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PLAINTIFF'S EXHIBIT THb. NEW EM,LAND )OL RNAl. It INK J.111 -i> I1 CASE RECORDS OF THE MASSACHUSETTS GENERAL HOSPITAL Weekly Clinicopathological Exercises FOUNDED BY RICHARD C. CABOT Benjamin Castleman, M.D., Editor Betty U. McNeely, Assistant Editor CASE 4-1967 Presentation of Case First admission A sixty-three-year-old man en tered the hospital because of a head injury and for investigation of progressive dyspnea. Three weeks previously, when he came home from his office, a lump and some blood on the back of his head were observed. He was unable to relate what had happened and subsequently appeared normal except for a slight decrease in hearing. There was no history of tinnitus, dizzy spells, headache, loss of consciousness, seizures, weakness, pares thesias or difficulty with locomotion or speech. For several years he had been dyspneic, with a chronic cough productive of up to 30 ml. of mucoid, blood-free sputum dailx. The dyspnea increased in severity shortly before admission, to the point that he was unable to climb more than 2 flights of stairs without stopping. He had had no pain or discomfort in the chest or pulmonary infections. He had smoked 2 packages of cigarettes daily for forty sears. During the sear before entry he lost about 15 pounds in weight. There was no known exposure to tuberculosis. He had been employed for twenty-five years as a letter carrier and had previously worked for thirteen sears as a painter and for five years as a riveter. Thirty-fixe years before admission he had worked for tsvo years on the construction of coke silos. From the age of eighteen to twenty-three years he had been a boxer. For four years there had been swelling and restriction of motion in the joints of the fingers. Physical examination revealed a pale, slightly cachectic man with an abrasion over the left occi put. The cervical veins svere flat. Multiple rubbery Ismph nodes, 10 to 1.5 cm. in diameter, svere pal pable in the right and left supraclavicular areas and in each axilla, and a firm, round nodule, 3.5 cm. in diameter, was felt over the costal cartilage ol the right second rib. The anteroposterior diameter of the chest xvas increased, and the lungs svere Inperresonant. There was severe limitation of mosement of the right hemithorax, and the diaphragmatic excursion was estimated to be less than 2 cm. The breath sounds were of poor quality, and the expira tory phase svas prolonged, with expiratory svheezes and coarse rhonchi. The cardiac impulse could not be felt; there was no murmur or friction rub The edge of the liver was felt 2 fingerbreadths be loss- the right costal margin. Slight clubbing of the fingers and toes and cyanosis of the nailbeds svere obserxed Neurologic examination svas negative. The temperature was 98F., the pulse 72. and the respirations 25. The blood pressure svas 110 ssstolic, 60 diastolic. The urine svas normal. The hematocrit ssas 3S 5 per cent; the white-cell count svas 8000. ss ith 74 per cent neutrophils. The erythrocs sedimentation rate was 46 mm. per hour. The glucose svas 77 mg., the urea nitrogen 15 mg., the calcium 9.4 mg , the phosphorus 3.6 mg., and the protein 7.0 gm. the albumin 3.7 gm., and the globulin 3.3 gm.) per 100 (_/_ ml. The alkaline phosphatase svas 7 2 Bodansks --, units. Serum electrophoresis showed that the albu- ^ min svas 43 per cent, the alpha, globulin 9 per cent, rj-; the alpha., globulin 13 per cent, the beta globulin 17,-j> per cent, and the gamma globulin 18 per cent. Ex-<jp( animation of a specimen of arterial blood revealed^j that the partial pressure of oxygen was 63 nun. of__j mercury, the partial pressure of carbon dioxide mm. of mercury, and the pH 7.44. The glutamic oxalacetic transaminase (SCOT) svas 10 units. The Fir.i rf. I /''I'lmwii/fi>ot Film of (he (./w't. Reveulo,^ I hn io-mnd. of (he Rlenm m (he R/^hf Hern/thnio\ (.ulnfunlion t\ vtoble m the piema oxe>/\>>n.r (he irjt iitnf)h)u^>niti leaf (anowi \ol JTh \,\ 4 MEI)1( \l l\EEI.l K.EM E-l IM ER and "Give usynore money" becomes the retrain ot the profession.\Furthennore, the universal exchequer financing ofVhe service endows everyone pro viding it with a vested interest in denigrating it. so that it presents thX unique spectacle of an under taking that is run down by everyone engaged in it. He admits that it i\ because medical care under the National Health SeVice is rendered free to the consumer at the point <JV consumption that supply and demand are not kept\n balance by price. In deed, the demand, for all practical purposes, is un limited, and with every newVfevelopment in treat ment it tends to increase. Or\the other hand the supply is limited by governmental action through the parliamentary votes for the\National Health Service and in the hospital service\the Minister of Health then decides how much eachNhospital board shall be allowed to spend each year. There is thus in effect a rationing system of medical sarre deter mined by political expediency On the other hand Mr. Powell points out that the