrated to be antecedent Nevertheless it is not safe to issume that the situntion cannot in certain instances be reversed we are not justified in positively rejecting chronic infection as a possible factor in the etrol ogy of bronchogenic carcinoma serious CHEMICAL IRRITANTS This class of possible etiologic agents is lurge and it has attracted much attention both in the clinic and in the laboratory Again the underlying supposition for a long ·ETIOLOGY 13 time, was that a chronic metaplasia, induced by what was essentially an irritant, could, in a certain number of in stances, progress to a frank malignancy The earlier work on cell physiology tended to discredit this view, at the present time it is again of interest because it has been found experimentally that excessive cell division can occasionally alter the enzyme pattern of a cell permanently However, most chemical agents which have been proven to be of etiological significance to malignancy are thought to operate in a different manner They would seem to modify cell structure directly Although they can be accompanied by an irritative effect, this is not a necessary part of their action, and certain of them have no detectable irritant action at all They are carcinogens The idea was developed out of the finding of Yama giwa and Ichikawa that repeated applications of coal tar to the ears of rabbits led to the development of malig nancy at the site of application This was confirmed in numerous experiments with mice, and in 1930 a London group directed by Kennaway first isolated a purified product from tar (benzpy rene) which was very active in inducing carcinoma In the next few years, several hun dred such hydrocarbons of varying degrees of effective ness in inducing malignancy were discovered It was during these subsequent experiments that it was found that inflammation was a side effect to the carcinogenic action The ability of a compound to induce cancer did not correlate with its inflammatory properties It was also apparent that the effect of the carcinogen was sometimes quite specific While some compounds induced malignancy at the site of application, others showed a consistent predilection for a particular organ of the body, regardless of the route or site of administration As early as 1925, Murphy and Sturm had come to the conclusion that the high percentage of bronchogenic carcinoma ·14 LUNG CANCER which they lind observed in mice punted cutuneously with conl tar was not the result of inhalation of fumes as had been supposed It was, they concluded, the reaction of bronchial tissue to the systemic effects of the tar Then, niethy Icholanthrene was des cloped With this substance it proved possible to elicit bronchogenic carcinoma in mce by any method of administration subcutincously, intravenously, intraperitoneally, orally, or by local applı cation These discoseries has e unfortunately become more complicated rather than simplified with time The carcino gens in the earlier experiments were a group of hydrocarbons with closely related molecular structures, and it seemed for a time that the carcinogenic action was to be accounted for simply in terms of such structures There after, however, totally unrelated substances were found to be likewise carcinogenic It is, nevertheless, tentathely assumed that the circi nogenic properties of such substances arise from a similar effect upon cells Tlie studies of Miller and Muller hue been particularly relevant to the question of how such substances operate These workers found that p dimethyl aminonzobenzene when administered to rats bound itself tightly to certain proteins of the Inter cells, but did not affect the cells of other organs This susbtance almost in variably produces carcinoma of the Iner Subsequent ex periments have tended to confirm the supposition that carcinogens which have a prediliction for a particulir organ are in some way collected and bound by the cells of that orgın Such substances apparently unite with the enzyme or enzymes effecting cell growth without destroy ing the cell itself The transformation from normal growth to malignant growth us in the nature of a mutation Not only does the ·ETIOLOGY 15 transformation parallel gene mutation in many ways, it seems at times to be virtually an identical process That x ray radiation can be used to induce genetic mutation, and that it may, in certain circumstances, lead to the development of malignancy, is well known It has further been demonstrated that several of the highly carcinogenic hydrocarbons are likewise potent agents in producing genetic mutation Alustard gas has carcinogenic properties in addition to its well-known action in inducing mutations Between two such specific processes there is not, of course, a onc-to one relationship However, there is a substantial degree of correlation, and it is reasonable to assume the processes are not dissimilar Another experiment il observation should perhaps be mentioned although its significance to cancer theory is by no means clear Several of the substances which are known to be carcinogenic under certain circumstances may, under other conditions be useful as agents in the treatment of malignancy Again, ray radiation is the best illustration of this dual function, but mustard gas shows the same range of effects Urethine, which is used in the treatment of chronic leukemia, has also been de monstrated to be a carcinogen, leading to pulmonary malignancy in mice Our knowledge of carcinogens and the way in which they operate is derived largely from work in the laboratory, and the extension of theory from experiment to niture must be made cautiously However, there seems no good reason to doubt that the pulmonary malignancies found in chromate industry workers and pitchblende miners as described liter, are the result of a carcinogen in an industrial environment Other situations are more doubtful We tre probably justified in assuming a carcinogenic effect when in nature a substance is found to gne ·16 LUNG CANCER rise to carcinom, on the other hand, it is possible that such agents may eventually be shown to have a different mode of operation at different times Schneeberg.Jachy mos radiation. One of the earliest instances in which cancer is found to be an industrial hazard was the discovery of an inordinate amount of lung cancer among the miners of Schneeberg Although the ore from this mine contained silica, bismuth, nickel and arsenic, it is generally agreed that the agent responsible for the high incidence of malignancies is pitchblende The disease is thus the result of prolonged, although moderate exposure to radiation, and the mode of operation is com patible with the theory of carcinogen The percentage of miners succumbing to lung cancer is quite high In 1935 Lange found that between 60 and 70 per cent of all miners at Schneeberg died of broncho genic carcinoma, thus rate his apparently existed for sev eral hundred years At Jachymov, where the diagnosis was made much later, 18 of 25 autopsies between 1929 and 1931 revealed the same condition it is to be noted that although the whole body, and particularly the skin, is exposed to radiation the high rate of malignancy is exclusncly pulmonary Chromium Pfeil added this mineral to the list of in dustrial carcinogens as recently as 1935 Although the total number of cases so far reported has been small, in the situations investigated, the carcinogenic action of chromium iould seem to be a powerful one Machle and Gregorious surveyed 193 deaths among chromate workers 66 of these men died of cancer not appear to be as specific for the lungs as pitchblende, but the lungs were affected far more frequently than any other organ The studies thus far reported are sufficient to indict some element in the environment of chromate workers as definitely carcinogenic The history of such employment ·ETIOLOGY 17 hence becomes 1 significant fact in diagnostng chest disense Thus far however, neither chromnim nor its compounds has been proven in the laboratory to hc crr cinogenic This might mean that something else in the environment of these workers is the specific carcinogen On the other hand species is so important to carcinogenic action that chromates may be carcinogenic for human beings even though they are inert for laboratory animals Silicosis When free sılıca penetrates the alieoli and smaller bronchioles of the Jung it stimulates connective tisstic cells When the silica is present in sufficient quan tity over 1 considerable period of time silicosis results llowever stica is chemically one of the most inert com pounds in nature and it is not believed to be an effect upon the epithelial elements in which bronchogenic (91 cinoma vises Nevertheless it has been suggested thenti history of silicosis is of some significance in malignancy In 1932 Fried reported finding at autopsy a very small bronchogenic carcinoma associated with pneumocontosis and extensnc metaplaşır Chur found bronchogenic carcinoma in the autopsy studies of 36 cases of silicosis Klotz found four tumors in rutopsying 50 cises Such findings we not conclusive of u relationship but they are suggestive Perhaps some substance commonly issociated with shca in small amounts all on future study prove to be carcmogenic it seems doubtful that sılaca itself will eier be found to have such an effect Other industrial hazards There have been numerous other industrial products suggested as possible igents in the genesis of bronchogenic carcinoma but studies to date Marc been inconclusnc Homburger at Inle Medical of nichel copper refineries ve somewhat more predisposed ·LUNC CANCER 18 to bronchial malignincy than the population at large Arsenic is known to be carcinogenic when it is in pro longed contact with the superficial epithelium perhaps it predilects to bronchogenic carcmoma when it is in haled as dust It is not unlikely that other substances found in certain industrial situations will be proven to be of significance in the etiology of bronchogenic carcinoma NON-OCCUPATIONAL CARCINOGENS AND THE QUESTION OF INCIDENCE It has been possible to show a convincing etiological relationship between certain specific exposures and bronchogenic carcinoma, because something approvimating a controlled situation exists in the investig ited industrial situation there the lizard is not occupational, statistical cvidence is more difficult to evaluate Nevertheless mam investigators have for a long time believed that there are one or more agents in our general environment which predicate to bronchogenic carcinoma Tlus conclusion is based in lurge part upon the conuction that there is been in recent years a real nse in incidence of the dise ise, and it is reasonable only if such an increased incidence is beleed to exist This question of rising incidence is perhaps the most debited in contempoiary medicine The basic fact is that every large collection of cancer statistics in the last twenty-five years has shown a steady increase in the num ber of cases of bronchogenic carcinoma which are found yearly in the Triopli and Holland study at New Orleans, nie broucliogenic carcinomas were found at autopsy lictueen January, 1918 and January, 1928, betu een the lat ter date and July, 1938, 186 such cancers were reported in the same institution Similarly, in the trbulation of 10 000 autopsies at Johns Hopkins Hospital from 1896 to 1930, VacCallum found about a five-fold incrense be ·ETIOLOGY 19 tween the first and last decades of the stud All studies over a comparable period of time show about the same rate of increase The question at the present time is whether or not this increase is a real and not a statistical one So istute a student of the sulject as Fried for instance as recenth as 19:19 concluded that this apparent increase its an Busion There we four major factors which must be taken into account in et lunting such studies We cannot estimate the effect of any one of them with any precision (1) The first is simply the increased interest in the condition We tend to find a disease such as bronchogenic circinoma in proportion to our willingness to look for it The publicity that the disease has recerved in the last 20 years is in itself sufficient to effect the reported in cidence (2) Incidence is certain to rise as dignostic methods are improved Some of this apparent increase is to be accounted for ly the increased use of ray bronchoscope and microscope 13) Chemotherapy has undoubtedly played some put in the apparent increase of malignancy In many in stances today here able to diagnose bronchogenic car cinom i because confusing secondary infections are nt least temporarily cleared by the new drugs exposing the tuinor body to roentgenologic view There can be no question that many of the patients of 20 years ago who were thought to suffer from some chronic lung infection actu ally expired as a result of in undiagnosed bronchogenic Cicironin (4) The last major factor to be considered is the ste udy increase in longevity Cancer of the lung being primarils a disease of middle age it follous thit as a gretter percentige of the population reaches this cancer the the number of cases of cancer will incre is. The in ·20 LUNG CANCER creased incidence to be anticipated each year from this aging of the population is small, but none the less real Thiese four elements are of importance in estimating the current status of cancer of the lung and they have un doubtedly accounted for some of this apparent increase It does not follow, however, that after these have been allowed for, there may not be a sizeable residue of increase luch represents a genume rise in incidence It is easy to sec an increased medical efficiency and an aging popula tion as responsible for the steady increase in incidence from 1900 to 1910 These two factors are not clearly ade quate for the persistence of this increase over shorter periods in the last few years The report of the Public Health Service, from death certificates, shorts a radical and constant increase in the number of bronchogenic car cinomas from 1930 to 1940 Perhaps this may be ade quately accounted for by better diagnostic facilities and an aging population But it is very doubtful that these reasons can account for all of the surprisingly consistent increase for each year from 19.10 to 1945 Steiner, on the basis of an examination of 36,864 autopsies mide at Los Angeles County Hospital betueen 1918 and 1916 con chided that there had been a real and absolute increase in incidence during this period From 1923 to 1937, curcu nomz of the lung was found in 06 per cent of all autopsies and constituted 4 3 per cent of all malignancies Between 1943 and 1946 this disease was found in 2 3 per cent of all autopsies and accounted for 113 per cent of all malig nancies This increase ty as not accounted for by a chang ing sex ratio nor was there an increase in cancer of the large intestine or pancreas None of the factors to wluch rising incidence has been attributed seem significant upon close inspection Most recent studies with smaller groups point in the same dnection In a comparison of bronchogenic cura ·ETIOLOGY noma with carcinoma of the stomach, larynx and bladder, Ariel, et al. found the former increasing relative to the other types In 1931 bronchogenic carcinoma comprised) 21 per cent of all cancers diagnosed, in 1916 it was 317 per cent Gastric cancer, which shows alout the same age incidente, showed no significant increase, thus mmınız. ing the possilmlity that a change in the character of the hospital population has of much importance Fulton found a regular increase in Luerpool from 194 to 1918. from 145 per million population to 207 per million Perhaps it is safe to say that 95 per cent of recent status tics lvearmg on tus question suggest that there has been a real increase m lung cancer Of the studies which point 2 the other direction, that of Clemmenson and Bush in 19-47 (Brit I Cancer), rould seem to carry a good deal of weight Tling compared the figures for Denmuk at large with the findings nf the Central Tuberculosis Sta tion of Copenhagen where superior diagnostic methods had been in use They found that in the latter situatson there lid been only a scry shght increase in bronchogenic (arcinon between 1936 and 1945, while in the countn at large they found a rise comparable to that reported else where Cether they found in the population at huge that the ratio of men to women with the disease increased in this persoal from 5 to 3 1 During the same period the MC Yato in the Central Tuberculosis Station rcm ined untuh constant at about 8 1 Thies concluded that the apparent incre ist in lung mortality is, to a very large ex tent conditioned in improvenients in dngnostic mcans, and it can be expected to continue until the ser ratio amounts to thout eight males to one female Incidence is not a subject upon which one can dogmn? tize wafels kunt it is absons that the weight of cudence farors the presumption of a real increise The Copenhiges studs is mypressite, but not conclusive It runs ·22 LUC CANCER counter to the general observation that the greatest increase to this time has been reported in urban areas, and it is by no means clear why diagnostic facılıties should affect the sex ratio This altering ratio would scem, in fact, to mitigate agamst the conclusion expressed It is the author's opinion at the present time that there has been a real increase in the incidence of lung cancer, and further, that we must expect the present rate of in crcase to be continued If bronchogenic carcinoma is not already the most common form of malignancy in males, it can be expected to assume this position within the few years We also anticipate a sizeable inciease in incidence among females Smoking If there has been a genuine increase in bronchogenic carcinoma beyond that accounted for in terms of an aging population, it would seem that it should be attributed to some changing element, or elements, in the environment of modern man It is doubtful that the whole range of industrial liazards is sufficient to account for 1 per cent of the carcinomas reported yearly, these industrial hazards are not likely to have any marked influence upon national statistics If there is a real increase in the incidence of cancer, it implies some very wide spread carcinogen, transcending occupational hazards Of such potential agents, tobacco smohe is the nearest to common acceptance Adler was the first to suggest that tobacco might be etiologically significant, there has been since that time a steady series of reports on the question Vost recently Schrek, et al, found evidence of a real relationship, and Wynder and Graham published a study of 684 cases of proved Bronchogenic carcinoma with a myjor effort to provide proper controls Their conclusion was that 'ex cessive and prolonged use of tobacco, especially cigarettes, seems to be an important factor in the induction of bron ·23 ETIOLOGY chogenic carcinoma” They found that 965 per cent of 605 men with bronchogenic carcinoma had smoked nore than 10 cigarettes a day for 20 years or more as com pared with only 737 per cent smoking this quantity among the cincer free controls About 85 per cent of the patients with cancer in this series had been smoking for 30 years or more Over half the patients with the disease were chain smokers consuming 35 or more cigarettes daily as compared with only 19 per cent ch am smokers among the controls Breslow of the California Public Health Service curefully correlated smokers and non smokers in a very thorough study in which histories were taken by spucully trained investigators His conclusion Mis similar to that of Graham ind Wunder he found 2 consistent correlation between lung cancer and cigarette smoking Lung cancer can ind docs occur in non smokers but it is about two and a half times as frequent mong tho e who smoke cigarettes in significant amounts Opposition to the theon of the carcinogenic action of (igarettes depends to a great extent upon experimental work No carcinogen has been demonstrated in work with tobacco products Tobacco tar applied to the skin of mice has been of no effect Flory his produced papillom is with distillations of tobacco tor but they did not become cir cinomatous This negative evidence admittedly is not con clusive a substance which is carcinogenic for one species is frequently harmless for another Also inconclusive though interesting is the findig of Fried that studies of lungs of her smokers failed to reveal changes in bronchi pulmonary parenchymi that could be attributed to he rvy smoking Most imestigators particularly since the work of Hynder and Graham seem inclined to recept cigarette smoking as predilectmg to bronchogenic carcinom! Whether the carcinogen is one of the tars in such smole Or ·LUNG CANCER or arises from the burning paper, is not known It is also not certain that the agent, if any, is a true carcinogen It is possible that bronchogenic carcinomi ariscs as the re sult of an atypical and protracted reaction of the host to some normally harmless constitutent of the smoke Every doctor is familiar with the problem of the relation of smoking to chronic and non-specific ill health A certain percentage of such patients can be "cured' by withdrauing their cigarettes, others presenting themselves with very similar symptoms are not helped by such a with drawal It is tempting to see in the responses of the first group of patients something cry like an allergy It is further tempting to sce in them potential victims of bron chogenic carcinoma As numerous writers have pointed out, the dingnosis of this carcinoma is frequently compli cited by a long hustory of chronic and usually atypical lung disturb inces In our own experience, patients with bronchogenic carcinoma very frequently present a history compatible with a chronic and comparatively muld bron chual allergy, which in many instances seems to be due to the Irabitual use of tobacco Petroleum products. It may be that the lavish use of tar and petroleum Oils, so characteristic of modern culture, will finally prove to be more important in the genesis of bronchogenic carcinoma than smoking The agents most commonly suspected in this general indictment so far have been road dust containing tar, gasoline fumes and cihaust fumes from automobiles, and industrial fumes If they are proven to have carcinogenic properties, therr incre ising prevalence in the modern landscape would be sufficient without anything else, to account for the rapidly increasing incidence of pulmonary malignancy The basic experimental work with regard to these agents was that of Campbell, who clicited pulmonary tumors in 74 per cent of a group of mice exposed to road ·ETIOLOGY 25 dust contuming two to three per cent tar only 14 per cent of his controls developed the disease There is further somne clinical support for the theory Vountin and Dorn in public health survey in 1939 found a higher propos tron of bronchogenic carcinoma in urban dwellers than in ? similar age group of the rural population Public Health surveys consistently report substantial differences in incidence betucen industrial and rural areas Similar studies in England come to the same conclu sion with perhaps more authority since in these studies the influence of varying climatic conditions shifting popu Intion and differences in diagnostic frchtes is apparently at a minimum in the most recent of these studies that of I S Fulton covering the years 1941 to 1918 fond pro nounced difference between urhan incidence in Lucrpool and the rural incidence within a comparatively surround ing small are In the leavily industrial areas incidence 175 about 27 cases per 100 000 population in three rural ulers the figure was thiec cight ind 10 coses per 100 000 Fultou bekeved that these figures reflected i real and sub) stantial difference in incidence between the two groups Thurs difference in incidence very possibly results from rying degrees of exposure to ur cont uning petroleum products METABOLISM AND HEREDITY Although the relationship between exogenous agents ind the nitite constitution of the individual to date has proven to be almost impenetrable it is obvious that con stitutional factors are important Vany men mye spent long lates in the most carcinogenic of entironments-in the Schmelzorg mines for instance and died full of cars ind ibsoluteh free of any audence of bronchogenie ma lignincs It one time interest in the relationslup of malignancy ·26 LUNG CANCER to the native constitution of the individual centered on the theory of microscopic "cell rests” of embryonic tissite which remained quiescent into adult life, but which could become suddenly actue and malignant This theory has been generally abandoned as a comprehensive account of malignancy, but some clinicians would still see indifferentrated and/or adenocarcinoma as the product of such rests The difficulty is that such cell rests have neier licen demonstrated Further, most pathologists are doubtful of an etiologic theory which proposes a separate origin for the different lung cancer cell types, since most lung tu mors show a mixture of such cell types, and frequently all possible variations will be found in different parts of the samne turnor The present tendency is to see the important factor of "native constitution" as reflecting the complicated system of hormones and related substances which govern physiol og) The importance of such compounds in the genesis of carcinoma of certain tissues is well established To in stance one example out of many, it is well known that men who receive diethylstılbestrol over a long period of time are subject to a higher incidence of mammary carcinoma Although laboratory findings are not entirely consist. ent, in general it lias been found that the administration of sex hormones are apt to induce malignant growtlas only in scx-liormone conditioned areas It is possible that such tumors are somen hat exceptional in their genesis Tumors can sometimes be induced in other organs or areas of the body by the administration of hormones, but such grouths are commonly benign Lipsclutz, in his work with guinea pigs, found that peritoneal growths never progressed to malignancy in human beings, benign gronths seem generally to be more susceptible to malignant degeneration than normal tissue ·ETIOLOGY 27 Again, then, there seems to be a situation which can only be expluned in terms of two factors cooperating to producc malignancy The hormonal factor would seem to be overwhelmingly important in the genesis of tumors of the sex-conditioned areas-mammary, testicular, prasa tato tumors, and so forth But such a factor is also very clcarly indicated in tumors of other parts of the body, although the effect of this hormonal factor sccms to le secondary to that of the erogenous carcinogen Age and ser predilections are convincing cudence of the influence of hormones upon the genesis of bronchogenic carcinom (Figure 1) 340 300 250 200 MALLS FEMALES 50 NO 10 Figure 1 20 so SO- 40 $0 $0 0 40 70 70-00 20-90 90 100 4ge under distribution of 1070 patients with henching ek CA This predilection for age groups above 40 us oull scem almost certainly to indicate a general physiological conclı tion as a prerequisite for the disease The overwhelming proportion of men among the patients with bronchogenic carcinom i points the same direction It seems most un hich that cigarettes or other specrilized environmental ·28 LUNG CANCER influences can account for a 9 1 ser ratio, although they may influence it At least as important as this statistical evidence is the long interval that is frequently encountered between er posure to a known carcinogen and the development of the pulmonary malignancy In many of the cases found among the Schneeberg-Jachymov miners, the disease de veloped from six to nine years after retirement A sinular situation exsts among cigarette smokers, malignancy not infrequently appears some years after smoking has been discontinued It is possible that this interval represents ? delayed reaction to the carcinogen, it may be that the ap pearance of the malignancy can be delayed for years after the process is initia Thus explanation is, however, the least bhely one, it is far more reasonable to assume that the process initiated by the carcinogen requires a particu la loimonal substrata for the development of malig nancy Although no specific bodily substance has even been suggested as critical to the genesis of bronchogenic circinom clinical evidence, supported by experimental and statistical findings, miles it probable that some sich sulistance exists IIcredity. Whether or not heredity is an important factor in the genesis of bronchogenic carcinoma would seem to be at this time a secondary problem Unless the embryonic cell rest thesis is established, wluch scems in prolable heredity is not apt to become the critical prob lem to lung cancer etiology Although laboratory work on this subject is of interest, it is not conclusive It is well known that struns of mice ai e been bred which will predictably develop bronchogenic circinoma almost 103 per cent of the time This does not proie that bronchil mulignancy is a hereditary disease, as the latter term is usually defined If the etiology of lung cancer inches a dynamic relationship between host and carcinogenic ·29 ETIOLOGY agent as much clımcal and experimental work suggests It need not occasion surprise that hosts can be de eloped which virtually eliminate the necessity for an exogenous agent The general view is not contradicted by such a finding Experimental work on this subject is dependent then upon an understanding of the relationship of the host to the tumor-a subject which as has been said is admittedly not understood Further the clinical approach that seems open at the present time has been largely unexplored The few studies that have been attempted so far on possible differences in racial susceptibility have been insufficiently controlled The earlier impression that bronchogenic can cer was a characteristic of civilized races has been denied by French workers in North Africa There have been to our know ledge no statistics from Asiatic nations which might be compted to Euopein or American statistics with any confidence There is some important but inconclusne endence that in the Umted States the egro is perhaps somewhat less susceptible to bronchogenic carcinoma than the Cou casian Ochsner found the ratio of white to Negro patients admitted to len Orle ins Charity Hospital for cancer of the stomach to be about 23 similar to the all idmission ratio But the ratio was about 2 1 for bronchogeme air cinom Arkin ind Wagner found a simiar picture at Cook County Hospital with Vegrocs ccounting for 30 per cent of all admissions and only 9 per cent of jl ases of bronchogenic circinomi The difficulty with such studies is that they are not able to take into account the dignosis en ironmental and longevity differences that perhaps exist between the two rices it seems possible that there is a substant difference between the rices in susceptibility to bronchogenic circinombut very carefull controlled and evalunted studies are necessın to ·30 LUNG CANCEL prove these differences The same conclusion must apply to our own finding, follow mg Steiner, of a pronouncedly different ser-ratio bets cen sluite and Mevcan palıçnts, the latter showing about three males to two females with tlus discasc as compared to the 8 ) sex ratio for the whole series nona It must be emplasized that these findings are really inconclusite, the suggestion that liercdits is an important factor is the disease cannot be discarded on the basis of our present eudence Strong hereditary factors are thought to be operatue in other forms of neoplasms, particularly scrolerma pigmentosıtm, neuroblastoma of the retma and multiple polyposis of the colon, and hered. tary factors may well be operatue in bronchogenic carcimay further be pomted out that of heredity is established so firmly as to be significant to such diagnosis, the licreditary factor can be expected to be qmte specsfic It » uphely that a familial history of other forms of malignancy will ever be of especial sigmficance in the diagnosis of lung cancer No review of the ctiology of bronchogenic circinoma can be definitive Our information simply does not add up to a colerent system that can be neatly summarizeti Almost every major finding can be confronted with an othei experiment, or another chical obsersation, which seems to suggest a contradictory conclusion Most sarh. edh, in bronchogenic carcinoma there is considerab'e dilficulty in adjusting clinical to experimental evidence, and esther kind of information, when unsupported by the other, lacks authority It seems most likely that bronchogeme carcinoma is the product of two more or less independent series of escnts The process appears to begin with an irreversible alteration of structure is a cell or a group of cells The possibility that chronic irritation can, by itself, lead to ·ETIOLOCY 31 such an alteration must be lept in mind but this has not been established clinicall it a certain that particular ngents can and do accomplish this transformation by direct action upon cell structure these agents are circino gens whatever their specihe nature it has been proien that there are many such carcinogens in nature investi gitors generith assume that thei operate m essentanth the sime niunner Tht second condition required for the development of loronchogenic circinoma seems to be the weakening or clininition of the intracellul ir mechanisms of the area or of the whole orginism which limit grouth of units of culls to a functioning relationship with the iest of the organum The long mensal that is frequently soted le tween exposure to known carcinogen and the develop ment of a tumor is to ou mind or crwhelming adence that the human organism is usually ihle to mhibit the growth of abnormal cells It concen able of course that the cell mutation dk piends tipon the teresi hormoni suliserata for its accom plishment but it is dificult to see how i carcinogenic action could rem un potent il for long 1cus except by in stre dy altered cell Tlus is in re I shere there is little direct evidence to support any theory but it seems most reasonable to assume that the circinogen omplishers the cell alteration shortly after exposure the development of the frik mulignancy they must nu ut the desclopment of a suitable environment It is known that inicroscopic Cersscal miligumces can be quescent lor vents and pro static cancers inpirently line the same property These choc il findmgs may pustify the assumption that i similar situation eusts in the case of bronchogenic circinom i It is necessirt to modify even so generala description hy recognizing igin that these transforutations are not absolute but relatne rien within such in apparently ·32 LUNG CANCER distinct and comparatı ely homogeneous form of malig Dancy as bronchogenic carcinoma, it is obylous that these two processes do not bear a consistent relationship to each othier or the malignant growth Where the diseise occurs in children, it seems that the dominant consideration is the hormonal one In other individual mstances the clmician frequently gets the impression that there is no natre resistance to the growth In radiation exposure, on the other hand, the exogenous, carcinogenic factor is obviously dominant Perhaps in all cases, both factors are in play, but they do not have a consistent relationship to one another This is hardly an exact etiological description of bron chogenic carcinoma, since ei en so much lean es evidence out of account Nevertheless, we are accumulating facts, and from these facts we are able to build hypotheses in the way that has been so fruitful for the sciences gencrally Much remains to be learned, but moderate optı mism is not out of place We are making progress toward an understanding of the disease ·Histopathology 2 At least some of the obscurity in which the etiology of bronchogenic carcinoma is currently hidden results from our imperfect understanding of the lastopathology of the diserse Few tumors are so markedly pleomorphic as those found in the lung Not only does microscopic appearance vary widely from one tumor of the lung to another but also equally wide variation is very often observed within a single tumor In spite of this inconsistency however morphologic studies would seem to be of real importance Even though the morphologic distinction between lung tumors is imprecise it is usually possible to describe the individual tumor in terms of a predominant cell type In statistical studies of casc histories in wluch such mor phologic distinctions Inve been attempted the findings suggest that the picdominant cell type possibly reflects an ctiologic situation distinct from that of other cell types There are sex and perhaps age predilection differences between one cell type and another Such cell types scem also to affect tumor location tumor beliviour and prog nosis At the present time we do not have sufficient informa tion available to evaluate these differences authoritatively The conclusions derived from collections of case histories are tentative because the individual casc histories are so often inadequate in regard to histologic structure Death (33) ·LUNG CANCER 34 certificates should include more exact information, includ ing predominant cell type and primary location whenever these facts are available Every tumor case coming to autopsy should be carefully analyzed in terms of its mor phology, with particular attention to the cell type at the point of origin This is a responsibility of the entire pro fession А prior necessity to improved reporting of lung cancer cases is a morphologic classification for these lung tumors which will be etiologically and clinically significant and casıly determinable histologically Such a classification seems to be at hand Most students are now willing to accept a thrce fold division of the bronchial tree malg nancics into squamous cu a, adenocarcinoma and undifferentiated carcinoma The distinction of squamous cell carcinoma from the other two types seems to be ac cepted generally, but it has been denied that there is a significant distinction between adenocarcinoma and un differentiated carcinoma Womack and Graham have for a long time denied the significance of such a division, and most recently, Reinhoff did not attempt to separate the two cell types On the other hand, most workers feel that there is a striking difference in the microscopic appear. ance between the two classifications Adenocarcinoma and mixed cell types are perhaps found in conjunction more often than either is found with squamous carcinoma, but this is not a marhed tendency Further, there seems to be a significant statistical distinction between the two cell forms most studies The opposition to their separation seems to arise, to some extent at least, from etiologic theory Womack and Graham believe that squamous cell carcinoma is pro duced by exposure to carcinogens, and that other com mon lung tumors arise from fetal buds in the broncht (Chapter I) The distinction between adenocarcinoma ·35 JUISTOPATHOLOCY and undifferentiated carcinoma may prove in time to be an artificial one but clinical cridence cannot be or ganized to suit etiologic theory In our judgment there is sufficient evidence to justify the distinction between adenocarcinoma and undifferentiated carcinoma Other classifications have been suggested from time to time At the beginning of the century most lung can cers were reported as sarcomas Although these tumors were actually carcinomas a bronchogenic sarcoma is not an impossibility Blick in 7 survey of literature on the subject found sır substantnted instances of sarcoma al ready reported and added one more The malignancy is characterized by exceptionally slow growth usually in and around the bronch by Iate and limited metastasis and by marked sensitivity to roentgen ry therapy There is also possibly a distinct alveolar cancer Smith Knutson and Watson have recently reported 20 cases which they described as Terminal Bronchiolar or Alveolar Cell Cancer of the Lung They found the tumor distingushed by a malignant epithelial lining of the ah coli without pronounced bronchial invoh ement The difficulty 15 in establishing an origin for such a growth Viller did not find in epithel al lining in normal bronch Fried be lieved there was such a lining Even if Tried is right however one cannot assume that these presumably fully des eloped cells have the possibility of malignant trans formation Many students believe that the theol ir cell circinoma is actually in atypical de elopment of the squa mous cell PATHOLOGIC CLASSIFICATION Lung cancers cannot ordinarily be distinguushed one from another on the basis of their gross appearance These tumors tend to be hard and grinular and white gray or pink in cross section Squamous cell carcinoma is more

·40
LUNG CANCER
EARLY ASPECTS OF MALIGNANCY
Each of the common forms of bronchogenic carcı
noma has a readily apparent relationship to normal tissue
of the trachea and the bronchi According to Viller, there
are four distinct cell groups to be considered in the tra
chcobronchinl tiec These are the basıl cells, situated juist
Figure 5

·HISTOI ATTIOLOGI above the basement membrane the intermediate cells lying on top of the basal cells ciliated epithelial cells whuch constitute the lining of the structure ind mucous producmg goblet cells which we found interspersed among the clated cells As the bronchi approrch the terminal alveol the goblet cells gradually disappear and the ciliated cells lose their cila without any other major modification of cell structure These four normal cell types are i microscopic yppearance on jously related to the malignant transformation of the normal cells which they resembled It is most unlikely however that the fully developed goblet or the ciliated epithelial cells have the potentiality of further development which would make them capable of duision Instead pathologists generally regard the multi potential basal cell as the origin of all new growth in the bronchi normal or malignant Thus these common forms of lung malignancy would be the result of an abberation basically the same in all instances but in oh ing minor differences affecting the rate of cell division and so forth There could readily be in such ? situation different forms of mulignancy with different chnical and morphological characteristics but these dis tinctions would not of necessity be sharp ones There re mains the possibility of course that one form of cancer or mother arises from embryonic rests as mentioned in Chapter 1 Eudence concerning the beginning of malignancy in the human lung is nitorills scint In a series of routine Inn, sections Petersen Ilunter and Snceden found five minute grou this wluch they regarded as definitely circı non tous Further studies were inconclusive with regard to such major questions is the origin of malign inc) Per haps the most significant observation of these workers is that four of these five growths were found in con junction with bronchiect isis and fibrosis Autopsy reports ·42 LUNG CANCER on small tumors have been made in sufficient numbers to suggest that, if pulmonary malignancy does not originate in areas of metaplasia, it begins with an aberrant meta plastic piling up of the epithelium Experiments with laboratory animals have been inconclusive with regard to the beginnings of a tumor The complexity of the modern view of cancer growth has been discussed in the first chapter, practically all of the original theories have had to be abandoned for highly qualified concepts There has likewise been some modifi cation of our basic definition of malignancy as autonomous and irreversible growth Because clinically-observed can cers were characterized by steady enlargement, it was assumed that malign'ıncy was a process which, once in tinted, proceeded without delay and irreversibly to the destruction of the host However, it has been discovered that even large tumors are sometimes dependent upon the maintenance of a certain hormonal substrata for con tinued development, prostate tumors can be arrested for long periods of time, although not permanently, by the administration of female sex hormones More spectacular is the recent report of the arrest of an ulceratie carcinoma of the bladder by the inactivation of that organ This situation of dependency by a seemingly-mature tumor on a particular hormone balance is not, to our knowledge, paralleled in the instance of bronchogenic carcinoma However, these instances prove that the complete autonomy once attributed to malignancy is unsupported by the present findings More important to the study of lung cancer is the ob servation that, in certain organs, microscopically visible clusters of cells which have all the histologic criteria of malignancy can remain in situ for long periods of apparen! inactivity, although classical tumors usually develop at these sites in time It would seem that malignancy is not ·43 JIISTOPATIJOLOGY ? consistently steady development and very early mulig nancies do not necessarily follow the pattern devised for larger growths It would be a mistake to assume a latent period for bronchogenic carcinoma merely by analogy with other types of malignancy On the other hand we cannot as sume that such a situation does not exist In cytologic studies we have found some reason to suspect that there may be a distinctie early phase of the disease wluch is characterized by the production of an enormous number of free cancer cells without a proportionate development of the tumor body A tumor at the carina of a patient which was so small that it was not found during the first two bronchoscopies was proven by cytologic studies to be exfoliatmg countless free cells into the bronchial secre tions Thus fir there is not enough evdence to speak with assurance but it is at least possible that bronchogenic carcinoma undergols a stage of development shorth after its mception characterized by rigorous cell produc ion in which these malignant cells are not organized into tumor body The case histories which we collected from nearly institutions did not lend themsehes to analysis regardmg a Very important aspect of lustopathology-the relation of cell type to typical development llou eier in generali sufficient number of studies of this subject have been made to confirm the common clinical observations on the disease Gebauer ind Koletsky have erchi inalyzed col lections of case histories to this end Squamous cell carcinoma It is apparent that squa mous cell carcinom i has its origin approximately 70 to 80 per cent of the time in one of the primary branches of the bronchni tret at or very near a bifurcation although in isolated instances it may originate in the neighborhood of the tracher Presumably ut bugins in the layer of basal ·LUNG CANCER cells in the bronchus and its growth is primarily extra bronchal, into the parenchyma, around a smaller bron chus Squamous cell carcinoma usually interferes with the functioning of the affected lobe by constricting, rather than by filling, the bronchus In its intrabronchial develop ment it seems especially Jable to erosion, consequently, it may produce distinctive clinical symptoms early in its course The tumor body itself, in the parenchyma, is some what more likely to undergo necrosis and cautation than other types of bronchogenic carcinoma, probably because of an inadequate blood supply Although statistical findings have only a limited applı cation in clinical practice, it is worth noting that squr mous cell carcinoma is generally much slower to metast 1 size than other types Such metastasis, when it occurs is usually via the bloodstream, with perhaps a predilection for cerebral metastases The aversion of squamous cell carcinoma to the lymphatic system is oftentimes marked It is not unusual to find at autopsy that this growth has actually detoured around a lymph node On the other hand, it is ruthlessly invasie of non lymphatic contiguous structures, and often becomes inoperable by reason of its penetration into the pleura The so called “Pancoast su perior sulcus tumor,' with its early and punful extension into non-pulmonary structures, is usually a squamous cell tumor of an upper lobe Adenocarcinoma. This form of malignancy generally begins farther out in the lung than does squamous cell Gebauer found that 70 per cent of these growths originated in secondary brunches of the tracheo bronchial tree, and another 20 per cent in the smaller branch bronchi Much more of the tumor body is endo bronchially located than is characteristic of the other pul monary malignancies It frequently penetrates the bron carcinoma ·JITSTOI ATSIOLOGI chuai lumen eurly in its course and by this growth it may occlude the bronchus wlule still quite small The enlarge ment of the endobronchial growth is generally toward the trachea On rare occasions a small adenocarcmoma may seem to be entirely intra bronchial In most instances however the intrabronchal growth will be accompanied by the extension of the tumor into the parenchyma from wluch it is usually delimited rather slurply Roentgenolog ically or at autopsy an adenocarcinoma sometimes ap pears as two parts thinly joined through the point of origin Adenocarcinom is are not particularly fast growing as malignancies go but they may met ist isize widely quite erly in their course Lymphatic sprend is particularl notable such metastases may appear as a series of con nccted tumors at avtop Not infrequently the carinal lymph node metastases exceed the original growth in size Blood streum metastases are also common These malignancies also insade blood vessels more readily than any other pulmonary growth A squimous cull carcinomi is apt to produce blood streahcd sputum because of its mucos al erosion adenocarcmomis may also produce such blood streaked sputum but one frequently encounters episodes of frank lemoptysis is the tumor m vades small blood vessels Pulmonary hemorrlage may be the immediate cause of death of larger vessels are attached Undulferentiated carcinoma Over one half and per haps three quarters of 21) round cell ort cull and spindle cell circmomis originate m a m un stem bronchus Vost of the remainder begin in 1 secondary bronchus although they have been reported in a peripheral location This cell type would seem to have a predilection for the right lung and for upper lobes Grouth is predominantly extrabronchial as with sun ·46 LUNG CANCER mous carcinom but undifferentiated carcinomz has a notorious predilection for ini ane growth into the medi astmum fixing and distorting the bronchial tree and choking the vital structures in that area The tumor is one of the most nonselective of common malignancies However it does not readily occlude the bronchus of origin and on occasion it may be seen to extend for long distances within the bronchial structures without pene trating the lunien Atelectasis is therefore uncommon Although one encounters exceptional cases in gen eral undifferentiated carcinoma may be safely asserted to be the most rapidly growing tumor of the bronchial tree and it runs the shortest course Its growth within the Jung is usually along the bronchus of origin but it is also uregularly infiltrative into adjacent parenchyma and may extend into the pleur? Undifferentiated carcinoma like adenocarcinoma has ? pronouced affinity for the lymphatic system It is some times seen to follow lymphatic channels in its spread and it also tends to metastasize widely through the lympha system Adjacent lymph nodes are almost always in volved and secondary lymphatic involvement may be so extensive as to obliterate normal lymph node structure ind over shadow, both roentgenologically and clinically the site of origin Lymph node metastasis may be more extensive in undifferentiated carcinoma than in adenocarcinoma we feel that the gross abdominal node and cervical node involvement is seen someu hat more fre quently in the former In addition undifferentiated carcinoma is very apt to metastasize via the blood stream In the series of cases reported by Koletsky almost half the patients wath un differentiated carcinoma were found at autopsy to have secondary grou ths in tlie liver and the adrenals with the pancreas providing the next most common site ·HISTOPATHOLOGY 47 THE SIGNIFICANCE OF PATHOLOGIC CLASSIFICATION The corrclation of cell type with clinical behavior is a Sery tentatne procedure It must be emphasized that we have no reason to expect that there will ever by any kind of dependable, one-to-one relationship between these two aspects of bronchogenic carcinoma Our object is to determine the predilection of a particular morphologic type for a certain kind of clinical behavior The results may prove to be of more service to the study of etiology than in clinical prognosis Furthermore, the information relating to this subject which has been reported so far is probably more than a few percentage points from the true situation To repeat what was said at the beginning of this chapter, the con fusion surrounding the subject arise from two causes (1) Students are not in complete agreement as to proper classification, so that the same tumor might be differently described by competent pathologists, and (2) the pams taling autopsy studies necessary for correlation with clinical findings are feu The difficulties involi ed are apparent when statistical studies are examined The basic test for these studies is the percentage of cach morphologic form in total inci dence There should be some kind of correlation between different studies on this basic question, there is not in such studies, squamous cell carcinoma has been reported as comprising from 5 to 65 per cent of total incidencea disheartening range in our own study of 1070 autop sies, it was necessary to depend upon the sitten reports of pathologists (Figure 6) In this series about 40 per cent of the tumors which were classified were squamous cell carcinomas It was apparent from these st ports, hou. cier, that too frequently the pathologists descriptions were based upon few sections Furthermore, the percent.