public is encouraged to believe that rationing in medical care wasNhanished by the National Health Service and that ifie very idea of applying rationing to medical care immoral and repugnant. Nevertheless, waiting times^ for clinic appointments and waiting lists for admis sion are obvious manifestations of a rationing sys tem. But, again, Powell points out that the necessity for these covert forms of rationing springs from "Parkinson's law of hospital beds," which asserts that the number of patients always tends to equality with the number of beds available for them to lie, in and he admits that even given the insight and the will to do so, the politicians could not alter this law. / Turning to the differing points ot vieyy of the politician and the doctor Mr. Powell recognizes that by tradition and training, the doctor Upholds the independence ot individual professional judgment and accepts responsibility for each patient whereas the politician is concerned with thg general conse quences of individual decisions./Furthermore, he points out that in all governments the decisions of policy must be taken by the layman. There is no doubt that Poyrell himself does not believe that apparently free medical attention at the time of need is the right /nethod of providing a national health service. Indeed, he concludes that a change in the relation of/nedicine and politics will only be heralded wherythe number ot family doc tors and the volume/o( consultation and hospital treatment tendered /outside the National Health Service shows a marked and continuing rise Mild it will be noted that this is quite the reverse ot Pro fessor Miller's v/ewl Nevertheles/f the tragedy of Mr. Powell s critical appraisal ot/xhe present situation is that although clearly an/expert diagnostician, he can offer no treatment/ admitting in his final sentence that he aas pursued an argument in a circle -- "the circle in\wh(ch Medicine and Politics are imprisoned in theNxational Health Service." expressed in other words the tragedy seems to he that tnb doctors and the politicians are running on parallel Hnes that will never meet, but if they do not, the patients will eventually be the losers. co r-- NO TO to CD h~ Oo Yol. 276 No 4 (. \SE RECORDS OF THE MASSACHUSETTS C.E\ERAL. HOSPITAL 2:M rheumatoid factor was positive at a dilution of 1:32. Tests of pulmonary function revealed a vital capac ity of 2.3 liters (56 per e*-;t of the predicted value), with a one-second vital capacity of 1.2 liters; the maximal breathing capacity was 20 liters per minute (15 per cent of the predicted value). Cytologic exam ination of the sputum was negative. An electroen cephalogram was normal. Lumbar puncture yielded clear cerebrospinal fluid under a pressure of 180 mm.; the fluid contained no cells; the protein was 32 mg. per 100 ml. An electrocardiogram demon strated a sinus tachycardia and low voltage; there was no evidence of right ventricular hypertrophy. X-ray films of the chest (Fig. 1 and 2) revealed a slight reduction in volume of the right hemithorax, with diffuse pleural thickening along the right hemidiaphragm and lateral chest wall; a few plaques of calcification were seen in the thickened pleura; the right hemidiaphragm could not be visualized. Mul tiple rounded densities, the largest approximately 10 mm. in diameter, were visible in the right-lung field. The left-lung field appeared clear, but in creased linear markings were evident, and there were calcified plaques overlying the diaphragm on the left side. The heart was not enlarged. Incom plete fractures of the left sixth and seventh ribs anteriorly were demonstrated; the adjacent bone appeared normal. A barium-swallow study (Fig. 3) showed indentation of the esophagus below the carina. Films of the skull were of poor technical quality, a fracture was not identified. Bronchodilators and antibiotics were adminis tered, with slight improvement of the dyspnea. The patient was discharged on the twelfth hospital day. Final admission (three weeks later). He remained well until two days before entry, when his sister heard him cough and then fall; she found him dyspneic but alert. On the morning of admission he was again heard to fall to the floor and found with blood coming from his nose. A seizure was not ob served, and he appeared alert. He denied chest pain or hemoptysis. Physical examination showed a man in moderate respiratory distress, with cyanotic nailbeds and clotted blood in the left nostril. Examination of the chest and abdomen and neurologic examination revealed no change. Fit.L RE 3. Detail oj nil Oblique l'/ew nj file Biirium-billeil Eoiphfiiiu.f, Slwu'inir Indeutation JilO Below the Cnmiti IHE NEW EM.LAM) JOl RN U. Oh MEDIUM. |.m Jt>. !'ii)7 ST0566775 The temperature was 98.6F., the pulse 120, and the respirations 24. The blood pressure was 140 systolic-, 90 diastolic. .The urine was normal. The hematocrit was 38 per cent. The sodium was 148 rnEq., the potassium 4.9 mEq., the chloride 102 rnEq., and the carbon diox ide 24 mEq. per liter. The urea nitrogen was 17 mg. per 100 ml. An electrocardiogram showed a sinus tachycardia, with low QRS voltage and minor Twave flattening. An x-ray film of the chest showed no change. The patient was increasingly dyspneie and had difficulty raising tracheal secretions. The neck veins became distended, and a diastolic gallop was heard. Digoxin and meralluride were given. Early in the morning of the second hospital day he was found dead on the floor of his room. Differential Diagnosis Dr Fei.ix (... Fleischner*: We are discussing a man of sixty-three years with chronic pulmonary disease. We hear of considerable cigarette smoking and are given a fairly thorough vocational history. I am glad that the questioner did not stop with the job of letter carrier for twenty-five years, but probed further and discovered the patient's thirteen-year activity as a painter and two years in cpnstruction work. Incidentally, I inquired at our State Health Services and learned that the building of coke silos entails no particularly harmful exposure. The physical findings in the chest seem to con firm the impression that he had chronic pulmonary disease -- namely, chronic bronchitis and emphy sema. The clubbing of the fingers and cyanotic nailbeds are also nonspecific changes, consistent with any type of chronic bronchopulmonary disease with oxygen desaturation. The slight elevation of the rheumatoid factor is nonspecific, too, and could have resulted from any type of granulomatous process in the lung. The laboratory studies dis closed moderate anemia and a markedly elevated sedimentation rate in the absence of tuberculosis or any other known inflammatory disease. The alkaline phosphatase level was high, and the question arises whether it points to bone involvement of some kind. Considerable arterial oxygen desaturation and slight hypercapnia were found. The marked reduc tion in the vital capacity and reduction in the timed capacity demonstrated by the pulmonary-function tests were indicative of emphysema of the obstruc tive type. We have no other information that would enable me to say anything about diffusion impair ment and venous admixture, both of which were probably present. I come, then, to the radiologic findings. Although the films of the skull are of poor technical quality, I can detect a fissure fracture on the left side extend ing through the occipital squama, coinciding with '(.onsulidni MMUm; radiologist. Massachusetts (General Hospital tlinual protessor <>l radiologv emeritus. H.mard Mediul School the location of the lump and the abrasion incurred three weeks before the first admission. I regard that lesion as incidental, however, since we have been assured that the neurologic examination was nega tive on both hospital admissions. The films of the chest (Fig. I) show overall symmetry, but we see some narrowing of the intercostal spaces on the right side, and the mediastinal structures are dis placed to the right. There is an opacity in the right-lower-lung field, but I cannot distinguish how much of it is pleural and how much pulmonary consolidation. Numerous streaks and flecks are evi dent in the right lung. In addition, there are multi ple dense, round lesions that might be characterized as "doughnut-like" since they have translucent cen ters. Such lesions have been described as "buttonshaped," and their appearance stigmatizes them as pleural calcific plaques rather than nodular pulmo nary lesions. On the left side, in addition to the two rib fractures, we find only a few streaks and one nodular lesion of a nondescript nature, otherwise, the left lung is clear. Perhaps the most important finding in this whole analysis, although it is not verv prominent, is the presence of calcification in the region of the diaphragmatic pleura on both sides. In an attempt for better definition of the palpable firm lymph node in the right infraclavicular region oblique views were taken. They reveal numerous soft-tissue masses in and about the pleura, with some nodularity extending into the pulmonary tissue (Fig. 2). There is a cortical defect in the anterior portion of the second rib on the right side that corresponds to the area where the hard nodule was palpated. The nodule, although indolent and firm, did not contain calcium or bone. Another oblique view of the chest with barium in the esophagus (Fig. 3) again demonstrates the anterolateral pleural deposits, but I wish to call attention to the indentation of the esophagus just below the bifurcation of the trachea, which is a very important finding. It is not just a peristaltic wave. On careful scrutiny one can see a soft-tissue mass that fills the bifurcation angle and compresses the right main bronchus. This alteration signifies marked en largement of the bifurcation lymph nodes, presumably by tumor. The x-ray films demonstrate, therefore, signs of pulmonary fibrosis in the form of strands and flecks, a nodule on the left side, presumably of the same nature, and localized bone involvement. These changes are in no way characteristic. Fibrosis occurs with many conditions, including