·48 LUNG CANCER age of tumors which were unclassifiable on the basis of these reports casts some doubt on the findings where class fication was possible In view of these difficulties, it scems best to summarize some common obervations with out pretending to a misleading exactness EPIDERMOID 317 PATIENTS 34 5% UNDIFFERENTIATED 294 PATIENTS 274% ADENOCARCINOMA 238 PATIENTS 222% UNKNOWN 167 PATIENTS 156% 0 200 300 400 100 Figure 6 Distribution of cell type in 1070 autopsıcd pitients with bronchogenic Ca One thing is clear, squamous cell carcinoma is the most common malignancy of the lung Our own figure of about 40 per cent probably represents its minimum incidence, it may comprise as high as 65 to 75 per cent of all primary tumors of the lung Squamous cell carcinoma is also primarily a disease of the male sex The proportion is perhaps 10 to 1 or higher The sex frequency of undiffer entiated cell carcinoma is uncertain, since published reports on this subject vary widely It probably does not have the degree of male sex predilection that squamous cell carcinoma hus, but it would seem to be more common in the male ser than in the female Adenocarcinoma on the other hand, is probably the most common form of lung tumor among females, who make up perhaps half of the total incidence of that cell type There would also seem to be a considerable difference in the average age at which the three forms become manifest Squimous cell carcinoma is overwhelmingly a dis ease of the elderly, although rarely it may occur in child ren Adenocarcinoma shows a mean age of from 35 to ·49 IIISTOPATITOLOGY 40 perhaps some 15 years less than the average age for squamous carcinoma Undifferentiated carcinoma shows a mean age range similar to that of adenocarcinoma Again conclusions must be tentatue but it seems that adenocarcinoma and undifferentiated carcinoma together are the most common forms of lung malignancy below the age of forty but that over the age of 45 squamous cell carcinoma is by far the most prevalent It should be pointed out that where etiologic agents have been estab lished for lung malignancy the malignincy is almost in variably epidermoid ASSOCIATED PATHOLOGY Most of the pulmonary pathology associated with bronchogenic carcinomi can be attributed directly or indirectly to bronchial obstruction Itelectasis is the most prominent secondary development in adenocarcinoma and epidermoid tumors The extent of such atelectasis will of course depend upon the location of the growth With adenocarcinoma the tendency of the intra bronchial por tion of the tumor to move upward toward the lulus produces at times condition in wluch the art 1 of telec tasis is seen roentgenologically to enlarge gradually Squimous cell carcinoma usually produces atelectasis ly constructing and eroding the bronchus exteriorly until it collapses Where 1 mujor bronchus is occluded the conse quent massie telectasis may produce compensatory cmphysema contrifter illy Atelectasis as followed sooner or later by infection since bacteria can multiply without landrance in the secrelions wluch are backed up behind the obstruction In our experience the beginnmg of such an infectious phase is often acute and resembles a mild pneumonia in its symptomology After the acute episode passes the infection usualls progresses into a chronic suppur ifte ·50 LUNG CANCER condition resembling bronchiectasis Eventually the in fection may proceed to widespread necrosis and abscess formation Abscess and cavitation may also occur within the body of the tumor itself, especially if the growth is a low-grade squamous cell carcinoma Any abscess has of course, the possibility of rupturing into the pleura and producing an emphysema Prior to the development of this process of atelectasis and infection, an intermediate process is sometimes seen roentgenologically As long as the occlusion of the bron chus by the tumor is somewhat less than complete, a oneway sake condition may develop, producing a tem porary emphysema in the parenchyma distal to the tumor body This is particularly apt to occur when the tumor is an adenocarcinoma Even when a growth does not occlude a bronchus, some degree of infection is probably always a secondary development Erosion of the growth through the lumen of the bronchus produces a condition favoring infection Very often there is also a certain amount of infection in the parenchyma surrounding the tumor body extenor to the bronchus Even when atelectasis is not a factor, this pirenchymnal infection may at times be considerable The extensive areas of infection frequently observed in un differentiated carcinoma, as determined by roentgenologic studies before and after a course of antibiotics, might suggest that there is some correlation between the amount of secondary infection (not dependent upon atelectasis) and the degree of invasiveness the tumor body manifests Out side of associated infection, the secondary pathol ogy attendent upon a primary lung tumor is atypical and bizarre Location of the tumor body is of course, critical to future developments There seems to be some relation ship between metastatic sites and their frequency and the morphologic type of the primary growth, but it is by no ·51 HISTOPATHOLOGY means a clear-cut relationship The table below listing these sites merely emphasizes the many possibilities In the erperience of the author, in many cases of inoperable bronchogenic carcinoma, life expectancy appears to depend upon factors in the relationship between the new growth and the host that are entirely unknown Some patients tolerate an enormous amount of neoplastic tissue without an excessive loss of strength, and survive until there is interference with a vital function Other patients respond very strongly to comparatively confined grow this, and death seems to come about by an unknown form of toxicity Clinically, one frequently obser es cases of early malignancy in which fatigue, loss of weight and other general symptoms are out of all proportion to any concea. able direct effect of the tumor ·Clinical Features 3 At least a majority of all patients with bronchogenic car cinoma are theoretically still amenable to surgery after the onset of symptoms Nevertheless, our actual operatne rate does not approach 10 per cent The difference be tween the theoretical rate of cure and the actual aclueve ment is the measure of our failure to diagnose the disease promptly In the last 15 years-the period in which thor acic surgery has become a feasible and practical pro cedurc-there has been no measurable improvement in diagnosis at all In our study, the inter al between the onset of symptoms and hospital entry has remained ap proximately the same, ay craging about 22 5 wechs Lind slog, Overholt, and Schmidt have described similar findings in recent studies There has been a great improve ment in diagnostic facilities and techniques during thus period, but the application of these techniques has been ineffective There are two distinct intervals involied in this delay There is inevitably a period between onset of symptoms and the appearance of the patient before the physician There is a further interval before a proper diagnosis is made The reduction of the first inter al, between the onset of symptoms and the first medical examination depends upon education of the public The layman must be trained to have a serious regard for minor chest symptoms (52] ·CLNICAL FEATURES 53 (without educating him to hypochondria) and preferably, to periodic physical examinations To date we have depended upon carefully organized campaigns by cancer control groups to accomplish this indoctrination So far as bronchogenic carcinoma is concerned, these campaigns have probably been without demonstrable effect The pa tient continues to procrastinate and neglect chest symp toms Such campaigns must be continued, since they are our only means of reaching a large proportion of the population, but we cannot expect that they will be of much benefit except over a long period of time On the other hand, it seems probnble that the personal influence of the individual physician, exerted over the widest possi ble area, would be able to cffcct a substantial improic ment in the percentage of bronchogenic carcinomas subject to crcision when diagnosis is mide, and that Ius influence would operate much more quickly and directly The reduction of the second interval, between presen tation and diagnosis, is one of the primary problems of contemporary medicine (Figure 7) It is often assumed, however, that the solution is again one of simple education, that we can bring about early diagnosis simply Ivy stimulating the medical profession to an increased aware ness of the disease This is evidently not true The clinical aspects of bronchogenic carcinoma have been the subject of writing and discussion for many years without concrete effect It must be recognized that the problem is one of complexity for every patient who presents himself to the physician with cough, moderate wheeze, some maluse or dyspnea, saguc chest pains-that is, with the early symptoms of bronchogenic circinomu-thiere are hundreds who present themselves with a similar group of com punts u huch can be traced to minor respiratory infection or to no detectable organic difficulty Further, this large group of patients who seek medical attention cluely for

·54
LUNG CANCER
30
25
20
WEEKS
15
ONSET
D TO ENTAY
ENTRY TO
DIAGNOSIS
10
Wh
o
1935 36 37 38 39 40 41 42 43 44 45 46 W7 48 49
Figure 7 Teme inter al between onset of symptoms and hospital entry
(interrupted Ime) and between hospital entry and time of dignosis
(solid line) from 1935 to 1919
reassurance is drawn in large measure from the same age
group in which carcinoma is most apt to occur That the
physician is reluctant to advise an extensive course of
roentgenologic and other diagnostic studies for the major
ity of his patients is understandable, and there is little to
be accomplished by insisting upon the absolute signifi
cance of minor symptoms
An increased awareness of the problem is of course
necessary Every patient with minor chest complaints
not immediately traceable to a known cause must be con

·CLINICAL FEATUTIES 55 sidered, briefly at least, potentially carcinomatous But the question asked in such instances must be rephrased The question is not, "Are these the symptoms of bronchogenic carcinoma?" but, "Could a malignant process in the bronchus conceivably give rise to these appearances?" Further, it must be recognized that modern diagnostic techniques cannot, in this situation, replace traditional arts The thorough physical examination is a necessity, and symptoms must be evaluated m terms of a carcfully taken history The physician's insight into the patient's problems must in many instances continue to determine his attitude toward the patient's symptoms The difficulties in the diagnosis of bronchogenic carcinoma arise from the fact that there is not, even in a broad sense, a symptom complex which can be regarded as typical of the disease The primarv pathology has its origin m an area in which much silent growth is possible As a consequence, most symptoms and signs are more or less secondary in nature, and their relationship to the tumor is eccentric Thus applies to respiratory symptoms, as well as to symptoms of a systemic nature and to those of extension or metastasis (rigure 8) Respiratory symptoms Interest naturally focuses on the common respiratory symptoms, since they do not preclude operability However, such symptoms are not in variably found in bronchogente carcinoma In our series, approximately 15 per cent of the 1,070 patients did not hrie, upon entry into the hospital, distinct bronchini symptoms The symptoms wluch led these patients to seck medical attention were those due to metastasis Further. more, a substantial proportion of the remaining 85 per had compl unts that were predominantly those of mctastasis minor chest symptoms were discovered only modentally when the pitients were criminel Thus group of patients, which probibly comprises betucen 25 and 35 cer ·56 LUNG CANCER 85% 67% RESP SYMP. COUGH CHEST PAIN DYSPNEA HEMOPTYSIS DYSPHAGIA 57. 43%. 427. 33%. 61% GEN SYMP WT LOSS WEAKNESS ANOREXIA DIGESTIVE DISTURBANCE 42 49% 36% 167. 34% METAST SYMP CNS COMPLAINTS 16%. ABD. PAIN 1% MASS 7% BACK PAINOX O 100 200 300 400 500 600 700 800 900 Figure 8 Symptomatology in 1036 autopsied patients with bronchogenic carcinoma per cent of the total incidence of bronchogenic carcinoma, are from the beginning, hopeless, so long as we must de pend upon surgery Cough and sputum. In our s. ive cough, attributable to the pulmonary found in 67 per cent of all ble with most that there was ch. considerably chogenic carcir, > (see Ft TC comp Prren Nei 1 ·CLINICAL FEATURES 57 mificant degree of intrabronchual growth will almost invariably produce cough Such a symptom may be the errliest to appear, and may persist throughout the course of the disease The tumor, even when quite small, acts as a foreign body within the bronchus of origin Unless the grouth is peripheral, a cough will develop which represents the natural effort of the protectie mechanism to espel the obstruction Such a cough is frequently distinguished from the chronic 'lack" which is characteristic of the present-day adult population by a distinctly parorysmal character When it first appears it is customarily ignored, and is most apt to be noted in retrospect Lien a small intrabronchial tumor will obstruct the drainage of bronchial secretions If the tumor is peri pheral cough may be productive from its first appearance Initially, the sputum raised is often described as gray and micoid Very slıortly after secretions begin to collect, however some degree of infection is likely to develop It is our observation that the development of an infection is apt to be intinted by 1 mildly acute inflammatory process, winch the patient describes in retrospect as "flu" Perhaps the most diagnostic early symptom of bron chogenic carcinoma is a productie cough which is al). normally persistent We have seen miny patients who first come to our attention because of an acute respiratory in frction which failed to clear after the initial episode At other times malignancy will be suggested by remission und recurrence a series of “pneumonias" Vany more cases of bronchogenic carcinomu would be operable at diagnosis of time were not lost with repeated courses of antılyotic therapy in these instances With the des clopment of infection the sputum be comes mucopurulent Unless the progress of the infection is impeded by the use of chemotherapy, such spritum will ·LUNG CANCER 58 become frankly purulent in time and it will usually be copious If the tumor progresses to bronchial obstruction cough and sputum may disappear completely for a time but case histories suggest that there are frequent periods of temporary patency when a bronchus is occluded by tumor in which purulent sputum is raised copiously Chest pain In our series chest pain was found to be the second most common respiratory symptom occurring in 43 per cent of 1 070 patients Ariel and his co workers in 7 series of 1009 patients found this chest pain to be the symptom which led the patient to seek medical atten tion in 276 instances it was the most frequent presenting symptom in their series Frequently one sees the pain accompanying broncho genic carcinoma described as intense This probably re flects the advanced stage at which the disease commonly is diagnosed In our own practice we have noticed that in the earlier stages of the disease there is frequently chest pain but it is not severe The majority of our patients who have reported such a symptom have described it in mod erate terms as an annoyance rather than a major dis comfort It was most frequently described as a persistent aching unrelated to respiratory movement although not especially severe it was so notably persistent is to be oppressive This type of pain does not necessarily suggest inoperable extension it appears to be due to local com pression of the bronchus with consequent ulceration and bronchial spasm It may also result from invasion of puł monary blood vessels There may be at some stage in the development of the disease a typical pleuritic pain for a short period This may persist until a pleural effusion develops Such pain is not necessarily indicative of pleural inyol ement Severe chest pain frequently occurs in advanced stages of the disease the patient describes it as sharp and knife ·CLINICAL FEATURES 59 like and the physician finds it difficult to alleviate Such an occurrence generally suggests extri pulmonary in olie ment either of the pleura the chest wall or the mediasta mum Vediastinal involvement is suggested by sharp pain referred to the back We have also observed a ridicular type of pain which autopsy studies suggested was the re sult of nen e root molement in the posterior medi astı מונות In a consideration of the clinical aspects of broncho genic carcinoma it is important to remember that some hind of chest pain will be found almost half of the time and that such pain docs not necessarily indicate that the growth is inoperable it is less important to attempt 1 classification of the forms that such chest pun can take Dyspnca In our study we found dyspnca to be as common a symptom of bronchogenic carcinoma as chest pain This condition is due to mnadequate orygenation of the blood and suggests non functioning lung tissue In general this symptom was neither prominent nor scucre At least one third of the normal lung ciprcity is reserve and the body is consequently able to tolerate 1 more or less massi e collapse of lung tissue of the process is gradual enough to permit adjustment Ilowever there is no con sistent correlation between the degree of dyspnca and thic amount of lung tissue imoled lle have observed a num ber of patients in u hom dispnea 1.25 present even though the malignant growth is small and uncomplicated st is probable that the dei clopment of ch spnet is more com plicated than our present understanding of the condition takes into account Occasionally a sestre attack of dyspnea de claps in conjunction with bronchogente carcinom. Such a symp tom implies that 1 lirge imount of tissue his Icon with drzwn rather stiddenly from the total vital cipicity of the lung Thus may come about because of the development ·60 LUNG CANCER of a massive pleural effusion, or it may herald the onset of lobar pneumonia Where severe dyspnea dei elops with out evidence of pneumonia or pleural effusion it is pre sumed that an extra bronchial growth has constricted a major bronchus Hemoptysis. This is another symptom from which un warranted conclusions concerning operability are some times drawn It may appear as occasional expectoration of small amounts of bright red blood frank hemorrhage, or blood-streaked sputum The last type of hemoptysis is by far the most common It is occasioned by ulceration and infection of the bronchial mucosa or the intrabron chial portion of the tumor It is a common finding in squa mous cell carcinoma, it is much less common in the other types of bronchogenic carcinoma, which do not erode the mucos? It may be present at all stages of the squamous cell carcinoma, and it is not infrequently the presenting symptom This tendency is partially responsible for the more favorable prognosis of this type of tumor, bloods sputum is not likely to be neglected for long and there is a greater chance for evly diagnosis Hemoptysis occurred in 35 per cent of our patients and at least three fourths of the time it was reported 15 blood-streaked sputum When pure blood is expectorated it suggests an undifferentiated carcinoma or, even more lhely an adenocarcinoma Squamous cell carcinoma las a marhed aversion to blood vessels, the other types do not General symptoms. The relationship of non specific systemic findings to bronchogenic carcinoma is not always clear Most commonly observed are weight loss weil ness, anorexia chronic fatigue and noctridosis, they can be roughly duuded into symptoms of sepsis and loss of strength These are, of course, characteristic of the ad vanced stages of the disease on the other hand, they are not in themselves evidence for any such conclusion ·CLI\ICAL FEATURES 61 Fever and sepsis The interest in general symptoms is duc in part to the growing realization that careful atten tion to such developments i patients over 40 can con tnbute to early diagnosis of bronchogense carcinoma is more and more commonly recogmzed that some lung infection is frequently an early side-cffect of bronchogenic carcinoma In many instances as has been mentioned leser and sepsis have an acute onset Tried found that 73 per cent of his series of lung cancer patients were diag nosed during or following an acute respiratory infection Of course there may be no acute episode inituting such an infection a long segment blocked off from the trache is susceptible to pathogens of a very low grade of activity und the beginmng of an infection my be mordrons In either instance cancer is suggested rather than the re Verse Patients with lung cancer almost always have some degree of fever at least intermittently Other es dence of sepsis is anablc Night sweats occur but not us frequently as in prients with tulierculosis Loss of strength Werkness loss of weight anoress and chrosse fatiguc are characteristic finelings so als need states of bronchogenic carcinoma md clic systemie mbal anct that they represent in xy be directly responsible for the death of the patient Hioneer they tm occur iery carly in the course of the disease although they Te not 50 pronounced wlien the malignancy is pulmonary 15 when It is gastric In many mst inees they seem to be directly tracerble to secondary suppurite processes We wie Ben especially impressed by numerous instances lou ter where such did not appear to be the case le lanc found markeci loss of weight in ustanicus where the sec ondary mlection its onld met istuses absent and the tumor Pods small Such loss of scight is frequently ac comapamed by a lassitude Buch is also out of a propor tion to oblcctae findings We bellic that such simptoms ·62 LUNG CANCER accompanied by moderate cough or any other slight res piratory sign, should strongly imply bronchogenic carcı noma In such cases, malignancy must be ruled out before any other diagnosis can be made with assurance Metastatic findings. There remains a rather large group of patients in which the first serious manifestations of a disease process are due to metastasis In our study, 34 per cent of the patients first sought medical attention because of synıptoms which were due wholly or in part to metastatic lesions It will be noted from the figure that many of these cases represented mediastinal involvement A tabulation of these findings merely emphasizes the infinite variety of metastatic sites possible and is without much profit (Table 1) A thorough physical examination and a detailed casc history will frequently uncover minor Brain 272 TABLE I SITES OF MALIGNANT EXTENSION OR METASTASES (1070 Autopsied Patients tith Bronchogenic Carcinoma) All Types Squamous Undit Adeno Site Number Per cent Per cent per cent Per cent Vetastases limited to Inlar LN 98 92 126 65 46 Hilar LN 790 738 58 9 945 613 201 504 37 3 55 6 619 Liser 479 448 65 0 382 Adrenal 428 400 19 1 518 354 Fleura 308 288 220 291 Kidney 286 267 22 0 365 207 Heart 200 170 212 167 Abdominal LN 202 189 166 119 051 Opposite Jung 199 186 147 163 Pancreas 120 II2 59 183 Spleen 87 81 59 129 Cervical LN 81 57 55 88 Intestine 48 56 70 30 Skin and subcutaneous tissue 84 41 38 31 24 No metastases 103 96 13 5 71 387 214 23.5 84 71 63 • The bra n ns exám ned n only 399 cases ·63 CLINICAL FEATURES signs and symptoms that will indicate coexistent disease sites Perhaps it should be pointed out that just as debility by itself does not prove a patient inoperable, so physical vigor does not prove the reverse Among our patients who first sought medical attention for symptoms arising from metastases, many appeared to be in ercellent physical condition, and did not consider themselves seriously ill Such patients, however, usually farled usth alarming r pidity after the onset of symptoms PHYSICAL EXAMINATION The patient is very apt, then, to present himself for medical attention with one or more complaints of a rather low order of severity In a large majority of cases there will be at least one complaint which is respiratory (Table II) Although it may be impracticable to hospitalize such TABLE II PIO SICAL FINDINGS (10 0 Autopsied Patients with Bronchogenic Carcinoma) idence suggestive of pulmonary disease 780 Pleural Effusion 353 Cross metastatic ke sions 482 Significant L N enlargement 182 Abdominal mass 150 Skin nodule bont innss brain tumor etc Clubbing 98 Ilorner Syndrome 21 73% 33% 453 178 149 147 93 patients for diagnosis, a thorough physical examination Is certainly obligatory, and in most instances of lung can cer there will be suggestive findings of the nature of the malignant lesion is kept in mind Wheeze. Ordinanly, the first evidence of a diseuse process which is detectable by ordinary physical eramına tion is a wheeze Hokcier, au liecze duc to a new growth cannot readily be distinguished from the miscellaneous ·62 LUNG CANCER accompanied by moderate cough or any other slight res piratory sign, should strongly imply bronchogenic carci noma In such cases, malignancy must be ruled out before any other diagnosis can be made with assurance Metastatic findings. There remains a rather large group of patients in which the first serious manifestations of a disease process are due to metastasis In our study, 34 per cent of the patients first sought medical attention because of symptoms which were due wholly or in part to metastatic lesions It will be noted from the figure that many of these cases represented mediastinal involvement A tabulation of these findings merely emphasizes the infinite variety of metastatic sites possible and is without much profit (Table I) A thorough physical examination and a detailed case history will frequently uncover minor TABLE I SITES OF MALIGNANT EXTENSION OR METASTASES (1070 Autopsied Patients uith Bronchogenic Carcinoma) All Types Squamous Undit Adeno Site Number Per cent Per cent per cent Per cent Metastases limited to Hilar LN 98 92 126 65 46 Hilar LN 790 738 58 2 945 643 Brain 201 • 504 37 3 55 6 619 Liver 479 118 272 650 382 Adrenal 400 291 548 354 Pleura 308 288 220 38 7 281 kidney 286 267 020 365 207 Heart 214 200 170 212 167 Abdominal LN 202 18 9 166 25 1 119 Opposite lung 199 186 147 163 235 Pancreas 120 112 59 18 3 Spleen 87 81 59 129 71 Cervical LN 61 57 55 88 63 Intestine 60 56 30 70 48 Skin and subcutaneous tissue 41 38 24 31 84 No metastases 103 96 13 5 71 • The brain was exam ned in only 399 cases 428 ·CLLICAL FEATURES 63 signs and symptoms that will indicate coeristent disease sites Perhaps it should be pointed out that just as debility by itself does not prove a patient inoperable, so physical vigor does not prove the reverse Among our patients who first sought medical attention for symptoms arising from metastases, many appeared to be in crcellent physica) condition, and did not consider themselves seriousls ull Such patients, however, usually failed with alarming ra pidity after the onset of symptoms PHYSICAL EXAMINATION The patient is very apt, then, to present himself for medical attention with one or more complaints of a rather lou order of seventy In a large majority of cases there will be at least one complaint wuch as respiratory (Table 21) Although it may be impracticable to liospitalizo such TABLE 11 THYSICAL FADAGS (100 Autopsted Palunis auth Bronchogenic Carethonia) Evidence suggestue of puffionary disease 750 Pleural Effusion 353 Cross metastatic lesions 482 Significant La enlargement 182 Abdominal mass 150 Skin boule bone miss brain tumor etc Culbing 98 llorners Syndrome 20 33% 458 17% 146 93 13 patients for diagnosis, 1 thorough physical examination is certainly obligatory, and in most instances of lung can cer there will be suggestre findings of the nature of the malignant lesion is kept in mind Wheeze. Ordinarily, the first evidence of a disease process which is detectable by ordinary physical examina tion is a wlieeze However, a wheeze due to a neu grouth rannot readily be distinguished from the miscellancous ·62 LUNG CANCER accompmied by moderate cough or any other slight res piratory sign, should strongly imply bronchogenic carcı noma In such cases, malignancy must be ruled out before any other diagnosis can be made with assurance Metastatic findings. There remains a rather large group of patients in which the first serious minfestations of a disease process are due to metastasis In our study, 34 per cent of the patients first sought medical attention because of symptons which were due us holly or in part to metastatıc lesions It will be noted from the figure that many of these cases represented mediastinal involvement A tabulation of these findings merely emphasizes the infinite variety of metastatic sites possible and is without much profit (Table I) A thorough physical examination and a detailed case history will frequently uncover minor Site 65 915 55 6 650 548 387 Pleura TABLE I SITES OF MALIGNANT EXTENSION OR METASTASES (1070 Autopsied Patients uith Bronchogenic Carcinoma) All Types Squamous Undit Adcio Number Per cent Per cent Per cent Per cent Metastases limited to Inlar LN 98 92 126 46 Hlar LN 790 738 58 2 613 Bruin 201 504 373 61 9 Lier 479 448 27 2 399 Adren u 428 400 29 1 354 220 hidney 286 267 220 207 Heart 214 200 170 167 Abdominal L N 202 18 9 166 Opposite lung 199 186 147 Pancreas 120 11 2 59 84 Spleen 87 81 71 59 Cervical L N 61 63 57 55 60 56 48 30 Skin and subcutaneous tissue 41 84 38 24 31 103 96 13 5 71 Tleban 15 exam ned only 39) cases 308 28 8 281 365 21 2 119 235 951 163 183 129 88 70 Intestine no metastases ·CLIVICAL FEATURES 63 signs and symptoms that will indicate coexistent disease sites Perhaps it should be pointed out that just as debility by itself does not prove a patient inoperable, so physical vigor does not prove the reverse Among our patients who first sought medical attention for symptoms arising from metastases, many appeared to be in excellent physical condition, and did not consider themselves seriously ill Such patients, however, usually failed with alarming ra pidity after the onset of symptoms PHYSICAL