several types of pneumoconiosis, and rarely has any distinguishing features. The old-time descriptions such as a "hazy groundglass appearance" and a "shaggy heart shadow," used in cases of asbestosis, belong to an abandoned vocabulary. I have deduced already that there was a malignant tumor in the chest on the basis of the deposits in the pleura and the medias tinal lymphadenopathy. The problem is how to con nect the chronic pulmonary disease and the malig nant pulmonary or pleural lesions in this patient Vol. 276 No. 4 CASE RECORDS OF THE MASSACHUSETTS GENERAL HOSPITAL 2:0 Q / / O O ( In my opinion, the bilateral calcification of the diaphragmatic pleura is the key to the diagnosis. Calcification in a thick pleural scar was a relatively common finding formerly and is still seen from time to time' after empyema, tuberculous and other pleu ral effusions and traumatic hemothorax. In such cases it occurs usually at the mid-level of the chest, and in a large survey it was found that in 97 per cent of the cases the pleural calcification was unilat eral if it was associated with a hemothorax or em pyema. In most cases of asbestosis, on the other hand, the calcification is bilateral and is usually in the lower portion of the chest, in the costal pleura, the diaphragmatic pleura or the mediastinal pleura. In this case we find bilateral diaphragmatic calcifi cation. Pleural calcification has also been described in association with silica and talc pneumoconiosis. It is possible that there was an admixture of asbes tos in those cases. A few general remarks about asbestos and asbes tosis are in order. Asbestos is composed of several chemical compounds -- silicates of iron, magnesium and aluminum. The fibers are separated from crushed rock. The ancient Egyptians, Greeks and Romans definitely knew about the nature of asbes tos; in fact, Plutarch tells about its use as the per petual wick in the lamps of the Vestal Virgins. Re cent archeologic discoveries in Finland, where much asbestos is still mined, showed that the Stone Age man used asbestos, more than six thousand years ago. We are interested in asbestos because of its extensive utilization in modem industry, being woven into textiles and ground and mixed with cement and plastics to make insulating materials and other products. Asbestosis has been known medically for about three decades. The dust is in haled in a fibrous form. When the serious nature of massive inhalation was first realized the fibers used were about 200 /z in length, but much shorter fibers, 2 to 5 /a, are employed now. There is some evi dence that the inhalation of the shorter fibers is changing the nature of the disease and making it more chronic. In the earlier days asbestosis devel oped after only two or three years of exposure and often ended fatally within that period. The pulmo nary lesions differ from those of silicosis. Observa tions in man and experiments with animals in the early phase of the disease have shown bronchiolitis, with extension of the inflammation into the adjacent alveoli.1 At a later stage widespread, progressive fibrosis of the lungs develops, with involvement of the adenoid structures. The inhaled dust soon be comes coated with iron-containing protein to form asbestos bodies, which are said to be indestructible. Radiologically, the disease is characterized by signs of diffuse interstitial fibrosis, without grossly visible nodularity, occupying mainly the lower lung fields. The picture is sometimes very similar to the altera tions seen in cases of scleroderma. Involvement of the pleura is very common in cases of asbestosis. For example, in a series of 24 patients with asbestosis 19 proved to have pleural involve ment.2 Kiviluoto,1 a Finnish radiologist Who studied the disease among workers in open-air mining, ad vanced an interesting theory regarding the patho genesis of the pleural involvement. He postulated that the asbestos fibers or needles penetrate the lung surface and with the respiratory up-and-down move ment scratch the parietal pleura, causing minute hemorrhages, with subsequent fibrin deposition, organization and eventually calcification. There are certain unusual characteristics. In a large calci fication due to an old empyema one generally finds the shell of calcium at some distance from the ribs, whereas the calcification due to asbestosis always lies close to the ribs. Another interesting feature of this disorder is that despite the presence of calci fication there frequently are no pleural adhesions. One can successfully induce a pneumothorax, and the pathologists often find no adhesions, in contrast to the obliteration of the pleural space ly yostempyema scars. It takes a long time for the pleura to become calcified. Calcification is an extremely rare finding in people who were exposed to asbestos less than twenty years previously. The intensity- and duration of exposure does not seem to be significant in this regard, but if the exposure to asbestos dates back thirty or forty years the likelihood of finding pleural calcification is fairly great. It also takes a long time for the asbestos to mani fest its carcinogenic quality. The most important aspect of this disease is the fact that the asbestos acts as a carcinogen. In a recent review of 307 deaths among asbestos-insulation workers in New York and New Jersey, Selikoff and his co-workers2 reported that 53 had bronchogenic carcinoma, 34 had cancer of the stomach or colon, and 10 had a malignant mesothelioma of the pleura or perito neum. Dr. Knowles discussed a similar case at one of these conferences three years ago.5 The urgency of the problem recently led to a conference of the New York Academy of Sciences on the subject of the biologic effects of asbestos, and the ensuing volume6 contains practically everything 'Nat is known about asbestosis as well as numerc ques tions about unsolved aspects of the dis ,-e. In cluded in the data is a list of all the occupations in which one can contract asbestosis, compiled by Hueper,7 from' the National Cancer Institute, in Bethesda, Maryland. Among them are mining, load ing, shipping, crushing, milling and other ways of handling this mineral, as well as spraying of steel construction, the undercoating of automobiles and insulating pipes and handling of the filler in rubber goods and pipe coverings, insulation blocks and insulation jackets. However, nonoccupational asbes tosis is of particular interest. Kiviluoto3 first used that term when he discovered that the air in the mining area in Finland was so polluted that even cattle contracted asbestosis. We now have a newterm, "residential" asbestosis, and among those exposed, for example, are people who live along in THE NEW ENGLAND JOURNAL OF MEDICINE |an. 'Jti. I'.'iV ST0566777 roads on which asbestos is trucked ;and inhabitants of houses with asbestos insulation; Asbestosis no longer is a rare occupational disease! of interest only to the physician who deals with workers in asbestos mines and mills and with insulation] construction or demolition workers and pipe fitters. It, concerns virtually everyone. In the last ten jor fifteen years the use of asbestos has multiplied geometrically, in width of usage and in depth of amount. The abra sive dust from the lining of the brakes of our cars, from tiles, from house paint and from a hundred other sources pollutes our air. A pathologist in Bel fast, North Ireland, has declared that a fourth of the population in that region has nonoccupational, resi dential asbestosis of sufficient degree to pave the way for thel development of neoplasia, the repre sentative speaker of the Ministry ofi Health in Lon don has stated that in more than half the fatal cases of asbestosis some kind of cancer ;is present, and Thomson and Graves,8 in Miami, i Florida, found asbestos bodies, admittedly in a small number, in the lungs in| 20 to 30 per cent of 500 consecutive autopsies. The general contamination of the urban atmosphere jby asbestos has obviously become a matter of public concern. ! I must return to the case at hand! and arrive at a diagnosis. On the basis of the vocational history, the increasing dyspnea accompanied by chronic bron chitis and clubbed, cyanotic fingertips and the ra diologic findings in the lungs and particularly the bilateral pleural calcifications in the lower portion of the chest,I the diagnosis of asbestosis of the very chronic type is justified. The recent Ideterioration of the patient's condition, with weight loss and ane mia, suggests a wasting disease. Against the back ground of long standing asbestosis, a malignant jtumor in the chest is a cogent conclusion. The ques tion is whether it was a bronchial | carcinoma or a malignant mesothelioma of the pleura. I think that a malignant lymphoma can be ruled out. In favor of the diagnosis of a bronchial carcinoma is the obser vation of partial bronchial obstruction in the right lower Inbe. < That is not absolute proof, however, since obstruction or even invasion often occurs as a result of involvement of lymph nodes by metastases. The absence of hemoptysis and the negative cyto logic studiesl provide a fairly strong argument against a bronchogenic carcinoma. In favor of a primary pleural tumor are the obvious pleural involvement by tumor anld the negative arguments for a broncho genic carcinoma. Against a pleural tumor is the sta tistical probability. According to the latest figures by Selikoff et al.4 the odds are about 5 to 1 -- that is, 5 bronchogenic carcinomas to 1 mesothelioma of the pleura or peritoneum. : My conclusion is that the patient had asbestosis, with pulmonary fibrosis, chronic bronchitis, emphy sema and bilateral pleural calcification. He had a malignant pulmonary or pleural tumor, with medi astinal lymphadenopathy and extension into the second rib on the right side. Disregarding statistical probability and resting my case more on roentgeno logic! evidence, I give a malignant pleural mesothe lioma slight diagnostic preference over a bronchial carcinoma. I have too little supporting evidence to say whether the fracture of the occipital squama or a