EXAMINATION The patient is very apt, then, to present himself for medical attention with one or more complaints of a rather low order of seventy In a large majority of cases there will be at least one complaint which is respiratory (Table II) Although it may be impracticable to hospitalize such TABLE II PHYSICAL FINDINGS (1070 Autopsied Patients with Bronchogenic Carcinoma) Evidence suggestive of pulmonary disease 780 Pleural Effusion 353 Gross metastatic lesions 482 Signifcant LN enlargement 182 Abdominal mass 150 Skin nodule bone mass brain tumor etc 149 Clubbing 96 Homers Syndrome 21 737 33% 45% 17% 14% 145 96 26 patients for diagnosis, a thorough physical examination is certainly obligatory, and in most instances of lung can cer there will be suggestive findings of the nature of the malignant lesion is kept in mind Wheeze Ordinarily, the first evidence of a disease process which is detectable by ordinary physical examina tion is a wheeze However, a wheeze due to a new growth cannot readily be distinguished from the miscellaneous ·64 LUNG CANCER collection of sounds which are produced in the normal bronchus by loose mucous It may be noted to be rather dry and brassy, and the patient may observe that it is chronic When possible it is sometimes helpful if the pa trent is given one half or one grain of codeine orally an hour before arising and eximined immediately upon aris ing The codeine suppresses the cough reflcr and often results in the accumulation of sputum at the point of ob struction When the patient is examined the wheeze will then be prominent and more readily locılızed A persist ent uninteral wheeze in a patient over 40 is almost pathognomonic of serious bronchial obstruction The length of time that a partial obstruction exists in the bronchus so as to cause ezing probably varies widely On the basis of the number of times that the condition is recorded clinically it would seem to be a short period Consequently such a wheeze is most apt to appear when the history is taken When there has been an episode of acute pneumonia the patient will some times report a period of wheezing preceding the infection Emphysema The wheezing stage in the development of bronchogenic carcinoma is not infrequently followed by a yet briefer stage of emphysema The degree of em physemi depends primarily upon the location of the tumor Because bronchogenic carcinoma is characteris tically located in primary and secondary branches of the bronchil tree emphysema may be of great extent and detectable by careful physical examination A tympanıtıc percussion note may be a typical finding but diminished or absent breath sounds over the affected vea are more easily detected Emphysemn is suggested by unilaterally diminished respiratory movements In any case it is a fleeting appearance ind emphysema as a result of bron chial carcinoma is not commonly seen clinically Atelectasis The chronic condition accompanying ·CLINICAL FEATURES 65 most cases of bronchogenic carcinoma is atelectusis which follows complete stenosis of the bronchus It is very diffi cult to distinguish this condition from an infiimmatory process by a physical examination but in either case a roentgen ray examination is mandatory and the seg mental distribution of a sliados due to atelectasis will usually permit accurate differentiation The only condition is inch is likely to obscure an atelec tatıc lung segment is pleural Aud Tus is readily demon strated in a physical examination if it is extensive Sucha finding suggests a scrious pulmonary abnormality and demands further diagnostic studies We would emphasize again that of such fluid is withdrawn and found to be clear and free of tumor cells it does not prove that the primary pathology is non-cancerous Vlodernte amounts of clear flud are not infrequently found in the pleura due to lymphatic blochage or to lung infections secondary to malignancy Clubbing of the extremities Clubbing of the extremi ties is not of course a dependable finding in broncho genic carcinoma but when observed it may be very helpful in diagnosis This condition which scems to result from a deficiency in the aeration of the blood may 10 company any chronic lung infection However when the primary pathology is unfectious clubbing develops only after 7 considerable period of time On the other hand! it may develop very rapidly in the presence of n lung can cer in a matter of weeks Whenever such clubbing is ob served and there is not a long history of respiratory or circulatory disease bronchogenic carcinoma should be suspected Fried found clubbed fingers in 30 per cent of his patients with early bronchogenic carcinoma it oc curred in our series almost 10 per cent of the time Tracheal deviation Some tracheal deviation in the presence of atelectasis will usually be detectable on physi ·66 LUNG CANCER cal examination Even when such atelectasis is not pres ent, the position of the trachea should be determined It has been, in our experience, the most concrete physical indication of pulmonary pathology in a few instances where the malignancy was a predominantly extra bron chial, undifferentiated carcinoma Such grow this rather frequently displace the trachea to an appreciable extent suithout other prominent physical findings Metastasis. The search for metastatic findings is apt to secm a somewhat academic procedure in preliminary physical examination Honever, we believe that a physı cal examination should be routinely a complete examina tion, and that it must include the whole body When there 15 suspicion of Jung pathology in a patent over 40, this examination should be especially concerned with the possibility of nerve involvement, particularly those nerves passing through the mediastinum Superficial lymph nodes should be carefully palpated in the presence of any disease process Such a thorough physical eramination is still the basic procedure in the practice of medicine Most of the scientific procedures which have been developed and which have had an unfortunate tendency to replace the physical examination depend upon the physical er amination or the history to indicate the kind of informa tion required And it is to this purpose that all of the preliminary procedures of history taking and physical examination should be directed Even a presumptive diagnosis is gen erally impossible upon the basis of such findings, but if they are carefully analyzed they can ordinarily be trusted to suggest the possibility of serious pulmonary pathology requiring further study Upon the basis of such findings the physician must make his first important decision, he must decide whether or not further studies are required ·Roentgenology 4 Wiles upon the basis of a patient s symptoms and phy sı cal findings lung malignancy is considered possible a diagnosis must be made or ruled out as quickly as possible by means of specialized diagnostic techniques the chief of which is roentgenology The pleomorphic charıcteris ties of thus disease however make roentgenologic find ings difficult to evaluate There are to be sure certun "classic" x ray appearances in bronchogenc carcinoma but these are neither the most common nor are they the appearances offering the best prognosis Typically bron chogenic carcinoma masquerades as something else and the real nature of the condition will only be suspected by someone with long experience As a consequence effec of the disease should be of only minor interest to the clinican He after all must finally make the diagnosis and this requires that he understand the radiologists conclusions in the light of the latter s problems There must be mutual understanding and close cooperation between the two the radiologist will function most effec tively if he is able to interpret and evaluate lus findings with full knowledge of all clinical data in the light of basic pathology The ideal situation which is more and more [67] ·68 LUG CANCER being realized in practice, is one in which the clinician and the radiologist consult frequently, and where the clinicrun is routinely present at roentgenologic examına trons We shall not attempt, then, to describe exhaustnely the means for a roentgenologic diagnosis of bronchogenic carcinoma, these require the tecliniques of a specialist and cannot be covered in a chapter, or in a book Instead we shall try to present the knowledge of roentgenolog) which is required by the clinician for effective cooperation with the radiologist We shall describe basic appearances necessarily oversimplifying and try to indicate the find ings which are most apt to be misleading, if clinical ma terial is not given full consideration Lastly, we shall sug gest briefly the range of supplementary techniques by which an obscure roentgenologic appearance can some times be clarified Fluoroscopy. First, it is perhaps well to recognize that miny physicians operate their own fluoroscopes routinely for cardiac and other examinations, and that in many in stances the first roentgenologic study of a patient with bronchogenic carcinoma will be fluoroscopic examination in the physicians office The danger is that this procedure will sometimes replice a complete roentgenologic study If, however, it is regarded as a supplement to the physical examination, and if it is thorough, it can be of service in establishing the existence of a pathologic process, and the necessity for a complete roentgenologic study In our own practice, we have found that the usefulness of fluoroscopy depends in great part upon there being a definite proced ure which is routinely followed in the examination Such a routine prevents minor abnormalities from being over Zooked, shortens the examination time, and minimizes exposure The examination should begin with the patient facing ·69 ROENTGENOLOGY the projector The examiner should first note the gen erni configuration of the chest the size shape and position of the cardıc silhouette and then closely observe the mediastinal shadow Tricheal deviation is looked for Each cardiophrenic and costophrenic angle of the dia phragm should be curefully inspected for signs of flud formation After a general inspection of the thoracic cage with wide open shutters they should be coned down for a detuled inspection A methodical erimination of the whole area should then be made working from top to bottom le customarily use a literal shit in this detuled survey because minor abnormalities are often best de tected by 1 comprison of one side of the chest with the other Fluoroscopy has one re il di antage over roentgen ily films in that it permits observation of lung movement Even a pathological process of limted extent very fre quently disturbs the functional relationship of the tuo lungs or of segments of the sime lung Such a disturb ance can be detected in two ways hy fluoroscopy In the first place the movement of the two leaves of the dia phragm should be carefully compared at full inspiration at full expiration and during normal respiration Any disparity between them in extreme positions or any time lag observed suggests lung pathology It is also possible to compare the different segments of the same lung with each other This is done with a vertical slit By observing the position of the lung markings at full inspiration and expiration it is sometimes possible to detect an unequal expansion among the segments which usually suggests a limited area of emphysema due to partial broncu ob struction In any event fuoroscopy should not be regarded as anything more than a confirmation of the presence of an abnormality and a guide to further roentgenologic ·70 LUNG CANCER SUGGESTIVE MASS HILAR 45%. PER FHERAL17 NO MASS 30%. PNEUMONIA 357. PLEURAL FLUID 30%. ATELECTASIS 24% CAVITATION 10%. PLEURAL FLUID ALONE 77. ATELECTASIS ALONE RIB EROSION NEGATIVE 0 100 200 300 400 500 000 F gi re 9 ray find ngs -- 889 pat ents studies Such further studies should routinely include lateral views as well as standard posterior anterior projec tions If the formal roentgenologic examination is guided by further fluoroscopy oblique views may be suggested There have been many attempts to devise and illustrate certain classical xrny appearances found in bronchogenic circinoma a discussion of the subject in fact re quires that such standard apperrances be presumed It must be remembered however that the distinct appear inces described in literature are very apt to be inextric ably confused in the particular instance in our study of putopsy reports of 1 070 patients with bronchogenic car cinoma there were $S9 for whom adequrte y ray reports or the x ray films themselves were wailable A tabulation of findings (Figure 9) indicates that a tumor body was visible almost two thirds of the time However in a majority of these instances is the rest of the table sug ·71 ROENTGENOLOGY gests, there were other findings that tended to obscure the basic shadow In order to discuss the subject at all, it is necessary to discuss separate appearances It must be remembered, however, that separation of shadow from shadow is at times a difficult procedure (Figures 10, 11 12, 13) For convenience, we can classify roentgenologic ap pearances in bronchogenic carcinoma into three large groups (1) those instances in which the tumor body itself is the chief roentgenologic feature (2) those m stances in which the predominant appearınce is that of bronchial obstruction and (3) those instances in which the appearance is overwhelmingly of lung infection We shall point out from time to time the correlation of cell type to roentgenologic appearance when in our exper ience it is particularly significant, but we shall not make a point of establishing such a correlation in each instance We believe that the kind of correlation that Gebauer and Koletsky have attempted to establish between predomin ant cell type and clinical and roentgenological appear ances really exist but its interest and significance are etrological and not clinical The problem is to arrive promptly and accurately at a diagnosis of malignant neo plasm in clinical practice cell type is of little application at the present time Parenchymal tumors As has been pointed out else where between 5 and 15 per cent of all bronchial malig nancies arise in lesser branches of the bronchial tree The tumor body itself in these instances is apt to be the most prominent roentgenologic indication of pathology because obstruction of the airways is limited Such growths are often quite sphencal in shape with deceptively sharp contours Until these peripheral tumors become inoper able by reason of local extension into the chest wall or by metastasis, they are customarily quite silent Often

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Figure 10

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·76 LUNG CANCER times the patient with such a tumor will first scek medical attention for symptoms due to metastatic growths, or they may be discovered in routine examinations Roentgeno logically, they are readily mistaken for tuberculomas cysts, or benign grow ths Because of their silence, there has been a tendency in the past to treat such peripheral shadows as benign curiosities, until growth or met ustases appear The above description docs not exhaust the roent genologic appearances possible to peripheral tumors While there are no structures in the parenchyma of the lung which are able to distort neu grow this from spheri city by resistance, the predilection that certain of these tumors have for lymphatic tissue may completely alter their outline Such grou ths upon x ray examination are patchy and irregular in appearance, and may seem to be typical infections If such a grou th occurs in an upper lobe, tuberculosis suggests itself, if in a lower lobe, pneu monitis, or infarct These tumors may be seen to vary somewhat between examinations, due to coeustent infec tion but the basic shadow somewhat is that of tumor tissue, which will not regress under chemotherapy Holar lesions Hılır type carcinoma is usually de fined as malignancy arising near the midlıne of the thor acic cage which does not markedly occlude bronchi Sucht tumors are almost always anaplastic circinomas these grow ths may insolie bronchial structures extensa cly without causing obstruction At times the predominant appearance is of a roughly lobulur growth in the paren chyma adjacent to the bronchus of origin More often these tumors follow the bronchi or the lymph channels in their extension The roentgenologic appearance my vary from that of a solid somewhat irregular shadow with blurred edges, to a more or less prominent exaggeration of lung markings ·ROENTGENOLOGY In our experience hilar lesions are the least confus ing of all lung malignincies to roentgenologic diagnosis llowever when a solid more or less lobulated shadow in thus region is the chief roentgenologic finding both sar coidosis and Hodgkins disease must be considered in the differential diagnosis Also early gronths of the highly invasive type when they occur in this form may be mis taken for bronchial infections In some instances we have observed such an x ray finding interpreted as consistent with tuberculosis BRONCHIAL BLOCK Whenever a new growth is pronouncedly intrabron chial ind occurs m a major branch of the bronchial tree secondary conditions inevitably obscure the tumor body to a considerable degree For convenience these secon dary appearances can be divided into those which are predominantly infectious and those in which the most prominent evidence of abnormality is an uncomplicated bronchial block (Figure 14) In practice of course there is almost alw wys some degree of overlapping One seldom sces a roentgenologic film of bronchial obstruction with out some evidence of coexistent infection nor except in far advanced cases of the disease does shadow of mfec tious origin commonly obliterate entirely the shadow of tumor tissue or atelectasis Emphysema Westermark in an interesting study has PNEUMONIA 54% PLEURAL FLUD 42% ATELECTASIS 28%. CAVITATION 11% 0 50 100 150 200 Fg ro 14 ray find ngs D 338 pat cuts wth No Mas o XT ·78 LUNG CANCER distinguished three phases of lung pathology secondary to partni bronchial obstruction The first phase is that of hyperemia due to a decreased intra alveolar pressure the result roentgenologically is a faint darhening of the affected area The second phase is initiated by the devel opment of a one way valve condition which permits inspiration but inhibits expiration This is seen roentgeno logically as an area of increased radio penetration and lightness The third phrse is complete block with an overly distended lung and emphysema beyond the occlu sion This description is physiologically convincing lut its usefulness in clinical practice is doubtful It is well to keep this progression of events in mind but the sequence will seldom be observed We have not seen the first phase Westermark describes and hue seldom been able to dis tinguish between the Inter phases of development The significance of emphysema as a symptom of bron chogenic carcinoma has been discounted It is probable that an emphysematous phase does occur very often in Jung malignancy but it is usually quite transient There is no way of determining the number of patients with bronchogenic carcinoma who have detectable emphysema when they are first fluoroscoped our experjence would suggest that the number is small This group is important hou ever emphysema offers at least the presumption that the tumor is in a relatively curly stage of development and that the chances for successful surgery are good There is a tendency at the present time to over empha size the increased lung transparency characteristic of an emphysematous area Such a change in radiolucency may be very difficult to detect with assurance unless it is ex tensive The usefulness of this appearance is further di minished because some degree of chromc emphysema without other lung pathology is common among older males

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·LUNG CANCEN 80 Atelectasis Uncomplicated atelectasis seldom offers diagnostic difficulty on roentgenologic examination The affected lung segment is markedly denser than normal the trachea heart and mediastinum are retracted toward the abnormal side, and the diaphragm is elevated If the affected segment is the left lower lobe, the primary apperrance, that of the atelectatic lung tissue, may be more or less hidden in the heart shadow, but the consequent displacement of thoracic structures should prevent con fusion Literal x ray studies are of particular value in this situation However, atelectatic appearances will usually be to some extent complicated by infection Experimental studies suggest that atelectasis implies infection since unless there are inflammatory changes in the alveolar walls there will be sufficient gas exchange between the alveoli of one segment and those of adjacent segments to prevent segmental collapse In the earlier stages of atelectasis such infection is usually lon grade, and confined to the particular segment, with time, however, this infection will extend to adjicent tissue, and the segmental character of the lesion may be partially obscured Although this condition may occur in conjunction with minor infectious processes this situation is uncom mon When this characteristic appearance is seen roent genologically the underlying pathology should be investi gated without delay Most atelectasis in adults is due to new growths benign or malignant, although inflammatory disease and foreign bodies must be considered in the dif ferential diagnosis SECONDARY INFECTIONS It is impossible to describe exhaustively the appear ances possible to an infection secondary to bronchogenic carcinoma, since the course of such an infection will de ·81 ROENTCEVOLOGY pend upon a multitude of more or less fortwtous factors It is usually impossible, by ordinary roentgen ray films, to distinguish between a primary infection and one secondary to malignancy However, by careful analysis it may be possible, in secondary infections, to detect features which will suggest an underlying pathological process A tumor body is most apt to be completely mished by a secondary pneumonia, either chronic or acute This de velopment frequently occurs while the neoplasm is still quite small, it may occur before there is complete occlu sion of the bronchus of origin In such instances, the pneumonia may seem to clear completely following a course of chemotherapy However, it inevitably recurs Ordinary roentgenologic techniques are inadequate for the diagnosis of the primary condition Something of the same situation exists so far as bron chiectasis is concerned In perhaps 25 per cent of all bron chogenic carcinoma, a diagnosis of bronchiectasis is listed as a possibility on the basis of roentgenologic studies Because the shadow of infection in bronchiectasis is apt to be less dense, and less compact than a pneumonia shadow there is sometimes direct evidence of the tumor body to be seen Over exposed hard shots are very useful when there is the possibilty of a tumor induced bronchiectasis Roentgenologic films of a lung cavity due to central necrosis of a malignancy will be diagnostic in many in stances The cavity with thick, irregular walls suggestive of an invasive process, with or without a flud level is the most common appearance However, this finding cannot be depended upon A tuberculous cavity may have the appearance of sohd growth with central necrosis of limited extent a caremom? my hwe walls so thin that the total appearance is that of an infected cyst Up to one half of all bronchogenic carcinomas have ·89 LUNG CANCER infection as the most prominent appearance when first x rayed in the study of roentgen diagnosis by Cooper and hroll about a third of such cases did not suggest bronchogenic carcinoma to the roentgenologist It is obtrous that in this situation above all others the cooperation of the clinician ind the roentgenologist is indis pensable Although the symptoms of sepsis and purulent sputum containing micro orginisins will tend to confirm the roentgenologic findings of infection there is usually at least in retrospect facts which make such a diagnosis doubtful Anvthing in the roentgenologic findings clini cal course or hustory which is atypical mahes it mandatory that mulignincy be ruled out by further studies Perhaps the most common and frequently ignored indication of malignancy is the intractability of the lesson to routine chemotherapy This intractability usually mani fests itself in a failure of the lung fields to clear as symp toms disappear by repeated ntticks of pneumonia or by in inadequrte response of symptoms to drugs The most uscful procedure in avoiding unnecessary delay in arı ing at the proper diagnosis of malignancy is the repeated (ise of the roentgenray 1}} instances of pneumonia bron chiectasis and other mijor lung infections should be fol lowed until the lung fields are clear The history of the prtient should also be correlated with roentgenologic findings Many studies of case his tories in the pre chemotherapeutic era confirm the com mon observation that a lung abscess or a local lung infection was preceded by a history of an operation under anesthesia an infected wound of some sort marked oral sepsis, or dental extraction A diagnosis of primary lung abscess or primary pneumonitis should not be made with out such a hustory until the possibility of carcinoma has been thoroughly explored Something of the same situation exists so far as bron ·83 ROENTGENOLOGI chiectasis is concerned Though it is not invariably the case this disease usuilly develops in the first three de cades of life Therefore findings of bronchiectasis in ? patient over forty without ? clear history of chronic lung infection extending over a period of yers is in itself an indication of carcinoma rather than otherwise In such instances the burden of proof must remun with those who would arrive at 1 diagnosis of non malignancy Most effective use of roentgenology then depends upon the correlation of roentgenologic findings with every available bit of information which in turn depends upon the cooperation of the roentgenologist and the clinician At times the pre operatre diagnosis must depend upon these two sources of information alone In most instances however clinical and standard roentgenologic findings will be largely a guide to further studies Roentgenology itself can provide additional information by the use of supplementary techniques the chief of which are bron chography tomography and angiocardiography SUPPLEMENTARY ROENTGENOLOGIC TECHNIQUES Bronchography The most useful supplementary roentgenologic technique for the diagnosis of bronchogenic carcinoma is bronchography There is perhaps still some suspicion of this procedure on the theory that the iodized oil mildly irritates bronchial surfaces and leads to exten sion of an infection In our judgment hou ever chemo therapy has almost eliminated this risk and the inform? tion that can sometimes be obtained by this procedure is worth the slight disability Many types of obstruction in the bronchi are readily detected by this technique and roentgenologists with sufficient experience can frequently deduce the kind of obstruction with some accuracy Most characteristic of bronchogenic carcinoma is the string like” appearance of the 10dized oil on the roentgenogram ·84 LUNG CANCER as it finds its way past the occlusion of a carcinomatous ulceration Though many non-neoplastic conditions can bloch or partially bloch bronchi, bronchographic evidence of a long, intrusne lesion strongly suggests malignancy IIou ever, a lobulated, smooth contoured obstruction is not necessarily benign In our experience, morphologi cally proven carcinomas lave frequently been indistin guishable from typical adenomas by bronchography In most instances, a bronchographical examination will not be undertaken untıl bronchoscopy has been per formed since the nodized oil may considerably distort bronchoscopic appearances and make biopsy difficult Its use, then, is generally confined to situations in which the growth lies beyond the vision of the bronchoscopist It is most useful in diagnosing peripheral lesions, where the growth arises in second or third order bronchi, and is seen by ordinary roentgenology as an inflammatory process Peripheral inflammation alone almost never completely occludes the smaller bronchi, a malignant growth almost invariably docs When other evidence is unavailable, many surgeons would consider such a finding adequate grounds for surgical exploration Tomography. Tomography or laminography is a techmique for rapid vibration of both x ray tube and screen, by which all details of bodily structure are eliminated except in a specific plane In general, it is used for discovering and determining the size of cavities and for exact location of various abnormalities It is of special value in the analysis of peripheral lung inflammations when there is a suggestion of malignancy, by this technique it is frequently possible to prove the presence of solid neoplastic tissue within the inflammatory shadows It may also be of value in determining how extensively lymph nodes are ini oled in a disease process, which may suggest a diagnosis of malignancy It may be useful also ·NOEYTCEVOLOGY 85 in those instances of solid tumor obstruction of a major bronchus, outside the vision of the hronchoscopist, since It is posssble to show a solid shadow within and without the bronchus in question-an appearance which is virtu ally diagnostic Angiocardiography, The last radiologic technique of major significance is angrocardiography, it is as yet not very wsdely practiced but promises much It consists of the injection of vinyl acetate mtravenously, and on over exposed roentgen film talen shortly afterwards Distor tion of pulmonary vessels is a significant and readily ap parent finding, more diagnostic yet is the finding of com plete occlusion of scieral small vessels or of a pulmonary artery Since the blood vessels of the lung are hughly resistent to all pathologic processes except actual invasion by malignancy, occlusion of such vessels us more patho gnomonic than simple displacement Dotter, Steinberg and Holman report the diagnosis of 34 of 53 patients with bronchogenic carcinoma by the utilization of this proced kre The percentage is not spectaculur, but diagnosis of malignancy made by this technique is generally authora tive The fact remains, however, that roentgenology by it self is not diagnostic, and the tentativeness of suggested diagnoses arrived at by this means is much greater than a reading of literature on the subject would suggest Broner, Jones and Dolley reported several years ago 30 cases in which exploratory thoractatomy was undertaken in the expectation of finding malignancy, and in which the actual condition ranged from lung abscess and tuberculosis through the benign tumors and cysts Diagnostic techniques apparently included all the usual roentgeno logic techniques, crcept angiocardiography Though an exploratory operation which proves the primary pathology to be preumonitis, as an instance is a source of embarrass ·86 LUNG CANCER ment it must be expected from time to time and borne with good grace We do not have an infallible dngnostic technuque and it is inevitable that a diagnosis on the basis of roentgenologic findings and the clımcıl symptoms sul] from time to time prove erroneous It is necessary at times to explore patients without morphological evidence of malignancy, an exploratory thoracotomy in doubtful instances is preferable to dely Something should be said about the small percentage of bronchogenic carcinomas found in almost every large series which were discovered by other than radiological techniques either accidentally or at autopsy after a nega tive x ray report had been made In many such instances re examination of the x rays in question suggests that minimal evidence of abnormality was overlooked How cver it must be emphasized that roentgenology cannot be regarded as proving z negative diagnosis if there is other evidence of pathology The interval of time between the inception of 2 microscopically identifiable lesion and a lesion apprrent upon an x sny film has been variously estimated In some instances it seems to be as long as seven years Bronchography of course will sometimes give evidence of a tumor body too small to appear on in ordinary roentgenogram ·Further Diagnostic Studies 5 IT AIUST BF emphatically asserted that a dignosis of bron chogenic carcinoma not based upon morphologic findings is a presumptie diagnosis actual malignant tissue or malignant cells must be demonstrated in order that a diagnosis be authontative Where there is a presumptive diagnosis of malignancy surgery should not be unduly delayed while morphologic evidence is sought but a rer sonable effort should be made to demonstrate morphologi cally that the abnormal process is indeed malignant When surgery is undertaken without such evidence it must be expected that a certain number of bronchogenic carcinomas will be found at exploration to be benign conditions There are several techniques by which such morpho logic evidence can be obtained (Figure 15) The identifi cation of malignant cells in the sputum and bronchoscopic biopsy are the most important means of arriving at a morphologic diagnosis but other methods are available Excision and study of palpable cervical lymph nodes is of course a routine procedure when bronchogenic carci noma is suspected Unfortunately if cancerous tissue is found in thiese nodes the lesion is already inoperible and [87] ·88 LUNG CANCER drgnosis loses much of its significance Potentially of much interest is the minor surgical procedure of Daniels by which lymph nodes from the deep cervical areas are excised AUTOPSY 61% BRONCHOSCOPIC BIOPSY 167. LYMPH NODE BIOPSY 97. EXPLORATORY 57 THORACOTOMY PLEURAL FLUID 32 OTHER EXTRA 67 PULMONARY BIOPSIES 100 200 300 400 300 000 TOC Figure 15 First method yield ng histolog c proof of bronchogea e car c noma in 1 070 a tops ed pat ents o Punch biopsy is also available for morphologic diag nosis The suspicious lesion must be carefully located lry means of a correlation of posterior anterior and lateral roentgenograms or preferably the biopsy can be carried out under biplane roentgenoscopic guidance so that the exact relationship of the needle to the suspicious shadow can be determined Unless there is such guidance the biopsy specimen is likely to be withdrawn from the sur rounding area of secondary inflammation rather than the mass itself This was a frequent complaint in the early experience with the technique The tissue specimen with drawn by careful utilization of this technique is usually large enough to permit confident diagnosis The propriety of punch biopsy is still debitable Arbuckle reports its frequent use without untou vd rc sults However the literature of a fen years ago when the method was widely used contains reports of pleurri implantation of malignant cells at the site of the biopsy and also occasional extension of infectious processes For this rerson an exploratory thor icotomy is usually prefer red when the physician is confronted with a possible ·FUNTIER DIAGNOSTIC STUDIES 89 diagnosis of mulignancy which cannot be confirmed or ruled out by the standard morphologic techniques Bronchoscopy. It is obvious that maximum informa tion by means of bronchoscopy requires that the primary tumor body lie ner enough to the carina to be directly visualized There is a good deal of disagreement is to how many bronchogenic carcinomas fulfill this require ment (Figure 16) Although diagnosis by bronchoscopy MAIN STEM 14% 10% BRONCHUS UPPER LOBE 19%. 19% BRONCHUS MIDOLE LOBE BRONCHUS 47 LOWER LOBE 13%. 10%. BRONCHUS TRACHEAL. BIFURC RIGHT PERIPHERAL 2 LEFT DIFFUSE 180 90 270 300 450 Figure 16 Location of prmary tumor in 981 patients with bronchogenic Ca has been reported in up to 75 per cent of a series most claims have been somen hat more modest Oschiner re ported positive bronchoscopic results in 415 per cent of 147 patients resected Ariel ct al found that positive histologicul diagnoses depend on a good many factors beside the shall of the bronchoscopist including case selec tion and the willingness of the surgeon to operate without recourse to bronchoscopy Our own experience suggest that the lower figures are closer to the actual situation it would seem certain that less than half of all primary lung ·90 LUNG CANCER malignancies lie close enough to the carins to be posi tely dignosed by this technique As Figure 16 indi cafes much depends upon the location of the tumor a tumor of the lower lobe is twice as easy to detect as 2 tumor of the upper lobe POSITIVE VEST VE NEGATIVE 50% 27 15% POSITVC SU66E9NYE 327 NEGATIVE 72 POS TIVE 36 SUEGEST VE 31 NEGAT VE POSITIVE •% SUGGES VE 43 NEGA IVE 594 POSITIVE SUSÉES VE 277 NEGAT YE 94 POWTIVE SUGGESTIVE NEOANIVE 69/ + 17 A POSITIVE 532 BUSBESTIVE 452 NEGATIVE 34 POSmive 564 SUGGEST VE 16 NEGAT VE 28 A Figure 17 Results of bronchoscopy accord ng to locat on of turnor 397 pat ents When it lies within the range of the bronchoscope the tumor is usually readily noticed even when quite small The normal bronchus is very regular in appearance rang ing in color from a light pink to a light red and the carti lage rings are prominent and even A tumor which is microscopically visible will usually be marked by discol oration and will be raised above the les el of surrounding healthy mucosa Erosion is common Sometimes the mu cosa over the growth will appear to be of a normal color but malignancy will be suggested by prominent and tortu ous blood vessels over the top of the growth When there is a suggestion of abnormality which is yet unidentifiable ·FURTHIER DIAGNOSTIC STUDIES 91 the presence of new growth is sometimes indicated by the irregular appearance of the cartilage as the patient breathes The detection and evaluation of these appearances is a matter for the trained bronchoscopist but it behooves the physician to know the variations from normal which are significant The primary service that bronchoscopy renders is to permit direct visualization of the tumor body but there are also several secondary appearances which are signifi cant In this category is the fixation of the bronchni tree In health this system is very fleuble and in constant move ment While any abnormal process within the tracheo broncual tree itself or the dependent parenchyma mau lumnit this movement particularly if such an abnormality is accompanied by pleural adhesion the limitation of movement is apt to be marked in the presence of bron chogenic carcinoma in instances fixation is almost diag nostic when the etamination is made by an experienced operator Some distortion of the bronchial tree may also be noted even when the tumor has not nene trated into the lumen Where such distortion is seen in the trachea at does not of necessity indicate actual involvement of that structure and contraindicate surgery although prognosis at this point is admittedly poor Longitudinal ridges have been observed within a bronchus which indicate external compression and strongly suggest malignancy Whep bronchogenic carcinoma is suspected an im portant aspect of the bronchoscopic examination is a close inspection of the carina Even when the main tumor body lies entrely within the parenchyma and thus is beyond the range of the bronchoscope metastatic in Lolyement of the subeunal lymph nodes will frequently contribute to diagnosis At times such invohement will ·92 IUC CANCER be extensive and be suggested to the bronchoscopist by a pronounced widening of the curini When the metrstasis is not so extensii c, some lymph node invol ement will frequently be indicated by the fixation of that structure Agun it must be ciutioned that bronchogenic carcinoma is not the only condition which produces a pronounced enlargement of mediastinal lymph nodes and the evalua tion of such n finding must be made with care especially if there is cocxistent tuberculosis or a history of tuber culosis Bronchoscopy is of greatest use when it permits biopsy specimens to be taken from any abnormal areas of the bronchus Only when a positive biopsy specimen is se cured is the dignosis beyond question However when such a specimen is examined ind no malignant tissue is found it does not necessarily result in a negrtive drag nosis It is sometimes very difficult to distinguish between 1 tumor body and surrounding inflammatory changes and i biopsy specimen may be of inflmmatory tissue There is Tittle serious risk in taking such biopsy specimens but smail liemorrhages are sometimes occisioned for this reason the taking of biopsy specimens is usually postponed until the end of the examination If the patient is not morbund there are practically no contraindications for bronchoscopy The only real risk in the procedure in the lands of a skilled operator occurs if there should be in gren of serious ulceration or erosion in the tricher through which the bronchoscope might nccidentally penetrate The procedure is however physi cally uncomfortable in many instances and it is an eien inore acute psychological disturbance in others in our experience repeated bronchoscopies often seriously en nerı ate the patient Upon the physician then who is naturally concerned with the patient as a human being as well as a collection of symptoms with a case history ·FURTHIER DIAGVOSTIC STUDIES 93 devolves the obligation of preventing unnecessary use of the instrument Where there is a presumptive diagnosis of malignancy upon the basis of symptoms and roentgen ology, the surgeon should be contacted before arrangements are made for bronchoscopy, since at the present time many surgeons prefer to be present at the examina tron or carry out the procedure themselves When i tumor body lies in a mun bronclus or the lower or middle lobe bronchi, there is a good chance for immediate and positive diagnosis There seems little likel hood however, that the effectiveness of bronchoscopy will be greatly extended beyond what it has at present A mirror arrangement has been developed sluch, to a limuted degree, extends the range of vision and increases the possibility of upper lobe lesions being visualized There are also available specially designed forceps l» which biopsy specimens can be taken beyond the range of bronchoscopic vision in some instances better visualrzation of an upper lobe bronchus can be obtained by es tablishing a pneumothorax prior to the bronchoscopic ex amination Ench of these developments has proven, upon occasion, to be of real service, but they have not materially overcome the expected limitations of bronchoscopy It is difficult to foreste any possibility that such refinements of technique will be statistically significant, it would seem that in any large series of unselected cases, morphologic diagnosis by means of bronchoscopy cannot be expected to exceed 60 per cent CYTOLOGIC DIAGNOSIS Like bronchoscopy, cytologic diagnosis is something short of the infallible diagnostic approach that is desirable However, present evidence indicates that if the technique is properly applied, the percentage of positive diagnosis that can be made is substantially hugher than the per ·94 LUNG CANCER centage of diagnoses made bronchoscopically low effec tive cytologic diagnosis will eventually prove to be is still doubtful, the application of cell studies to lung secretions is still so new that it is difficult to predict its potentialities Of one thing, however, we are qute convinced In proper hands, a cytologic diagnosis, "consistent with ma lignancy," is morphologic and it is as reliable as a diagnosis based upon biopsy material This has been the first con cern of the students of cytology In Our laboratory at the San Francisco Hospital, we have found that our accuracy in avoiding false positive diagnoses approaches 100 per cent in a total group of over 2,500 patients suspected of lung cancer The technique has a major advantage over other means for morphologic diagnosis in its simplicity for the patients The sputum submitted for cramination must be raised from the bronchial tree, secretions from the throat and upper part of the respiratory system are uninforma tre It has been alleged that a fairly large proportion of patients will not raise such sputum, but in our experience of the raising of sputum is insisted upon with sufficient firmness, an amount sufficient for cytologic examination can almost always be collected The sputum which is com monly raised in the morning, just after the patient wahes, is generally the most satisfactory There is the additional requirement that such a sputum sample be processed be fore the cells have time to degenerate The inter al that can lapse between raising the sputum and its processing varies with its moisture content, but ordinarily it should be smeared within three hours of being raised As long as the sample is not allowed to dry, however, cells may retain their distinctiveness for a period of 10 hours The pro cedure is, then, of utmost convenience Sputum samples can be collected repeatedly without the slightest inter ference with other diagnostic techniques ·FURTIER DIAGNOSTIC STUDIES 95 Little special training is necessary for the procedures preliminary to staining Slides must be previously prepared by being thoroughly cleaned and marked with a diamond pencil, and cover slips must be available Ordı narily the accuracy of the diagnosis is increased by selection of the material to be smeared We have discovered that malignant cells are most apt to be found in opaque, granular bits of tissue, white to yellow in color Some experience is necessary to distinguish these particles from bits of food or pus Where such tissue flechs are not ob served, blood flecks should be chosen This selection of materials to be smeared is best accomplished by pouring the sputum sample into a watch glass and examining it against a black background Specimens selected for smearing should be removed from the sputum sample with rat toothed forceps, cut loose with scissors if necessary, and deposited on the pre viously prepared slides They should be smeared upon the slide as gently as possible We have found the best procedure to be the teasing of the specimen across the slide with a wooden applicator Immediately upon smearing, the slide should be deposited in a firative It is most important that the slide not be allowed to dry Even a moment's delay between smearing and fixation may result in some drying at the edges of the slide, resulting in loss of cellular outline and changes in the staining reaction Ordinarily three specimens should be chosen and fixed from each collection of sputum By this practice it is possible to cover the entire range of macroscopically Suspicious material present Paper clips on alternate slides will prevent contact of the smeared surfaces in the fixative The fixative solution consists of equal parts of ether and 95 per cent alcohol When specimens are being prepared for mailing before they are to be stained, they ·96 LUNG CANCEN should be left in this solution two hours (If staining is to follow immediately, a half an hour is sufficient) After two hours in this solution the slide can be removed, air dried and picked for shipping the smerred surface pro tected from dust After a slide has been prepared it can be permitted to stand for seven days if necessary with out loss of cell detul Throughout the handling of the shde, especul care must be taken to prevent the contact of slides one with another, since cellular elements can be thus transferred Ordinarily, the referring physician's responsibility ends at this point, the slides are stuned and examined at a laboratory However, the stung and preliminary screening can sometimes profitably be done by a specnlly trained abortory assistant who can elminate from consideration those slides which show no abnormal cells Final diagnosis, however, must be made by a pathologist who has been further schooled in this technique One of the disadvantages of cytologic diagnosis is that its effec treness requires the services of a pathologist with exten sive experience with cytological appearinces The reason that experience with cytologic diagnosis is necessary for accurate evaluation of cytologic findings is that the criteria for malignancy by this technique ure different from those of tissue sections A pathologist is accustomed to depend to a considerable degree upon histologic structure and evidence of invasiveness These mulignint characteristics are not seen in cytologic speci mens The cytologist must make a diagnosis on the basis of relatively few cells which are isolated As a consequence it has been necessary to discover criteria for malignancy which depend upon the appearinces of cells rather than upon determinable cell behavior Furthermore there is no single criterion of malig, nuncy 7 diagnosis must be made upon the conjunction of ·FURTHER DIAGNOSTIC STUDIES 97 several cell abnormalities These can be roughly divided into seven groups (1) Cell size (2) Nuclear predomi nance (3) Irregular nuclear contour (4) Hyperchrom? tism (5) Nucleolar increase (6) Vitoses and (7) Cell groups (Figure 18) Cell size is significant to diagnosis both absolutely and relatively It has long been recognized that cell hyper trophy is a frequent manifestation of malignancy We have found that cell enlargement is critical to dagnosis as it approaches an actual doubling of normal cell dimen sions We have never seen a benign cell in which there is a two fold enlargement of nucleus and cytoplasm over normal though such an enlargement is common in the presence of malignancy Enlargement of the cytoplasm alone is not diagnostic enlargement of the nucleus alone (to greater than 20 micra in diameter) is presumptive but not diagnostic A variation in size from one cell to another may also be of importance but to evalunte the significance of such variation requres a good deal of experience 1 certun amount of such variation is of course to be expected among normal cells Nuclear irregularity Here again experience is neces sary for an evaluation Normal cells hue frequently some distortion of nuclei However distortion of normal cells is usually seen to be due in torsion or buckling i nucle ir distortion significant to diagnosis seems independent of exterior force Such distortion is usually seen as sharp er trusions or lobulations Hyperchromatism This is the classic abnormality of cancer cells and under certain circumstances it may be regarded as diagnostic without further evidence of ab normality Vassile irregularly distributed chrom itin con densations are the most unmistakable evidence of liy per chiomatism but chromatın knots and thick nuclear rims

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·FURTHIER DIAGNOSTIC STUDIES 99 may also be important indications of malignancy Care must be taken, however, to distingush these latter fea tures from the appearances resulting from over-staining Mitoses. In cytologic examination, unlike tissue sec tioning, this criterion is not of much importance Mitoses are seen occasionally, but by themselves they are never diagnostic Nucleolar aberrations Nucleolar aberrations are verv common indications of malignancy R irely a single nu cleolus will be seen which is so large that by itself it is almost diagnostic of malignancy Vore commonly, a sig nificant aberration will take the form of multiple, moder ately enlarged nucleol Such appearances are important Figure 18 - Plate 1 (Sputum ) Tultilobulated malignant nucleus showing massive chromatin condensations The contrasting clear areas afford reas surance that there has not been a technical overstaunmg with hematorylın Note also the normal staining of the nearby polymorphonuclear leuco cytic nucle: The cytoplasm is abundant and shows considerable vacuol zation or reticulation This appearance is quite common among malignant cells but is also seen in histiocytes Plate 2 (Sputum ) The heart shaped maliga int nucleus shows an al normal clearing which contrasts with the thick nuclear runs and with the coars chromatin condensations The two oval nucli above and to the left are truly hyperchromatic but because of the diffuseness of the stainmg they can only be judged by the overall staining of cells on the shide Plate 3 Valignant cell with nuclear predominance The nuclear d ameter is roughly 18 micra no other cytological abertation is present Cells of this size with the degree of nuclear predominance have never been scen except in association with carcinoma Plate 4 Lobulited (multinucleated?) malignant cell Note the in equality of the lobes The course irregular unequal chromatin granules are cagnostic Plate 5 Malignant squamous cells showing marked hypertrophy Inter cellular bridges are faintly seen on this pictute There is no evidence of comification In addition to the marked general hypertrophy other signs of malignancy are the prominence and sharp angulations of the nuclear nm and the prominent nuck oli Plate 8 Malignant cell group showing arution in size Even without the huge cell the others of the group show sufficient vanation in size to be suspicious Note the sacuolization in many of the cells in spite of the fact that they arose from a squamous cell carcinoma ·100 LUIG CANCER but it must be remembered that these structures may vary quite widely in non malignant cells Cell grouping The significance of this arises from the tendency of malignant grow ths to fragment to disintegrate into cell clumps wluch scem to be a unit of growth When such clumps are found in the sputum they ue casily distinguished from pomal exfohated cpithelium by their smooth configuration is compared with the rough jagged appearance of epithelial sheets and by a crowded appcrrince characterized by prominent nuclei and a mutunl nuclcolır distortion It is apprrent that cytologic dignosis cannot be a mechmcıl process Because very few single appearances are in themselves pathognomonic a confident diagnosis of malignancy depends upon an evaluation of microscopic findings Since the distinction between benign and malig nint is very often a distinction between degree of aberra tion a positive diagnosis requires that more than one criteria for malignancy be fulfilled At first sight this might seem ? dubious diagnostic procedure But it must be remembered that a diagnosis of malign incy on the basis of a tissue section also requires evaluation although perhaps to a lesser degree A cyto logic diagnosis is not less reliable than a diagnosis based upon i biopsy specimen its criteria are different not less reliable At the same time cytologic studies have distinct ad vintages over other methods of diagnosis Vjost impor tant is the fact that the wet smear when properly handled preserves cell size and shape far better than is possible by other methods of fixing tissue for pathologie study Tissue dropped mto fiyrtive shrinks markedly under the best circumstances In the process of wet smearing on the other hand the cells are flattened onto the slide and ad here to it so that marked shrinhage cannot occur The ·FURTITER DLACNOSTIC STUDIES 101 appearance of the cells as seen by the cytologic method is then nearer the appearance that the same cells would have if it were possible to examine them in situ without staining As a consequence criteria for malignancy such as cell size, nucleocy top! ismic ratio and nuclear contour can be depended upon Because the nature of malignant cells can be accurately visualized by this technique it is hoped that cytologic studies will eventually contribute to our understanding of the process of malignant change A disadvantage of cytologic diagnosis is that it is im possible to eliminate the element of chance Every tissue malignancy is presumably disintegrative in its essential nature and constantly throws off live cells from the tumor body into adjacent cauties and tissues Since according to most present day investigators bronchogenic carcı noma originates in the basal layer of cells in the bronchi it is obuous that in a majority of instances some cancer cells will penetrate into the bronchial secretions and be available for cytologic identification Theoretically then almost all bronchogenic carcinomas should be diagnosible by this means There are however clinical limitations In the first place if diagnosis is not made before the tumor occludes the bronchus of origin adjacent infummation may completely send off the body of the tumor from access to the trachea and in this case malignant cells cannot get into the sputum The second major difficulty is that the penetration of such cells into sputum is apt to be intermit tent Although cells are exfoliated by malignant grow ths in the lungs in countless numbers not every collection of sputumn will contain such cells In our experience malig nant cells are frequently demonstrated intermittently in patients with known malignancies Because of the intermittent appeurance of malignant cells in sputum muximum use of cytology depends upon an adequate number of sputum samples being erimined ·102 LUNG CANCER In a recently reported series of cases, we were able to make a positive diagnosis by cytology in 125 cases of 241 bronchogenic carcinomas proven by other pathologic methods This is an accuracy of only 52 per cent How cver, in 32 of the 116 missed cases only one sputum sam ple was examined, and in a majority of these 116, less than five scparate collections were examined We have found that when five sputum collections are made for each pa tient, an accuracy of about 90 per cent can be anticipated Cytology is, then at least potentially more useful to drag nosis than bronchoscopy We have repeatedly attempted to improve the diag nostic accuracy of cytology beyond 90 per cent by per sistent eriminations However, we have found that if malignant cells do not appear in the first five specimens, they are very unlikely to appear subsequentiv In most instances this failure seems to be due to the fact that the tumor does not adjoin a patent bronchus, but we have been unable to prove that this invariably is the case It cannot be assumed then, that evtology will replace Joronchoscopy, but it becomes increasingly apparent that it will do much to repair the deficiencies of the older method As an example, 70 of the 241 previously men tioned patients with bronchogenic carcinoma had perr pheral lesions Such lesions are more apt to be amenable to surgery than lesions close to the hilum We were able to diagnose 36 of these lesions positively by cytology, whereas by bronchoscopy only ten of them were singled out as suspicious for malignancy" on the basis of second ary findings If five specimens had been available for each patient cytologic diagnosis would hue been possible in many more instances There is also some evidence that cytologic diagnosis is particularly effective when the malignant lesion is in uts earliest stages of development The free movement of ·FURTUIER DIAGNOSTIC STUDIES 103 secretions is an important factor in this situation, but in nur clinical experience with the technique we have fre quently had the impression that younger and smaller le. sions oftentimes throw oft more cells into the secretions than older ones The chagnostic value of this observation is obvious A modification of the cytologie technique, bronchol ogy, is also of some promise In this procedure, bronchi secretions are gathered hefore a biopsy is taken at bron choscopy Where secretions are not present in sufficient quantity for stiction withdrawal Bronchal walls can bol swabbed, or suspicious bronchi fushed with saline sol ton The secretions are then prepared in exactly the se way as sputum for cytological examination Herbut re ports that this procedure had added 20 per cent to his diagnostic efficiency Such an exammation should be undertaken wheneser a bronchoscopy s done As has been said, the technique of cytologic diagnous has not been thoroughly evaluated It is without question a major adiance in the diagnostic armamentarium of the physician, but the proper application nf the method for maximum effectiveness has not been determined The first problem has been to estalılısh its reliability this has been accomplished to a considerable degree For some time Woolner and VacDonald have been advising exploratory operations on the basis of cytological findings in 40 per cent of the 70 patients reported upon in their recent study surgical exploration has undertaken upon the basis of cytologic findings, without other morphologic evdence of malignancy We helseve tlus to be rational procedure The greatest saluse of cytology might seem to be in periodie examinations for mules over 40 Although the examination of slides is time consuming, and therefore somewhat expensie, the fact that cytologic diagnosis can often ghe certain endence of bronchogenic carcinom?