metastasis to the brain contributed to this man's death. Dr. John H. Knowles: I'd like to ask two ques tions1, Dr. Fleischner. Is it possible for a boxer to suffer severe rib fractures during boxing matches over] a period of years sufficient to cause multiple calcifications of the pleura on both sides of the chest? Dr. Fleischner: There might be calcification if he had a bilateral hemothorax forty years ago, but it would be a far-fetched explanation for the extensive calcifications principally in a diaphragmatic location in this case. Dr. Knowles: Secondly, how do you account for the abruptness of the terminal event? Dr! Fleischner: The tachycardia, diastolic gallop and jengorgement of the neck veins indicate that there was myocardial failure at the end. The roent genograms of the chest show some haziness that is probably indicative of pulmonary congestion. Therefore, I assume that the final event was con gestive heart failure. Whether the head injury or a cerebral metastasis or some other factor contributed to it,11 do not know. Dr'. Benjamin Castleman: Dr. Knowles, do you agree with Dr. Fleischner's conclusion that this man had a mesothelioma of the pleura on the basis of asbestosis? Dr! Knowles: Yes, I would have come to that diagnosis. Dr! Castleman: Dr. Bird, you followed this pa tient] in the hospital. Will you comment on your thinking about the problem? Dr], Kenneth T. Bird: As I recall, I related the abnormalities. of the right pleura to the history of a few years spent as a boxer. Dr! Castleman: In the record you listed your diagnostic impressions as the chronic bronchitis syndrome, rheumatoid lung disease and pleural fibrosis and calcification, secondary to either boxing trauma or rheumatoid disease. Dr! Bird: I don't think there's enough in the history to let us do more than speculate freely about the diagnosis of asbestosis. We have only the fact that [the patient worked for thirteen years as a painter. We have been concerned recently by the high] incidence of asbestosis among ship workers. Dr!. Castleman: I just noticed an addition to this man's occupational history. He passed rivets for two years, from 1919 to 1921, then heated rivets for three years, 1921 to 1924, and painted from i924 to 1937', but during the entire period from 1919 to 1937| all this work was done at a shipyard. Does that change your mind? Dr. Bird: That history was obtained by me with the courtesy and help of the patient and his sister. Vol. 276 No. -4 CASE RECORDS OF THE MASSACHUSETTS GENERAL HOSPITAL 2 So qu qqm us and I must say that I completely overlooked its possible significance. It's extremely unusual, how ever, for asbestosis to present primarily as a unilat eral disease. We are currently participating in a survey of 160 pipe coverers, about 20 of whom have asbestosis, and all of them have bilateral disease. Dr. Fleischner: As to the question of the asym metry of this man's thoracic disease, the asbestosis still could have been bilateral and symmetrical. The unilateral appearance is probably due to the devel opment of a malignant tumor on the right side. In cidentally, the elevated rheumatoid factor should not mislead us. That is a nonspecific alteration that occurs in association with lupus erythematosus and other collagen diseases, and SelikofF and his asso ciates found elevation of the rheumatoid factor also in cases of asbestosis. Dr. Gilbert S. Omenn: In view of the cyanosis and the arterial oxygen desaturation in this case, the hematocrit of 38.5 per cent was probably signifi cantly lowered. Would you postulate bony metastases to account for it, Dr. Fleischner? Dr. Fleischner: I suspect that there was more bone involvement than is evident in the right second rib. The elevated alkaline phosphatase level can prob ably be explained on that basis. Dr. Antonio M. Gotto, Jr.: I might add that I saw the patient on the night before he died. We were very puzzled by the two spells of falling that prompted the last admission. Earlier in the day, at the time of admission, the examiners did not find evidence of congestive heart failure. However, at eleven o'clock at night when I made rounds I found him dyspneic, with distended neck veins and a gallop rhythm, and we began digoxin and meralluride. Three hours later he was found on the floor of his room by the nurses. Somehow he had managed to get out of bed, and we assumed that he had had another similar spell, whatever its nature. We had a long attempt at resuscitation, but it was not suc cessful. Dr. Fleischner, do you think that there could have been cardiac involvement by the meso thelioma? Are the electrocardiograms or any of the terminal findings consistent with involvement of the heart? Dr. Fleischner: That is definitely a possibility, and I did think of it. Whenever one suspects a ma lignant tumor of any kind in the chest one should look for a rapid increase in the cardiac silhouette, which serves as a warning that the tumor has prob ably extended or metastasized to the pericardium from mediastinal lymph nodes, causing a pericardial effusion. Solid