·101 LUNG CANCER before the tumor body produces definite roentgenologic changes suggests that maximum utilization of the tech nique would include routine smears In any case it can be the most valuable single diagnostic deuce for the in vestigation of minimal symptoms where malignancy 15 eien remote possibility The more extensive use of cy tology which can be expected in the near future will waith out doubt markedly increase the percentage of broncho genic carcinomas which are amenable to surgery ·Surgery 6 One of the most impressive achievements in the bustory of medicine is the virtual perfection, in the short space of 18 years, of the technique of pincumonectomy Since the pioneer work of Graham and Reinhoff, almost every specialist in the field has contributed to the development of the operation As compared to an expected operative mortalty of around 50 per cent in the years following the introduction of total pneumonectomy a patient today has between 90 and 95 per cent chance of surviving the radical procedure Even these figures slight the magnitude of the achevement because today surgeons are able to operate on almost everyone who might be benefited the 84 per cent operative mortality that Graham reported recently was sustained in a group of patients in which the elaborate criteria of operability of former days was not necessary Although lung surgery is being increasingly applied to the treatment of other chronic pulmonary conditions, it is preeminently the treatment for bronchogenic rarca noma At the present time, it is the only method that offers any hope of cure, and it is perhaps even the only method which favorably effects the conrse of the drense It is the technique tou ard u hich the physician who diag noses bronchogenic cucinama liopes to derect kis patient louerer, as luas lieen sufficiently emphasized already in the course of this monograph a great many patients ( 1031 ·106 LUNG CANCER with bronchogenic carcinoma are already obviously in opcrable by the time the condition is diagnosed Statis tical reports on the exact percentage of patients unsuit able for surgery show a considerable variation, and it is difficult to arrive at a representative figure In surgical clinics there is apt to be a fairly high percentage of oper able cases simply because many of the inoperable ones have been recognized in early diagnoses and have not been referred for surgery The attitude of the surgeon is also apt to influence this proportion Graham reports about 40 per cent of his patients at present are worth oper ating upon, tus probably represents the highest possible cstimate for the overall, inclusive situntion (which must mclude city and county hospitals where the disease is more apt to be far advanced when discotered) In a great percentage of the patients who reach the operating table, an exploratory thoracotomy reveals the growth to be inoperable and a pneumonectomy is not performed Graham, who is conservative in selecting pa tients for surgery, is able to proceed to pneumonectomy about 65 per cent of the time Surgeons who perform thoracotomies more readily are apt to be able to continue to pneumonectomy less often Rosemond performs pneu monectomies at present upon about 55 per cent of all who are thoracotomized Lindskog and Bloomer, who did about the same percentage of pneumonectomies between 1945 and 1918, as compared to an earlier figure of 38 per cent, felt the improvement was due to an increased pum ber of pneumonectomies palliation Hence, 50 per cent can be taken as a representatie mein So far as the technique of the operation is concerned, it is hard to see how this figure can be improved upon, a pneumonectomy for bronchogenic carcinoma at the present time frequently in cludes resection of invaded areas of the visceral pleura, the chest wall, the diaphragm and even cardiac tissue ·SURGERY 107 The real question concerns the percentage of patients who are enabled to live a substantially longer time be cause of the surgical removal of 2 carcinoma The dcter mining consideration is not entirely the question of the five year cure possibility but of the material incie ise in life expectancy that can be anticipated This figure is extremely hard to estimate it is complicated by the fact that the willingness to undertale ever more radıcıl exci sion of my aded contiguous areas will presumibly incre 250 this percentage someu hat over our previous experience It is our impression however that in at least 40 per cent of the patients recensing a pneumonectomy there is no cvidence of a material increise in length of life We have carefully cu lewed 241 cases of bronchogenic carcinoma from various sources . these illustrite what we believe to be 1 repr e situation so far as the operability of lung malignancy is concerned These pa trents were found to have the disease at these institutions between Apnl 1947 and May 1950 Suroilal Percent Tume age Arcrage of Total Group 1 Clinically inoperable 117 patients 45 54 Expired 114 Cases Il 4 Wechs Alive 3 Cases 91 2 Averige 134 "Source of materi! Vorvers ty of California Hostal 83 Sun Cranc sco Cty and Co Inty Hospital 80 Stanford University Hospitals 6 Co inty Ilospital, and Tuberculosis Santoni 23 Goyemment llospitals 23 Private Hospitals and Physcans 20 Total 211 ·108 LUNG CANCER 2085 Group II Cxplored but not resectable 50 patients Cxpired 49 Cases 240 Wechs Alive 1 Case 61 0 Average 250 309 Group III Explored and resected- 74 patients Expired 61 Cases Alive 10 C2ses Averige 377 Weeks 960 N N As can be seen only 10 patients of the 74 resected are still alne at an average of about one and one half years after the pneumoncctomy This is 7 salvage rate of roughly 4 per cent of the whole group of 241 patientshardly an encouraging finding the five year cure rate will undoubtedly not exceed half this percentage The major effort of all members of the medical pro fession is naturally directed to increasing the percentige of cuires"--interest centers around the 10 per cent or so whose life expectancy can be substantially increased by surgery The whole cancer program is properly devoted to ob taining a further increase in the size of this group The limitation of surgery hou ever is readily apparent Gnen the same overall proportion of patients who proic beyond the help of pneumonectomy at thoracotomy and with the same rate of recurrence and the possibility of maters ally improving either figure to any great extent is a remote one tien if the speed and accuracy of diagnosis can be doubled at least four out of csery five patients who have bronchogenic carcinoma vall still remun beyond the help of the surgeon It is proper that the mun effort of medicine should bc directed toward an increase in the number of surgical ·SURGERY 109 cures no matter how difficult this may be However the indivdual physician cannot hmit his concern to the two in 20 or even the hoped for four in 20 patients who are within the reach of surgery These patients who are doomed and who are in the majonty are not the less entitled to the maximum effort of the doctor Surgeons often speak of their radical techniques as salvaging it is a useful concept By a program directed to the total care of the patient including his psyche there is some thing to be salvaged even m those patients who yo in eligible for pneumonectomy at diagnosis Something will be sad later of the means available for the management of those prtients who are deemed to be inoperable at diagnosis the point here is that well over one fourth of all patients with bronchogemc carc noma ure not in our calculations seceiving the attention to which they are entitled The whole group of patients who are subjected to operate procedures which do not materially increase their life span are to some degree actually mishandled so long as surgery is our only ap proach to lung cancer the deal is two groups of patients -those wlo are inoperable at dingnosis and those who are resected and cured Needless to say this is a theoretical ideal it could only be attained by a procedure which would radically reduce the percentage of cures which are now achieved The effort however must be directed to ward a substantial reduction of the group of patients who are now subjected to surgery without material benefit Again this responsibility is one which inevitably must devolve upon the physician maling the diagnosis The responsibility cannot eta by referring to surgery all patients in whom carcinoma is found the diagnosis must include an opinion as to operibilly If there is a chance of the surgery should be requested without liesi tation or delay but the physician must be as certun as ·110 IUG CANCER modern techniques permt that there is indeed a chance of cure The terrible psychological consequences to a pa tient when he lias been prepared for a pneumonectomy for the cure of bronchogenic carcinoma, and then must be told that the operation is not feasible, are memorable Very frequently the doctor, as a human being, must regret that the patient came off the table alıve The situation is hardly better in the case of recurrence On the other hand, if the patient is recognized as inoperable when the condition is diagnosed, a physician making full use of the modern armımentarum of drugs, and with the co operation of relatives-and perhaps with a special capacity for reassurance-can help the patient male good use of the time which remains The object, then, should be toward full dagnosis be fore surgery referral, and such a diagnosis involves a maximum effort to evaluate operability. The basis of such an evaluation is a further physical examination after the diagnosis of bronchogenic carcinomi, morphologically proven or presumptue, has been made it needs to be the classic painstahing, tedious and thorough examina tion supplemented by extensive rocntgenologic examma trons as suggested by the physical examination, and any other technique that promises information Of course, the findings of the bronchoscopist are criti cal, an invaded trachen, a tumor too near the carina to permit surgical closure, a rigidly fixed trachea, are all immediate contraindications Even moderate hoarseness, uplying in ok ement of the laryngeal nerve and some paralysis of the larynx, or a paralyzed diaphragm, may likewise be contraindicatory If such signs are lockmg further investigation mto the relation of the tumor to the mediastinum should be made roentgenologically Core relation of posterior-anterior and lateral films will some- ·SUNCENY 111 times determine whether or not there is mediastia) in Joh ement when the tumor is thought on the basis of such a correlation to lle suespiciously near the central shadow, edema of the face and neck even though mint mal will confirm veni caval ini olement An angiocardiographic examination may be very help ful in this presurgical study Dotter Steinberg and Hol man in a recent study of the subțect suggest four posi teve angiocardiographic findings which are considered evidence of moperability in the presence of bronchogem carcinon. They are i Partial or complete occlusion by tumar the left pulmonary artery within 15 cm of its ste of origin or of the right pulmonary arterv proximal to its point of bifurcation 2 Partial or complete occlusion of the great med, ıstınal Veins duc to tumor or polypord defects with the superior vena cava 3 \ſediastinal metastases seen by contrast dtiuneation of displacement and deformity of aduceut nascular structures indicating exfers il pressure + Localized thickening of the pericardium in the abs sence of pleural clise ise and adjacent tumor Though ingiocardiography has not been completelv evaluated its promise to preoperative examination is en There are in addition other specific signs of medias tinal abnormality which when a bronchogenic carcinoma has been demonstrated will normally be referred to that condition and which will indicate inoperability Any couraging inly gree of extension into the anterior mediastımum Perhaps ·112 I UNG CANCER the most important technique, however, is the careful clicitation of even minor symptoms as guides to further investigation Such attention to symptoms is even more important as a guide in the search for metastases The fact that cancer cells which reach the blood stream from the Jung pass directly through the heart into the great vessels male metastatic manifestations protean Analyses of such me tastases on the basis of collections of case histones, such as the one listed before, are more of an indication of the range of possibilities than an actual guide Next to the history and symptomatology, the most important pro cedure is a careful palpation of the patient's body, with particular attention to the Iner, spleen and lymph nodes In our series, we found that metastases to the bone was accompanied in every case by pain so the skeletal system need not be of particular concern unless there are symptoms referable to it The whole procedure otherwise should be conducted with a maximum of suspicion, and the patient should be immediately referred to an appro priate specialist when an abnormality is found that might even remotely be related to the broochogenic carcinoma It should be noted that when the patient knows that can cer is under consideration, the resulting psychic disturb ance is apt to be difficult to distinguish from the symptoms of a central nervous system lesion, a psychiatrist can often help determine whether or not there is an organic basis for the psychic disorder Again it should be emphasized that the object of this examination is to spare the patient the discomfort, mental distress and expense of an operation which cannot ma terally benefit him As such, it is necessary that inoper ability be proven by morphologic methods or the strong est of presumptive evidence when such evidence is not forthcoming, exploration must be undertaken ·SURCURY 113 If the patient is not proven to be inoperable after a thorough examination, he should be referred to a chest surgeon without delay The responsibility of the physician is here more or less at an end we have found that it is of help to the patient, and frequently also to the surgeon, if the patient is told in a general way what he may expect while under the surgeon's care The latter cannot be er pected to have the time to establish the personal relationslup with the patient that is so important a part of the physician's services, and something can be contributed to the operative procedure if the physician will take time for reassurance and an explanation of the preoperative procedures that the surgeon is apt to require The general supportue intention of venoclysis, when it seems likely to be called upon, should be made clear, and the import ance of injections and aerosol tibiotics toward minimız ing postoperatne infection should be explained The function of the preoperative pneumothorax may be dis cussed, and the patient should be prepared for further bronchoscopy if the surgeon so requires In general, the patient should be warned that his stay in the hospital prior to the operation will be occupied with numerous but routine measures When he is not so prepared, the pi tient, who is already disturbed by the seriousness of his condition, is apt to regard these measures as a series of alarming emergency procedures He should further be informed that for a short time after the operation there will be some difficulty with tracheal congestion and that for a few days drainage of the thoracic cavity is routine procedure The subsidiary techniques of continuous administration of whole blood to maintain normal blood volume, and control of lung function by intratracheal intubation, are cry important to the relatively low hospital dcath rate that is found in these cases at present The administration ·114 LUNG CANCER of a general anesthesia by a closed system with the intra bronchial tube is perhaps still the general practice, but Overholt prefers paravertebral block and local infiltration with general anesthesia available for use whenever its analgesic effect is desirable The operative approach is made anteriorly (Reinhoff) or posterolaterally (Overholt) The latter generally in voh es resection of the sixth rib When the diagnosis is in doubt, a frozen section of the abnormal tissue can be made and examined without dehy as soon as the chest wall is open, where such tissue is not readily found a pathologic cxamination of mediastinal nodes will prose or disprosc bronchogenic carcinoma with some degree of accuracy this point the surgeon can also estimate operability in terms of extension Closure of the bron chal stump, which in the past has been a weak point m the pneumonectomy procedure, is now accomplished by ligature 1 cm or so above the bronchial stump, fibrinous clotting in the proximal end helps secure an airtight clos tire, which is then covered by a pedicle flap of parietal pleura In this way closure does not indiefinitely depend upon the suture, which tends to cut through the bronchus Although pneumonectomy is a highly developed art today, about one out of five patients die within a month of the operation The chief cause is postoperative cardio vascular failure if the patient survives the first month, It is unlikely that he will die directly from the operation thereafter, but recurrences witłun the first year are very common Total pneumonectomy is not without its phy. siological sequelae, ordinary occupations and light actiity can be pursued in most cases, although there will be a tendency toward dyspnea After five years or so, the overdistended lung that remains is apt to lose efficiency O erholt and Schmidt report txo of ten five year cures to be respiratory invalids For this reason some surgeons ·SURGERY 115 prefer to follow a pneumonectomy with thoracoplasty, since the remaining lung is more efficient if its distension is limited There is a conviction in some obseivers that a patient who has had a pneumonectomy is especially sub ject to right-sided heart failure It has been generally assumed that the only rational approach to bronchogenic carcinoma was one which in cluded the widest possible crcision of possibly invaded tissue on the analogy of the radical mastectomies donc foi breast cancer The subject has been to some extent re opened by the report of Churchill and his associates, on the favorable results obtained in selected cases with a lobectomy Although they refrain from drawing conclu sions, their experience with the less radical technique sug gests that if the tumor has not extended beyond the limits of a lobe, and perhaps of the mediastinal nodes are not grossly involved, a lobectomy may be as efficient a tech nique as a pneumonectomy Which operation is to be undertaken is, of course, a matter for the decision of the surgeon at the time of operation, but it is interesting to note that lobectomies are not absolutely contraindicated in instances of bronchogenic carcinoma The advantages of the less radical procedure to the patient postoperatively are substantial Nothing has been said so far about the so called pallative pneumonectomy' This procedure is the subject of a great deal of disagreement, and probably in such in stances all extreme statements are craggerations As operative mortality has been reduced, there has been a tendency to operate on every lung cancer patient who is not immediately seen to be beyond help, this procedure is frequently justified by the assertion that palliation is at least possible in ou opinion, this point of ven is to be deplored The palliation achieved by radical excision can not be used as a means of evadıng diagnostic responsi- ·LUNG CANCER 116 bility The patient should not be encouraged to submit to radical surgery until there has been a realistic ap praisal of its possible benefit On the other hand, when a patient has been explored in entire good faith and found to be inoperable, and there are large amounts of infection in the carcinomatous lung, palliation by pneumonectomy is justified It is true, likewise, that a low grade squamous carcinomi can kill a patient by rotting away portions of the lung, in spite of the physician's best efforts, in these mstances, a pneumonectomy can be undertaken esen when there is no hope for cuse It is our impression that the average patient with an inoperable bronchogenic carcinoma is better off, all things, including his mental attı tude, considered, if palliation is less radical Except when the lung is rotting away, a flexible use of massive doses of antibiotics will usually be adequate to control the infection in the relatively short time the prtient has left Even though the infection remains troublesome, we believe this symptomatic treatment is superior to a radical and hope. less procedure involving shoch, hospitalization, and most of all, excessive psychologic disturbance for the patient Care of the inoperable cancer patient. Close rapport between patient and physician is always desirable, in the presence of a malignancy it is a stal necessity At every point in the diagnosis and trentment of the patient with lung cancer, his confidence in the physician is absolutely indispensable, it is a sine qua non The operative mortality and postoperative death rate attendant upon thoracic procedures is still appreciable, for this reason an explora tory operation without morphologic proof of malignancy absolutely demands that the patient be given a careful and realistic presentation of the 'hard facts” lie will accept such "hard facts only if his trust in the diagnosing physician is complete If an operation is undertaken and is successful, only the physician can relieve the patient of ·SURGERY 117 huis fear of recurrence As to the inoperable patent or the patient with recurrence his mental stability is very apt to depend upon the faith he his in his doctor Every phy sician will have his own approach to this problem of gun ing the patients confidence It must be emphasized how ever that the effort to win the patients trust must be begun early and exerted continuously It is not easy to make a diagnosis of malignancy and then try to win the patients confidence It is generally desirable to mtroduce the idea of cancer early in the diagnostic procedure of any male patient over 40 We have found it useful to tell every such patient that he is suspected of serious disease such as tuberculo sis cancer or syphilis and that the physicnın is obligated to suspect and eliminate the worst Wehuse found that hy introducing the subject of malignancy into the conver sation during the patients first or second sit he is en abled to accept the possibility and defend himself ag unst its implications by mahing light of it Also the very fact that cancer has been introduced into the conversation cisually very often permits him to unburden himself of his fear on the subject such an unburdening establishes immediately rapport between patient and physician that might otherwise require acels to des clop We have not found cancerphobia to result when the subject is intro duced in an off hand manner and the gun to the patient and physician if 7 diagnosis of malignancy must later be made is considerable The real challenge to the physicians art is the patient who is inoperable at diagnosis or who has postoperatie recurrence It is seldom advisable to attempt to conccal stich a finding such an attempt usually results only in loss of confidence in the physician On the other hand it is not necessary to elaborate on the diagnosis If after the initial disclosure the patient is allowed to take the lead ·118 LUNG CANCER in the conversation he will usually indicate the attitude toward the diagnosis that he would like to tale If the physicrin will follow such 1 Icad the patient is enabled to accept the dingnosis with a minimum of psychic shock and the sense of comradeshup thus established between prtient and physician in entire agreement can be very helpful It is most important that the patient feel that every thing possible is being donc In many instances he will put off the consequences of the disease by depending upon the discos ery of a miracle drug This attitude wall do hım no harm He should be examined frequently and every new symptom should be evaluated and if necessary countered with new drug or a new combination of drugs Repeated laboratory examinations can be made is suggested by symptoms From the physicians point of view these procedures muy seem a waste of time For the patient however they will be concrete cudence that everything possible is being done By deeply concerning himself with minor developments the physician can re lieve the patient of some of the anxiety attendant upon an incurable condition A patrent kith inoperable broncho genic carcinoma should be kept ambulatory to the last possible moment Vany of them are happiest if they can continue to be of service to their family and they should be permitted to pursue their normal occupations if they care to Many can become engrossed in an accentuation of their normal social patterns in shopping and attending the theater Others can fulfill themselves in a certain sense by doing those things to which they have always looked forward in any case every effort must be made to heep the patient occupied and interested in things about fum A major service that the physician can perform is to lend the seight of his counsel to the patients own im ·SURGERY 119 pulses The patient may be happiest if he remains at home but too frequently his family will be merely reminder of what he is losing in such cises he may prefer to take up his residence at a hotel Not infrequently he will actually want to remun at the hospital where he has been sent for observation and where because of his con dition he has become an important person There is no doubt that by a careful control of pain and infection and a proper use of diet and dietary supple ments a patients life can be maternally prolonged be yond that to be expected if he were not intensively treated One is never more impressed with the possibili tres of morphine and the entire field of narcotics than when they are utilized in various disguises in the treat ment of bronchogenic carcinoma Scopalamine can be added to standard narcotics as in Scheslinger s solution to give the patient a mental lift without his being aware of the reason Use of the various synthetic preparations which stimulate such as dextro amphetamine sulfate (Dexedrine SKF) can alleviate depression and anxiety In general it is best to prevent difficulty rather than alleviate it drugs can be used liberally At times the patients family can be more difficult to manage thin the patient himself Their contradictory re actions and desires can completely exhaust the ingenuity and the nervous system of the physician At least one responsible member must know the complete facts usu ally the patient will indicate the member of the family who should be informed However it is often best of those outside the immediate family are not told Where the family group is large their frequent inquiries and advice can be extremely trying but if the physician las accepted the care of prtient he must do his best in this difficult position lle cannot afford to minimize the importance of the family and the value of their help ·120 LUNG CANCER As difficult and exhausting as the care of an inoperable patient may be, there is truly no greater challenge to the physician in the exercise of the art as well as science of medicine There are very few instances in which he can be so confident of the value of his services This, then, is the general relation of surgery to the overall carc of the patient with bronchogenic carcinoma at the present time As luas been sud before, major im provement in this dim picture can come about only by carlıer diagnosis, and it would seem that the effectn eness of surgical techniques, cien with greatly improved diag nosis is still limited to a serious extent by the nature of the discase At best, the physician is confronted by a difficult problem in evaluation lle must make maximum use of the only teclinique whic off any possibility of cure, but at the same time, he cannot evade hus responsi bility to the patient by cultivating an overly optimistic view of the possibilities inherent in surgery His ap praisal must be realistic, and his decisions are critical in many respects, since he is the only one in medicine who can he crpected to give due weight to that inestimable factor, the personality of the patient ·Nonsurgical Techniques 1 7 ANY DISCUSSION of chemotherapy is a method of trenting bronchogenic carcinoma must have something of the chrracter of a prophecy There has been nothing brought forward which has even ipproiched in its effect upon any malignancy the criteria of a cure However substances have been developed which are carcinoid which have proven themselves to have an adverse effect upon malig nant tissue even when that tissue is bronchogenic carcı noma We have drugs it the present time that hill cancer cells although they are not effective enough to kill all cancer cells in any patient They demonstrate nesertle less the possibility of a successful chemotherapeutic agent for malignancy being developed and they suggest the general areas of drug therapy in which a cancer cure is most likely to be found The subject is particularly worth the attention of students of bronchogenic carcinoma be cause it is impossible that 1 quarter of lung cancer pi trents can be cured by other means Hormonal therapy Tumor therapy by means of drugs can take one of two directions In the first place 1 tumor can be approached by an attempt to alter radlic ully the environment in which it irose and to which it is ncctt tomed This is liormonal therapy in the treatment of certam malignant grow ths this approach lzs been of ( 121 ) ·122 LUG CANCER substantial service Estrogens have been used to induce prolonged remissions in breast cancer in postmenopausal women and these substances have also had a marked pal Irative effect in cases of inoperable prostatic cancers Tes tosterone on the other hand has been effective on occa sion in the treatment of breast cancers in premenopausal women Lastly progesterone has at times induced local regression in inoperable carcinoma of the uterine cervix As these examples indicate hormonal therapy is chicfly of use in the treatment of malignancies of ses conditioned tissue This may well represent our rudi mentary knowledge of hormones and their operation however and not be an essential distinction between sex tissue malignancics and malignancies of other systems or orgins Lung tumors may prove to be as dependent upon hormonal frctors although less obviously as prostate tumors The real question in regard to hormonal therapy con cerns the autonomy of malignant growths In the ex perience that has been accumulated in the use of hor mones for the treatment of malignancy it has become eudent that we must modify our concept of cancer Malignant growths are not necessarily autonomous Par ticularly in experience with prostatic cancers it has be come obvious that ? tumor may be fulminating and still be dependent upon certain hormones of the host Often it is years before these growths become truly autonomous There is a great deal of clinical evidence to suggest that bronchogenic carcinoma also depends for its genesis or its progress upon ? particular hormonal substrata in the host A delay of up to nine years has been noted be tween exposure to ? carcinogen and the inception of a clinically detectable cancer a fact which clearly imples the necessary operation of hormonal factors in the past we huve liad no way to investigate the status of such pa ·NOVSURGICAL TECHNIQUES 123 tients in the interval between exposure and the develop ment of a macroscopically visible tumor body scattered reports of findings discovered at autopsy in accidental deaths suggest that small clusters of tumor cells may re main in situ for an indefinite period before 1 frank lesion develops If the routine use of cytology confirms this sup position it may be that we shall be able to delay or pre \ent the development of autonomous tumor bodies by hormonal treatment It is possible that hormones will become a major weapon in the control of lung malignancy in coming years Specific chemotherapeutic agents At the present time however the avenues of direct attack upon the tumor cells themselves seem to have more immediate promise Chemotherapeutic agents aim at a direct effect upon the tumor cells and do not require for their effectiveness that the tumor be dependent upon the hormonal characteristics of the host These chemotherapeutic agents can be divided into three broad groups The first which is currently re ceiving the least attention is the attempt to develop substances which will have a deleterious effect ideally a lethal effect on specific kinds of malignant tissue Stil bamıdıne is the only compound at the present time which has attracted much attention and which can be so classi fied When used in cases of multiple myeloma adminis tration of the drug is followed by the appearance of baso philic inclusion bodies within the myeloma cells which appear to have the effect of dislocating their nucleopro teins Marhed clinical improvement follows in a substantial number of cases It seems doubtful however that the course of the disease is altered beyond the palliative clinical effect Ethylstubamine a related compound has been tried in an effort to improve upon the results of stil bamıdine but it has not been found to be superior to the original compound ·124 LUNG CANCER Stılbanıdıne is of more interest than is suggested by the clinical results so far reported because it seems to have a special affimty for these particulur malignant cells not explained by general theories of malignancy The inclusion bodies which appear in the myeloma cell do not ap pear in adjacent normal cells Thus, this one compound suggests a whole new field of potential cancer research it is possible that when the stılbamıdıne action is better kinderstood, other compounds with a specific effect upon a specific kind of malignant cell will be developed Cell poisons. Of more immediate interest to the stu dent of bronchogenic carcinoma are the cell poisons These are compounds which have a generally cytotoxic effect, which in sub lethal dosage particularly damages rapıdly proliferating tissuc llence, it is theoretically pos sible with one of these substances to destroy a rapidly growing malignancy without killing the patient in the process The possibility, needless to say, is still academic Interest in this class of substances arose out of the experiments with mustard gas during and following the first World War The nitrogen mustardis, in which nitrogen replaces the sulphur of the mustard molecule, were the first cell poisons to be tested for therapeutic effect upon cancer The action of these substances is still not under stood, their particularly violent effect upon living tissue suggests that they interfere, in some way, with the intracellular enzy me systems This would account for their pecularly virulent affect upon the more rapidly prohfer ating tissues, normal and malignant Among normal tis sues, bone marrow, mucosa (particularly intestinal), and lymphoid tissue are most markedly damaged by nitrogen mustard treatment In the long run the effect on bone marrow is the limiting condition when the drug is used therapeutically Microscopically, the effect of nitrogen mustard on such cells is seen as vacuolization of the cy to ·NON SURGICAL TECHNIQUES 125 plasm fragmentation of cell nuclei and marked swelling of cells Bastrup Vadsen in un in litro study found that the nitrogen mustard severely depressed the mitotic 1c tivity of the cells at first but such activity as was present was normal About twenty four hours later long after the mustard hnd disappeared from the broth mitosis was resumed but was abnormal This second phase is the one of most clinical interest One of the things which make the action of these cell poisons difficult to understand is this delayed reaction in which the significant effect of the poison begins to be seen only after the poison itself has dhsapperred Clinically the effect of nitrogen mustard is usually mild local thrombosis at the site of the injection nusen and vomiting a few hours afterward and skin rash in less than half the patients which develops some time later Within a few days 1 muhed and sometimes serious de pression in the leukocyte count appears This may persist for as long as three weeks The use of nitrogen mustard is limited by the development of this blood picture which must be watched carefully In animal experiments however it seems that the lethal effect of large doses of nitrogen mustard is primarily due to its effect on gastro intestinal mucost which is shed massively Rather oddly the effect of nitrogen mustard upon malignant tissue closely parallels the effect of irradiation not only in the microscopic appearance of cells after trentment but in the spectrum of its usefulness igainst the various forms of malignancy Thus it is most effective in the treatment of Hodgkins diseise frequently of service in the treatment of lymphosarcoma and at times it may murhedly alleviate the symptoms of chronic leukemiz Although at parallels radiation in its clinical application however there appears to lie distinct differences in the two methods of treatment Vost signific int is the find ·126 LUNG CANCER ung that I course of nitrogen nustard frequently re sensi tizes tumor cells that have become ridio resistant For thus renson radiation and nitrogen mustard therapy are frequently alternated Nitrogen mustard though it parallels radiation ther apy in many wazs hus 1 distinct adı intage in certain instances Arumal erperiments suggest that it is fired ls the various tissues within a few minutes of injection but its destructive effect is much slower than is the case with irradiation Larger dosage is thus possible Its effect is longer Iusting a positive inhibition of cell duision may be seen thurty days after injection-almost twice as long as with irradition Further dosage is more effectively controlled It is thus the treatment of choice in widely disseminated Hodgkins disease and lymphosarcoma Evrly trials of nitrogen mustard in the treatment of bronchogenic carcinoma suggested that not much was to be gained by its use tawener continued experience has somewhnt modified this early pessimism It has not been established that the nitrogen mustards are able to in crease life expectancy but subjective improvement is usuilly obtuned and in some instances there may be substantial obiectie improvement Rather frequently an in lid will become temporarily ambulatory following the tre rtment On direct inspection by caserostomy the tumor may at times be demonstrated to have regressed Dosage is usually 0 1 mg per kilogram of body weight each day for four successi e days The usual symptoms are observed-loss of appetite nausea and vomiting and decrease in the white cell blood count The latter develop ment must be watched closely However the violent reactions to the drug which were encountered in early experience ve incommon at the present time Adminis tration is uncomfortable but it is seldom so intolerable is to require discontinuince of treatment ·NOVSURGICAL TECINIQUES 127 The greatest positive effect is to be expected in the treatment of undifferentiated carcinoma Literature on the subject frequently refers to the relief of mediastinal symptoms obtained following administration of the drug Adenocarcinoma is least often benefited The findings of Lynch, Ware and Gaensler agree with most reported results According to their classification, 83 per cent of the undifferentiated carcinomas, 50 per cent of squamous carcinomas, 33 per cent of adenocarcinomas, and 11 per cent of the epidermoid carcinomas in their series showed demonstrable objective improvement when treated with mitrogen mustard At times we have felt that there was also some slight increase in life expectancy in cases of bronchogenic carcinoma treated with this drug, but this factor is so difficult to evaluate that we could never be sure that the drug really had this effect It is certain, however, that in many instances the sense of well being that follows a course of nitrogen mustard is so marked as to justify its use in any instance of inoperable lung cancer in which symptoms are troublesome * Nitrogen mustard” is hardly a specific description, since over 50 related compounds have been developed which can be so described Only two, however, are in general clinical use at the present time These are methyl bis (B chloroethyl) amine (FIN2), and methyl tris (B. chloroethyl) amine (HNB) Limited trials of the other mitrogen mustards have not demonstrated them to be markedly superior to these two Recently, however, sereral compounds have been announced that can be ad ministered orally, and which seem to have less severe side effects Perhaps the most promising of these new compounds is trisethylene-imino s-triazine (TCV) This compound can be administered intramuscularly or intraenously in a total dose of about 0 15 mg per kilogram of body weight When it is administered in this fasluon, its ·128 LUNG CANCER clinical effect 35 indistinguishable from the clinical effect of the older nitrogen mustards It can also be adminis tored orally in tablets of 5 mg once or twice daily until a total dose of about 04 mg per kilogram of body weight has been given When TEM is administered orally, side effects are less severe and better control of dosage is main tained its inhibition of the malignancy, however is not niore marked than that accomplished by the other nitro gen mustards In a very few clinical trials, its effect upon bronchogenic carcinoma in particular would seem to be considerably less than the effect achieved by the older compounds Though clinical tests of urethane have been disap pointing, in-vitro experiments would suggest that it is essentially of more interest than the nitrogen mustards In addition to the depression of mitotic activity, followed by abnormal mitosis, which the mustard demonstrates urethane seems able permanently to arrest cell day ision in metaphrse, a kind of physiological assassination that may in the future be of more interest than the irradiation like effect of the mustards These in vitro observations arc somewhat uncertain, since a relatively high concentra tron is required for significant depression of cell action Clinically, urethane has so far been demonstrated to have no more thin a pronounced hematologic effect in thera peutic dosage Therefore, its use at the present time is confined to the treatment of the leukemias in the treat Inent of multiple myeloma urethane muy produce remark able changes in the whole hematologic picture, with marked rise in hemoglobin and a decrease in abnormal serum proteins It is also the treatment of choice in chronic myelocytic leukemia Dosage for urethane ranges from 2 to 4 administered orally, until a total of 200 grams or more, has been reached The blood picture is the factor deter grams daily, ·MONSURGICAL TECHVIQUES 129 mining the length of treatment ordinarih urethane is administered until the leukocyte count drops to approxi mately 20000/cu mm Thrombopenia is hazard and toxic symptoms of nausea and vomiting as well as bone marrow depression must be anticipated in spite of much experimental work it has not been demonstrated that urethane can be expected to improve upon the results obtuned with nitrogen mustard or radiation therapy Folic acid antagonists Folic acid antagonists were first applied experimentally in the treatment of malig nancy when it was observed that folic acid and its conju gates had the effect of hastening the course of acute leu kemia From the beginning the antagonists proved to be significantly effectue In a period of five years folic acid antagonists have been used in the trcatment of about five hundred known cases of acute leukemia and that been established as the ele - Si nihcant improve ally the use of the drug although only about 15 per cent of adults so treated respond satisfactoril Acute lymphci tic leukemia generally responds better tlrm acute myelocytic leukemia Perhaps one reasou for the superior results that have been obtained in children is that they are ble to tolerate a larger total dose per kilogram of body weight llonerer there has not been shown to be 1 correlation betueen dosage tolerance and response The drug can be admin istered intramusculirly or orally Dosage may range from 5 mg per day si diys a week for a five year old child up to considerably greiter doses for adults There is no standard dosage procedure and for this reason oral 10 ministration is probibh preferred since staffords a more accur ite control Once the patients dosage tolerince his ben established the treatment should be continued until ·130 LUNG CANCER the blood elements return to normal limits, or until toxic reactions force discontinuance of the treatment During the period of treatment, the patient must be watched very closely because the danger of infection is acute Clinical side effects are apt to be sei ere, with nausea and vomiting prominent There may be ulcerntion of the mucous membranes and gastro intestinal hemorrhage, accompanied by severe abdominal pains, megaloblastic anemia, thrombocytopenia, cutaneous erruptions, and other disquieting symptoms Bleeding can sometimes be controlled with toluidine blue or protamıne sulphate Special care must be taken to prevent the development of a generalized infection However, prolongation of life at times markedly accompanies clinical improvement One child is still alive 30 months after the onset of the disease -an almost unprecedented life expectancy when the discase is acute leukemia Ultimately, however, the disease can be expected to become refractory to further admin istration of the drug, and the downhill course from that point is usually very rapid Aminopterin was the first of these folic antagonists, subsequently there has been much effort to develop re lated substances which will improve upon performance of the original At the present time, 4 amino N 10 Methyl PGA is probably the drug of choice On the whole, limited trials of folic acid antagonists in the treatment of other malignancies have not been en couraging In general, these drugs would seem to be of more potential value in the treatment of sarcomas than in the treatment of carcinomas, although in neither case, except in a few instances, have results been impressive Howei er, there is occasionally evidence of at least some subjective improvement when they are used in the treat ment of bronchogenic carcinoma Since this field of com pounds is still comparatively new, it is possible that an ·NONSURGICAL TECHNIQUES 131 antagonist effective against lung cancer may be forthcoming sooner or later The discovery of folic acid antagonists was not the result of any deduction beginning with a theory about tumor tissue, they were discovered experimentally Their specific effect is still somewhat of a mystery They appar. ently inhibit all cells in their intake of folic acid, this is indicated by the fact that their antı tumorigenic effects as well as their clinical side effects can be suppressed by the administration of the citro orum factor They are not, then, cell poisons-they are inhibitors Neither can it be said that they are specifically involved in cell growth children receiving the drug continue to grow and mature at normal rates The excitement that the folic acid antago mists have occasioned among cancer research workers is derned from the fact that they apparently specifically inhibit one critical enzyme of a cell from its normal opera tion It is theoretscally possible, then, to arrest a malignant growth indefinitely The ultimate failure of the drug comes about because the malignant cells are able to adapt themselves to this new situation in experiments, it has been possible to develop leukemias that are to some de gree dependent upon folic acid antagonists, the cells are able to convert the antagonists to compounds which can be utilized in place of folic acid There is no reason to believe, however, that other substances with such direct effects upon cell chemistry will necessarily be of tempor. ary effect All these partially effective and interesting techniques against malignancy are the result of rigorous and deter. mined imestigation of possibilities suggested by clinical practice or experimental observation It