encasing by tumor is much rarer. However, on the latest films in this case the size and shape of the heart were entirely proportionate and even on the small side, and so I couldn't come to such a conclusion. Dr. William Franklin: I wonder if the spells of falling were due to cough syncope in a person with chronic bronchitis and obstructive pulmonary dis ease. Dr. Fleischner: I thought of spells of carbon di oxide intoxication. Dr. Castleman: What conclusion did the students reach? Dr. William J. Powell, Jr.: The majority of the students thought that the patient had a primary bronchogenic carcinoma, chronic bronchitis and emphysema. Mr. Meissner was the student discusser today. Mr. William Meissner: My diagnosis was pri mary bronchogenic carcinoma, either of diffuse ori gin or possibly of bronchiolar origin. My second choice was a mesothelioma of the pleura. Clinical Diagnoses Chronic obstructive pulmonary disease, with brosis. Bronchogenic carcinoma. ? Pulmonary embolus; ? myocardial infarct. fi Dr. Felix G. Fleischner's Diagnoses Asbestosis, with pulmonary fibrosis, chronic bron chitis, emphysema and pleural calcification, bilateral. Mesothelioma of right pleura, ? with metastasis to brain. Fracture of occipital squama. Pathological Discussion Dr. Castleman: The post-mortem examination revealed that the entire right pleura was thickened and replaced by tumor that involved the parietal as well as the visceral portions, with no pleural space remaining. The tumor also involved all the medias tinal structures, including the parietal pericardium, and had compressed both the superior vena cava and the inferior vena cava. The right lung was com pletely encased by a layer of tumor with a thickness of several centimeters (Fig. 4). Therefore, this man had a very extensive pleural tumor that involved part of the pulmonary parenchyma, but only by extension and not by lymphatic spread. Calcification was evident in both the right pleura and the di aphragmatic portion of the left pleura. The tumor was adherent to the inner surface of the thoracic wall, with some extension into the periosteum of the ribs, but it did not actually invade the rib mar row (Fig. 5). The pericardial cavity contained about 300 ml. of reddish-brown fluid, and the epicardium was covered with fibrin and small tumor nodules (Fig. 6). The right ventricle was three times the normal thickness. That change apparently was not reflected in the electrocardiograms, perhaps because the cardiac chambers had been rendered virtually immobile. Histologically, the tumor was a fibrous type of mesothelioma in many areas (Fig. 7); in other areas, however, we observed the pseudoacinar and papillary arrangement, with cuboidal mesothelial cells, that is more characteristic of the mesothe lioma (Fig. 8). I 236 THE NEW ENGLAND JOURNAL OF MEDICINE Jan. 26. |'.67 ST05S6779 Figure 4. Posterolateral I'/ew of the Right Lung Encased by While Fibrous Tumor, Also Involving the Pleura) Mediastinum and | Pericardium. I v. v* ?>* ft- Figure! 6. Epicardium Replaced by Tumor and Fibrin, with | Underlying Somtal Myocardium. (X3t>) l Figure 5. Tumor Involving the Inner Surface, o] the Anterior Chest Wall. ,j In the diaphragm on the left side there was dense, acellular fibrosis, with a plaqut of calcifica tion 2 or 3 mm. in thickness and 4 cm. in diameter (Fig. 9). As Dr. Fleischner intimated, when a pa tient has bilateral calcification of the | pleura, espe cially involving the diaphragm, the burden of proof rests on the person who says that it jis not due to asbestosis. In fact, Seiikoff9 stated that when there is bilateral pleural calcification of this nature involving the diaphragm the cause is invariably asbestosis. Figure 7. Mesothelioma,'Predominantly Fibrous. tX200i and it's up to the examiner to find the asbestos bod ies. One almost never can detect asbestos bodies in the thickened pleura, and it's very rare to spot them among! the tumor cells; the place to look for them is in the [pulmonary parenchyma. Therefore, we made many sections of the lungs in this case. There was \ol. 276 No 4 CASE RECORDS OF ['HE MASSACHUSETTS GENERAL HOSPITAL Figure 9. Dmphnigm Replaced b\ Dense, Acellular Filnon* Tis sue. <X37) .4 focus of calcification i.s reident. only slight chronic bronchitis, with minimal fibrosis. I looked very carefully for asbestos bodies, espe cially in areas where there was carbon, which sometimes covers up a fragment of asbestos, but was unsuccessful. I then sent some of the material to Dr. Irving J. Selikoff and Dr. Jacob Churg, to whom I turned for consultation because I was con- AB Figure 10. Asbestos Bodies from the hhed Luna The i tubbing of the asbestos both is wet! seen to mentaUon in B. and the f,'tig- vinced that this patient had asbestosis. The best way to detect asbestos bodies is to ash the tissue, since everything will bum out, with the asbestos body remaining. They very kindly undertook that procedure tor me, and I received from them this morning several lantern slides disclosing asbes tos fibers. One photograph was taken of the squeezed-out lung, showing an uncoated fiber, and others, which were of the ashed specimen, revealed clear-cut asbestos bodies (Fig. 10). There is no question that this patient had asbestosis. This man proved to have a large subdural hema toma, dating back two months to the trauma to the head. The subdural hematoma may have accounted in part for the spells of falling. Anatomical Diagnoses Mesothelioma of pleura, right, with extension into mediastinum, chest wall and pericardium. Pulmonary asbestosis. Pleural fibrosis and calcification, bilateral. Cor pulmonale. Subdural hematoma, chronic. References I. Wagner, j C , and Skidmore, J W Asbestos dust deposition and retention in rats Ann. Xeu FiuA Acad. Sr. 132 t \rt I).77-86. 1965 2 Gaensler, F A Personal communication 4 Kiviluoto, R Pleural calcification as roentgenologic sign ol non- occupational endemic anthopfn llite-asbestosis. Acta Rndialo^ (Supp. 194) 1-67. i960. 4. Selikoff, I. | , Churg, J.. and Hammond, E. C Relation beiween exposure to asbestos and mesothelioma. Xeu- Eng / Med 272.560-565, 1965 5 Case Records ol the Massachusetts General Hospital (C.jse 62196.4) Seu' Eng f. Med. 269:747-754, 1964 6. Biological Effects of Asbestos Edited bv H E. Whipple. New lork Annals of the Wjc York tcadem\ of Sciences. 1965. Pp. 1-766 7 Hueper, W. 0. Occupational and nonoccupational exjxvsures ro asbestos hin \eu York lead. Sc 132 (Art. 11:184-195. 1965 8 Thomson, ) C, and Graves. VV M. Asbestos as urban an u>ntaminant -heb Path 81 458-464. 1966 9 Selikoff, l |. Occurrence ol pleural calcification among aslx-aos insulation workers inn \eu' iork Acad Sr. 132 (Art l,.45l-9>7. 1965 rC~O- UD vo LO O t~ CO 238 THE \E\V ENGLAND JOURNAL OF MEDICINE 1*111. 2ti. I`>h7 The New England Journalof Medicine Founded in 1812 as the New England [oirnal of Medicine \d Surgery and continued in 1828 as Vol. 1 of the Boston Medical and Surgical Journal Published \Veek\y by the Commitiee on Publications OF THE NmSSACHUSEITS MEDICAL SOCIETY famesVl. Faulkner. M D., Chairman Lamar Soutter, M.D. Robert P McCombs. M D. Alexander Marble. M D \ \rnold S. Reiman. M.D. /oseph GarlanW. M D . Editor Franz J Jngelfinger, VVD.. Dfpity Editor Associ a n FhJ i ors Jane F Deslorges. M.D. \\icholas M Nelson, M D. Ronald A. Malt. \\ Robert O'l.earv, \ssis r >. ntXlditor Howland P Hall. EniroRiu X^Vstant Editorial Board Maxwell Finland. M D Dale G end, M D. Vernon P Williams. M.D Richard Warren. M D. Benjamin C'.astleman, M D Robert \\ Buck. M D John J Bvrny. 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All that was required of the participants was that they send copies of their manuscripts or of their informal memos to Bethesda, ancf soon photo-offset copies would go out to an international membership at no cost to the participant! Two things happened to mar the beauty of this operation. First, in the areas of immunology and of nucleic acids, the contributions became so nuniero 11 s/that it took two or three months before copies could be made. Manuscripts submitted to Science, biochemical and Biophysical Research Communica' tions and Proceedings of the National Academy of Sciences appeared in print before the IEG papers were mailed. Second, some authors incorrectly in ferred that they were being asked to establish priority by submitting papers to the IEG immedi ately on their completion. The implications that the established referee and publication system would circumvented were not lost either on morally sensitive scientists or on editors of journals themselvXs. An appreciable number of immunopathologists Xoted to abandon their IEG. Nature devoted a long leading article to the defects of the system and suggested, that the $5,000,000 ultimately needed to extend theyIEG to all areas of research supported by the National Institutes of Health could better be spent to impiWe the quality and speed of publica tion of existing journals. Furthermore, it pointed out, scientists invariably know by word of mouth the important unptridished research in their field. Spoken and applnsd to leading scientists in nonclinical fields in mstor institutions, the criticisms were true, but they ignored both the scientist whose institution is not a Me^a and the physician in lab oratory medicine. UnlesX the physician had abdi cated clinical medicine, hX was unlikely to belong to a select scientific cliqueXlrrespective of the im portance of new data to his research, he would not know the content of privatelyX circulated preprints until they actually appeared inNournals. Delays of more than a year in publication meant that he was at least two years removed from th\creativity of his fellows in basic science. The IEG's should have been encouraged as a means of relieving this situation. Clearly, the mis sion of the NIH includes any measures that will enable investigators in biomedical fields\to know \ A S B E S T O S IS New E n g . J . o f M ed. ? 7 6 ( 4 ) : 2 5 0 -2 3 7 , 19^7 CASE RECORDS OP TH E MASSACHUSETTS GENERAL H O S P IT A L : CASE 4 -1 9 6 7 ST05SSTJI 2 so: T3 C o 1 v rH -P 03 3 O