may well be that such procedures will eventually proude the answers to the control of malignancy On the other land the clfart ·132 LUNG CANCER of biochemists and pathologists to understand the basic unit of growth, the cell, in the first place, and to understand the peculiar properties of the malignant cell in the second, are slower but more certain This kind of research is directed to that desideratum of cancer control, a chemo therapeutic agent with a deleterious effect upon malig. nant tissue specifically, and not to a cell poison which in discriminately attacks all rapidly proliferating tissue A scientific definition of malignancy must ultimately be plırased in terms of the abnormal enzyme pattern which distinguislies the malignant cells from the normal, and as responsible for the clinical characteristics of the tumor Interest in folic-acid antagonists arises from the fact that, with these compounds, the two approaches to the problem of malignancy seem to be drawing together Folic acid antagonists are not cell poisons, they are en zyme inhibitors They operate imperfectly, but they oper ate in the same general way that biochemistry assumes the ideal chemotherapeutic agent against cancer will op crate For this reason they are one of the most promising developments in modern medicine Irradiation therapy. Something should be said of the treatment of bronchogenic carcinoma by irradiation Exeryone agrees that it offers no hope at all of cure, or murhed increase in lfe expectancy, but cseryone agrees that it will relieve to a considerable extent the pain of chest wall and mediastinal nerve inolvement on the other hand, whether or not there is a sufficient clinical improvement and increase in life expectancy to make its use standard procedure in all inoperable cases has been debated for thirty years Our own judgment is that it should not be so used At times it seems to clear occluded bronclu, with temporary relief of atelectasis and a general improvement in the condition of the patient A marhed decrease in the size of the tumor has also been reported at ·133 NON SURCICAL, TECINIQUES times by roentgenological evidence The prent may briefly have the definite conuction that he is getting better It is our feeling that much of this is illusory Those studies of the problem which have most carefully pro vided controls almost uniformly indicate that there is little or no increase in life expectancy The ray treatments may benefit adincent infection but only fleetingly and it is to this that the reduction in tumor size and the clear ing of the bronch are dve in the majority of patients In short it is our opinion that the objective improve ment achieved by 1 course of ur dution is not sufficient to justify the disad, antages of these treatments in the usurl patient The observed emotional changes that some times are occasioned by such tre ztments overshadow the increase in life expectancy that my or may not be gained Ideally x ray should be resered for the treatment of symptoms due to nerve or bone intolemrnt m such in stances it can be of materil benefit This is not endorila the physicians decision houerer ll hen the patient or the patients tehtises ist upon roentgen ray treatments they cannot be demed The fundamental rese uch in radiologists » liecoming increasingly evident in chimical application Roentgen ru therapy has been judged by many to be stili in its earl stages of deselopment ·Conclusion 8 Much of the progress that has been made in medicine in recent years has been due to the application of scientific techniques and scientific methods to medical problems The gain has been undeniably large On the other hand this development would seem to be an unfortunate conse quence The central position of the physician is endan gered by the scientific procedures wluch have been designed to aid lum While there is no foreseeable limit to the benefits to be derived from science, thus scientific element must not be allowed to overshadow the art of medicine in the care of the human being There can be no substitute for the basic functions of the physician the ultimate evaluations requred of him are beyond the reach of scientific method This problem is app irent in almost every aspect of so compler a subject as bronchogenic carcinoma For ex ample, etiologic studies of this disease have been taken over, very largely, by specialists who are often not prac ticing physicians This specialization will undoubtedly contribute much to our knowledge of etiology But the practicing physician cannot abandon interest in the sub ject because much of the work has been taken over by biochemists and other specialists Aside from the etiologic facts immediately relevant to diagnosis, such as age and sex predilection, etiologic theory is a necessary back ( 1341 ·CONCLUSION 135 ground to a real understanding of the disease The dis couraging record to date in the diagnosis of bronchogenic carcinoma perhaps reflects a tendency to approach diag nosis mechanically On the basis of present diagnostic and surgical tech miques, it is possible to increase substantially the percent age of cures over the present rate The problem is not so much one of improved diagnostic techniques, but an earlier application of those techniques now available Early diagnosis of lung cancer depends upon a thorough application of basic medical procedures particularly the physical examination and analysis of the patient's history, in the light of an understanding of the protean possibilities of the malignant process Our problem has been the delay that occurs before the advanced diagnostic methods are applied Of course, major diagnostic problems remain even after the patient has been referred for further study Therc 15 no infallible diagnostic technique and most effective use of roentgenology, bronchoscopy, and so forth, demands a maximum of cooperation between the physician and the specialist, and the utmost flexibility In the great majority of instances, morphologic proof of the diseasc will be possible by means of bronchoscopy and cytology It is hoped that the simplicity and case of the latter technique will lead to its extensa e use in the diagnosis of pr tients with minimal chest symptoms We believe that the physician must re-assert hus ultrmate responsibility for the treatment of the patient after dingnosis is made it des olies upon the physician, not the surgeon, to exhaust his diagnostic techniques in an cffort to prove inoperability, before the patient is actually submitted to surgical procedures The physician must always concern himself with the "total care of the pri tient, operible or not, in a way that the surgeon cannot be ·136 LUNG CANCER cxpected to do We believe that the physician is obligated to save the patient the ordeal of a major surgical pro cedure wluch cannot materially benefit him Until recently, bronchogenic carcinoma was generally agreed to be intractable to any approach other than surgi cal However, there are an increasing number of reports of benefit obtained by the use of the nitrogen mustards Whether an increase in life expectancy has been demon strated is questionable, but this drug has apparently proven itself of service upon occasion in alleviating symp toms and improving the general condition of the patient This is 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Stemer P E Butt CV and Edmondson K! monary carcinoma rencaled it occropsy with nifty enct to increasing incidence in the Los Angeles County Hostal I lat Cancer Inst 11 11- 1950 135 Steiner P E ad Loosli C G The effect of human in fluenz S (Type 1) on the bculence of lung turnors in ce Cancer Research 30 380-392 1930 126 String C The meal ft fures of bronchial carcinoma ramburgh I si 355 1021930 ·148 LUNG CANCER Black II 35 137 Cardiovascular failure postopera Bladder ulcerative carcinoma of tively 114 42 Carina inspection of 91 Blood streaked sput im 45 60 from squamous cell carcinoma Cannal lymph node metastases 45 45 Carr J G 138 Blood stream Caucasian relation to Negroes 29 as route of metastasızıng of un Cavitation 50 70 77 differentiated carcinoma 46 Cells metastases 45 abnormaltres 97 Bloomer 1 E 106 142 basal of bronch: 6 Brain 62 ciliated epithelial 6 Brandt William xi clumps 99 100 Breslow L 23 137 fragmentation of mal gnant 100 Brewer LA 138 goblet 6 Bronchi basal cells of 6 Bronchial block 77 80 groups 99 100 Bronchial stump hyrerchromatism 97 99 closure of 114 intercellular bndges 98 99 Bronchial tree irregular nuclear contour 97 fixation of 91 Limitations of development 6 lobulated 98 99 Bronchiectasis 41 81 82 83 Bronchogenic sarcoma 35 malignant development of 7 malignant with nuclear pre Bronchography 83 84 dominance 98 99 Bronchology 103 mitosis 97 99 Bronchoscopic biopsy 87 88 multinucleated 98 99 Bronchoscopy 84 89 93 non-ciliated epithelial 6 results of in 397 patients 90 nuclear predominance 97 Bronchus nucleolar increase 97 99 long tud nal ridges in 91 prominence and angulations of Brower 85 nuclear rim 98 99 Buel Walter !!! rests 26 Burchenal J II 141 size of 97 Bumett W E 138 squamous show ng lypertrophy Buschke F 138 98 99 Busk T 21 138 type Butt, EM 145 correlation with clinical behasior 47 с relation to typ cal develop- Cahan WG 138 ment 43 Campbell 24 undifferentiated 6 Cancer producing substances 7 Central necross 81 Carcinogens 13 18 Cerebral metastases from squamous non occupat onal 18 cell carcinoma 44 Card ac tissue 106 Cervical L 62 ·149 miss 58 INDEX Cervical lymph nodes palpable mal.juse 53 excision and study of 87 Characteristics 4 inediastinal involvement 59, 62 Chart 17 metastases 55 Chemical action on cell structure sites of 62 metastatic findings 62 as cause 8 Chemical iritants 12 18 moderate wheeze 53 nerie root involvement 59 Chemotherapy 57 might sweats B1 as cause 19 intractability of lesion to 82 noctridosis, 60 Chest pain 53 56 58 pleural effusion 58 60 Clicken sarcoma 9 10 pneumonia 57 Children 32 respiratory symptoms 55 56 Chromate industry workers 15 sepsis Chromatin granules uregular un sputum 56 57 equal 98 99 symptoms 53 Chromatın knots 97 98 general 60 Chrom im 16 respiratory 55 56 Chronic infections 12 ulceration of bronchial musoxca 60 Chronic metaplasın 13 Churchill ED 115 138 weakness 56 60-62 Ciliated epithelial cells 6 41 weight loss 56 60 Clubbing 63 Clagett O 1 141 of extremities 65 Clemmensen 21 138 Coal tar 13 Clerf L II 138 140 Codeine for wheezing 61 Clinical features 52 66 abdominal pain 56 Cook 11 L Jr 139 Cooper Cir 139 anorexia 56 60 Cough 53 56, 57 62 bick pun 56 Craser LF 139 blood strcaled sputum in chemotherapy 57 Cruckshank DB 138 Cutler V 139 chest pain 53 56, 58 Cysts cough 53 56 57 58 62 diagnosis 53-55 mistaken for parenchymal tumors, 6 digestive di turbance 56 dysplasia 56 Citologic diagnoses 93 101 dyspnca 53 56 53 60 Accuracy of 91 102 technique 91 99 ettra polmonir) insolement 59 Cytoplasm fatigile chronk 60 enlargrment of 97 reticulation 98 99 frier 61 Ru 57 Vacuolization, 99 99 hemoptysis 50 60 lussitude 61 D lobar pneumonit 60 Diff VF 138 ·150 LUNG CANCER Daniels 88 Examination see Physical er Dans E 139 amination De Bakey Vichael 143 Exhaust fumes 24 De la Fuente 11 Extra pulmonary in olement 59 del Ragato J A, 137 De vedrine SKF 119 Dextro amphetarn ne sulfate 119 Farber S dney 139 Dagnosis 53 56 Fatigue chronic 60 difficulty of 112 Fctul bud, in bronchi 34 palpation 112 Feser 61 Diagnost c procedures 87 104 Fibrosis 41 Diaphragm 106 Fibrous stro na 36 paralysis of 110 Fıration of bronchial tree 91 Dick A 199 Flory 23 Dicthylstull estcrol 26 Flu 57 Dogostried sturtance 58 Fluoroscopy 68 Dolley 85 techniques 68 89 Dom Frigientation of malignant cells Dotter CT 85 111 139 100 Dysphagia 56 Frank hemoptysis 45 Dyspnea 53 56 59 60 Fred BV 11 17 19 23 35 61 postoperatively 114 65 140 Ftlton JS 21 25 140 E с Early aspects of mal garncy 40 46 Edmonson 11 A 145 Garland LH 140 Embryonic rests 41 Gasoline fumes 24 Emphysema 61 77 -9 Castric cancer 21 compensatory 49 Gebauer PW 43 44 71 1.0 rid oltuency of 78 79 General symptoms 60 Epiderm lancer incidence of Cant cells 36 48 Goblet cells 6 Epidermord cancer 49 Golden R 1-10 atelectasis 49 Goldm in A 140 Epithelial cells 6 Good CA 141 non ciliated 6 Graham EA 29 23 34 105 Epithelial pearls 36 106 10 1446 Ep thelium squamous strat fed 6 Gregorious F 16 142 Crosion of growth through lun en Gooss metastatic lesions 63 50 H Esophagoscopy 111 Esophageal malfunction III Ilauser II 140 Espen Lloyd W xi Jleart 62 Etiology 3 32 Jiematory lan stan 98 99 Ewing J 11 139 Hemoptysts 45 56 60 ·I DEX 151 K llenkin A 180 llente! 11 144 Herlut P 103 110 Herci ty 25-32 Hilar L A 62 Illar lesions 76 77 Fox ntgenologic appear inct 76 Histo)tes 98 99 Hlistopril ology 33-51 Floarseness 110 lodgkins disease 77 Hotlind 18 11 Blinger P H 10 Ilmın 85 111 Homburger 17 Hormonal factor as causc 27 Hloroers syndrome 63 Ioring ES 140 Haper C 140 Ilonter 78 Hyperchromatism 97 99 llyperemia 78 I Ichikawa 13 Incidence of all types 17 49 Industrial fumes 21 Infection 912 Intibiotics in 50) us a caue of lung cincar 8 Inoperable patients enre of 116- 120 Interncduate cells 41 Intestine 62 Intratrachealintulutan !! lolzed oil string like appearance in tay 8.3 Isaac F 141 hamofsh DA 141 hel PC 141 Kenn in EL 13 139 143 honnan ay 141 Kent L 141 Keratm crystals 38 hidney 62 Mine S 111 Alopr CT 141 Klotz 17 Knutson 35 Brisky S 13 46,71 141 holler PC 141 honzelmann F1 11 hraclzer AI 10 kroll C 338 L Lantnography see Tom pril Landing B I 142 Lange 16 Langer L 143 Insitud 61 leam ng RH 146 1 n/1 12 Leukemia chronn 15 Livan VL 142 Lubow AA 142 Life expectancy 51 Lindskog (L 52 108 142 I upschutz A 26 142 Lirer 62 undifferentiated and me grow ths in 46 I enlargement 63 labur pneume ni 60 Lactomy 115 Lobulated sells 999) Longitudinal rulges in lt nur 91 Loos CO 155 Lorenz E 14 Limphatic leukemia 129 Lyinpli nodde by spy no 89 J Jackson 11 Johnson CR 141 nes j C 85 111 ·152 LUNG CANCER Lymphatic system allinity of un differentiated carcinomis for 46 Lymph node metastases 48 Lynch J P 127, 142 M MacCallum 18 MacDonald 103 Machle, W 16 142 Malarse 53 Mass 56 Malignancy development of 7 Malignancy, early aspects of 40-16 Mammary carcinomas see also Milk factor 26 Mammary growths 27 McDonald J R 142 144 146 McClelland J N 145 McGrath Allen k Jr, XI Mckay DC 142 Mckinley CA 143 Mediastinal invokement 59 62 Mediastinal lymph nodes enlarge ment of 92 Mediastinal metastases 111 Vediastinum 110 111 examination of nerves in 66 Megaloblastic anemia 130 Vetabolism 25 32 Metastases 62 66 112 abdominal L N 62 adrenal 62 brain 62 cervical L N 82 heart 62 hilar L N 62 intestine 62 kidney 62 liser 62 opposite lung 69 pancreas 62 pleura 62 sites of 62 skın 62 spleen 62 subcutaneous tissue 62 to the bone 112 Vetastatic findings 62 Metastatic lesions gross 63 Viethylbis amine 127 Methylcholanthrene 14 Viethyl tris amine 127 Milk factor, mammıry carcinoma 9 10 Miller ER 13 40 142 Miller II 139 Morphologic distinction between I ing tumors 33 Vountın 25 Voyer J II 142 143 Mucosal erosion 45 Mucous producing goblet cells 41 Multilobulated malignant nucicus 98 99 Multiple polyposts of the colon 30 Vurphy 13 Mustard gas as a cause 15 Viustard gas as a treatment 15 Myelocytic leukerna 128 Myeloma multiple 123 108 Myers J A 143 N Matne constitution 26 Necrosis 50 Negrocs ratio to Caucastins 29 Mene involvement 133 Mere root involvement 59 Neubauer , 143 Neuhof H 143 Neuroblastoma of the retint $0 Nickel copper as a cause of long cancer 17 Might sweats 61 Mitrogen mustards 124 129 Noctridosis 60 los ciliated ep thelial cells 6 ·153 INDEX Mon surgical techniques 121 133 undifferentiated carcinoma 127 alxlominal pains 130 urethane 128 adenocarcinoma 127 Noms C1 143 agents 123-124 Luclear extrusions 97 4 Amino N 10 methyl PGA 130 Vuclear lobulations 97 aminoptenn 130 Nuclear predominance of cells, 97 atelectasis 132 Nuclear rim prominence and sharp Bastrup-Vadsen 125 angulations of 98 99 B-chlorethyl HV2 127 Tucleocytoplasmic ratio 101 B-chlorethyl I 3 127 Nucleolar increase of cells 97 99 bone involvement 133 Nucleus of cell enlargement of 97 cell poisons 121 129 0 chemotherapy 121 citrovonim factor 130 Oat cell carcinoma 37 38 45 cutaneous eruptions 130 Occlusion of artery drug therapy sce Chemotherapy complete 111 epidermod carcinomas 127 pirti! 111 estrogens, 122 Occlis on of veins ethvistlbamine 123 complete 111 folic acid antagonists 129 132 partial in Ilodgkins disease 125 126 Ochsner A 09 89 113 hazards of 129 Operative approach 114 hormonal therapy 121 123 Opposite lung 62 inhibitors 130 Ottom in RC 111 irradiation tl erapy 132 133 Chertolt RB 52 114 143 leukemia 129 130 lymphatic leukemia 129 P meths Ibis am ne 127 Palliative pneur onectomy 115 methylerts am nr 127 Pancorst superior sul us tumor 44 my clocytic leukemia 199 Tancrers 62 mycloma multiple 123 199 und fferentiated carcinoma nerve involvement 133 grout! s mn 48 nitrogen mustards 124 129 Papanicolaou C143 progesterone 122 Papillomas from tobacco tar 23 protam ne silphate 129 130 Paravertel ral block 114 sarcomas 130 Parenchyma extension of tum r side effects 130 into 45 sq nous coil carcinom 12 Parenchyma infiltration of indt stubamid ne 123 121 ferentiated carcinoma into TE 127 128 48 testosterone 122 Parenchymal t mors 71 thrombopenie, 129 mi taken for sts toliuud ne blue 130 mistaken for bereuls * Insethslene-imino s triazine roentgenolog c appearance 78 19 188 p dolog cal cl ssification 494) ·154 LUNG CANCER antibiotics in infection 50 telectasis 49 cavitation 50 emphysem i 50 compensatory 19 in parenchym 50 epidermoid carcinoma atelec 12528 49 erosion of grow th tl rogh Jumer 50 infection 49 50 intibiotics in 50 I fe expectancy 51 necrosis 50 sq amous cell carcinom 50 atelectasis Punch biopsy 88 difficulty of 47 significance of 47-19 P dimethylaminonobenzene 14 Perry TV 144 Perci trdium thichening of 111 Peripheral lesions 102 bronchography for 84 Peritoneal growths 20 Ietersen AB 41 144 Petroleum products as Cause 24 Phillips S N 141 Physical examination 63 66 Pitchblende as cius 15 16 Pitchi lendem ners 15 Pleura 62 Ple iral eff iston 58 60 83 rleural fluid 70 77 88 Pneumoconiosis 17 Pneumonectomy 105 106 life expectancy after 107 108 pallatie 115 116 technique 114 with thoroplasty 115 Pneumonia 57 61 70 77 81 repe ed attacks of 82 Pneumothorax preoperative 113 Potter R 1444 Prichard S 142 Progesterone 122 Prostate tumors 27 42 Protamine sulphate 130 Protean manifestations 4 Psychic disorder organic lasis for 112 Psychosomatic 15pects of surgery 109 110 Pulmonary bloo l sessels ins is on of 58 Pulmonary hemorrhage 45 Pulmonary malignancy origin of 42 Pulmonary pathology associated with broncl ogerie carcinom abscess 50 R Rabbit pap lloma 10 Rabbit tumor 9 Radiolucency of emphysema 78 79 Ratio of whites to egroes 29 Reh EP 141 Reabsten HB 137 Reingold Irving mm 1444 Reinhard E IL 144 Retnhoff HF 34 105 114 114 Relation to tuberculosis 11 Respiratory stuptors 55 56 Rib erosion 70 Rigler LG 141 Road d ist 24 Roblins GF 141 Roentgenology 67 86 ang ocardiography 83 85 86 atelectasis 77 roentgen appearance of 80 bronchial block 77-80 bronchiectasis 81 89 83 bronci ogenic carctnoma appear ance in 67 bronci ography 83 84 bronchoscopy 81 ·I\DEX 153 cavitatson, 77 Schneeberg Jachimos ridation antral necrosis 81 16 correlation of cell type to roent Schrek R 141 Scrologe appearance 71 Secondary infratione rontgeno emphysenin 77 79 logic appearance of 80-83 radiolucency of 78 79 Sepsis el 82 findings in 889 patients 70 Oral 82 Alvoroscopy 68 Ser distribution 27 28 hilar i sions 76 Sex hormones 26 42 Hodgkins disease 77 Sex incidence in cell types 49 hyperem 78 Shafts LV 141 10-lized oil string like apre ir Shimkin VB 141 145 ance in 83 Shour 17 Liminography : e Toniogrphy Silver 17 mc dristinal shadow 6S Silicosis 17 over exposed shots benchaal in Simons L) 1.45 bronchiectasis 81 Sinclair ( 145 parenchymal tumors 71 Shin 62 peripheral lesions broncho Sruth Judith D x graphy for 84 Smith RR 35 145 pleural fund 77 Sneden 141 Solin 141 pneumon 77 secondary 81 Spindle cell carcinoms 37 38 15 repeated attacks of 82 Spleen 62 radiolucency of emphysem 78 Sputum 56 57 79 arpe or inct of rlls in 99 sarcordosrs 77 bloox strethed 15 mulignant cells in 89 secondary infections, 80 83 preparation of studies 95.90 sepsis oral 82 tomograply 83 81 83 purulent 83 tuberculosis 82 ser also tology dugnows Sumous celler inom 31 50 Vinyl acetate injected intra 60 127 cnously 85 * tay findings in 338 patients 77 agt 1949 ateltasis 49 Rosemond CP 108 141 Rosenthal Walton ni bual strekerl sputumn from 13 Round cell cure mom 37 43 these lopment of 11 suculent 47 48 Rerilis vtrhan ens tronment 21 23 lymphats sustom 41 S Froscopi appx inner 36 X 19 Sarcoidosis 77 site of origin 1341 Sarcoma 35 130 Sepumus sfratzfiel cpatu fruen Schael DJ 141 Stermin C 115 Schmucit IC 52 II 113 Steinlx rg 5 111 ·156 LUNG CANCER Steiner, PE, 20, 30, 145 Stılbamidine, 123, 124 Strang, C, 145 Sturm, 13 Swenson, P C, 146 Subcranial lymph nodes, 91 Subcutaneous tissue, 62 Surgery, 105-120 aerosal antibiotics, 113 anesthesia, 114 angiocardiography, 111 barum, orally, 111 bronchial stump, closure of, 114 cardiac tissue, 106 contraindications, 110, 111 "cures," 108, 109, 110 dexedrine, SKF, 119 dextro-amphetamine sulfate, 119 diaphragm, 106 esophagoscopy, 111 esophageal malfunction, 111 inoperable, 108-110 care of, 118-120 intratracheal intubation, 113 lobectomy, 115 mediastinal metastases, 111 occlusion of artery, complete, 111 occlusion of artery, partial, 111 occlusion of veins, complete, 111 occlusion of veins, partial, 111 operative approach, 114 palliative pneumonectomy, 115 116 paravertebral block, 114 pencardium, 111 pneumonectomy, 105, 114 hfe erpectancy after, 107, 108 palliative, 115 with thoracoplasty, 115 pneumothorax preoperative, 113 postoperative cardiovascular failure, 114 psychosomatic aspects, 109, 110 thoracic cavity, damage of, 113 thoractomy, 106 tracheal congestion, postopera tely, 113 vena cava, superor, polypord defects in, 111 Vena caval mvolvement, 111 venoclysis, 113 visceral pleura, 106 whole blood, administration of 113 Symptoms, 53, 56 abdominal pain, 56 anoreva, 56 back pain, 56 chest pain 58 cough, 56 digestive disturbance, 56 dysphagia, 56 dyspnea, 58 general, 60 hemoptysis, 56 mass, 56 metastases, 55 respiratory, 55, 56 time interval between and hospital entry, 54 time interval between hospital entry and diagnosis, 54 weakness, 56 weight loss, 56 T Tar, 13 Taylor, A B, 146 TE , 127, 128 Testicular growths, 27 Testosterone, 122 Thomas, Jesselene H, X Thoracic casity, drainage of, 113 Thoracotomy, exploratory, 86, 87, 88, 106 ·NDEX 157 Thrombocytopenia, 130 spindle cell carcinoma 45 Tobacco as a cause, 23,24 28 Urban is rural environment 24 25 Tobias James i Urethane 129 Tobias G., 139 Urethane as cause 15 Toluidine blue 130 Urethane as treatment 15 Tomography 83 84 85 Trachea fication, 110 Tracheal congestion 113 Tena cara superior polypoid de postoperatively 113 fects in 111 Trachcal deviation 65 66 Tena caval invoh ement 111 Traut II F. 143 noclysis 113 Tripol: 18 ingl acetate injected intra Tnsethylene imino s titrine 127 enously 83 128 urus induced malignincy 10 Tuberculomas parenchy analt nors isceral pleura 106 mustaken for 76 Toolker CA 141 Tuberculosis, 11 81 W Tumor location of primary 89 Wagner 29 Tympanitic percussion B1 Mandal !! 146 Hard Cameron 3 llare 129 Ulceration of bronchial mucosas Waterhouse J AJL 148 60 Watson 35 Ulfelder II 140 Weakness 56 60 61 62 Und:Ferentiated carcio0113 31 33 Veight loss 56 60 38-10 45-46 60 127 Westennark 78 alfnity for lymphatic system 16 et smucar ( age 19 49 beezing 53 63 Btectisig in 46 codcine for 61 cervical noile in 46 unilateral 61 gross abdominal pode in 46 11Tole I lood 113 growth of 45-46 Il inter B 1.16 growths in adrenals, 40 Holpaw SF 140 growths in liver 16 Womack 31 grow this in pancreas 15 Hoplner LB 103 146 incidence, 43 Il ynder F L 22,23 110 in Meclistinum 46 tretastasızıng of, 46 wa blood stream ff Ierodermi pigmentation 30 ray find ngs in 338 patients 7 ont cell carcinom 15 ray as caus 15 parenchymi infiltration into 46 rate of growth 40 ray se alm Roentgenology round cell carcinoma 15 ray radition as treatment 15 sex 19 site of predikation 45646 Tamagra 13

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