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Translation # Date of material: N/D Language: German Translated by: Date: Forwarded to: L. Carpenti 5/23/80 Writer: Addressee: A CONTRIBUTION TO THE ETIOLOGY OF THE DIFFUSE MALIGNANT PLEURAL MESOTHELIOMA Ater Slegal, Smith and Greenburg, with the "Talc Plaques" described changes in the pleura as attendant circumstances of a taicosis caused by tremolite talc, there have been especially in recent years, reports about mostly double-sized, calcifications of the pleura as a consequence of having been exposed to minerals containing fibers. Taking into account the fact that talc is often adulterated with asbestos, and that tremolite belongs to the group of amphibole asbestos, changes in the pleura caused by asbestos seem to be, as compared to other minerals, by far the most important. These were almost exclusively described in connection with asbestosis. Bohlig, Jacob and Muller claim they found it with increasing frequency and to a severe degree with a rising degree of asbestosis in asbestos workers in the area of Saxony - Thuringia. They already noted that these calcifications of the pleura do not always go hand in hand with a dear lung fibrosis. . Kiviluoto, Cartier and Anspach proved an endemic risk in absestos with these pleural calcifications. The latter reported about 429 cases from the Dresden area, out of which 54.57. experienced a job-related exposure, 35.9T experienced a risk due to the emissions of the industries proces sing asbestos in Dresdon. With the help of anamneses of working and living experiences, the links could be established, and could be con firmed through particles of asbestos in the saliva and through sections in some cases. At that, only in rare cases, a clear lung fibrosis could be found. In most cases, especially for people that were ^risk/a^l because of.emissions, there were no fibroid tissue reactions: only asbestos particles could be found. In connection with beihg exposed to asbestos, there is not only an observation of increased carcinomata of the bronchi, but also tumors of the pleura and the peritoneum. Jacob and Bohlig had already pointed this out. In recent years, Vayner and associates described 84 cases of diffuse malignant pleural mesotheliomas in the North-Western Province of South Africa, which involved exposure to asbestos in some way. Other recent studies confirm these observations. !* 156-705 HFM- 005086 SCF-FORD-1971 8003 1171 2 It was of interest to note how frequently, beside the calcifications of the pleura that were observed in Dresdon, there were also observations of such diffuse malignant mesotheliomas. For this purpose, those cases were studied that had not yet been registered with the silicosis information centre, and that could be observed in the years from 1950 to the first quarter of 1964 in the Pathological Institute and in the Clinic of Radiology of the Medical School Dresdent All in all, 41 cases were studied in detail, out of which 12 were diagnosed by X-Ray, 20nanatomically and pathologically and (copy illegible) by both methods (see chart). The attempt was made in retrospect to establish anamneses in detail about job and living environment from the survivors of the deceased, which often proved to be very hard. The section material from the above mentioned institute was checked under consideration of a possible exposure to asbestos for fibroid changes in the lungs and asbestos particles, since in earlier years the connection with an exposure to asbestos was hot recognized. The cases 1-6 from the period 1933-1941 can be excluded from the deliberations, since by coincidence, X-Ray films of these cases exist, but notsection material is given, and no job-or-living anamnesis could be established. But these six cases demonstrate the fact that the pleural mesothelioma-was by no means absent from the area around Dresden, even in the years before the war, at a time when the literature had only few reports about the occurrence of such pleural mesotheliomas, and that they could be linked to the asbestos industry that existed since before 1900. Among the cases that were given since 1950 as diffuse malignant pleural mesotheliomas, there was to be observed: . a.) in 9 cases, a job-related exposure to asbestos (25.71) b. ) in 9 cases, a risk in the living circumstances through asbestos dust (25.751) c. )~ 2 cases a silicosis (5.7%)o d. ) in 7 cases no exposure could be determined (20%) e. ) in 6 cases, a discussion was entirely impossible (22.9%) Group a includes 9 women. The ages ranged between 50 and 71 years, a median of 62.5 years. Four women were less than 60 years old. Four women worked as weavers and winders, two women worked as punchers of materials containing asbestor, one woman as a roller, and two women worked in the asbestos hose and ribbon production. The duration os exposure was two years. This woman had worked as a puncher. Two women worked for 10 and 30 years. The duration of exposure could not be determine for one woman. But there is no doubt that this woman, as a weaver, was exposed to asbestos through her job. The diagnoses were established once through X-Rays, 7 times anatomically and pathologically and once with both methods. HFM- 005087 8003 1172 3. Five cases showed fibroid changes in the lungs and asbestos particles, two of those were clear asbestosis cases. In the other cases, the fibrosis in the lungs existed only to the slightest degree. Asbestos particles alone were found in two women; in one case neither asbestos particles nor lung fibrosis could be found. One woman is still living. Mo asbestos particles could be found in the saliva. From the X-Rays, there was no clear fibrosis in the sense of an asbestosis. The time between the first exposure and the observation of the pleural mesothelioma was, on the average, 37.4 years, the shortest time was 23 years, the longest 45. Group (b) consists of four men, between 55 and 80 years old. The median age was 64.4 years. Further, part of this group are five women, between the ages of 54 and 70. The average age being 59.6 years. They had lived either in close propinquity to the Dresden asbestos factory, or they were emplyed in a shop close the factory, without being exposed to asbestos through their own occupations. The diagnosis was established in four cases through the section alone, in five cases the X-Ray diagnosis could be confirmed through a section. Of the four men, the only case of a slight lung fibrosis and some individual asbestos particles, were that of an 80 year old man, who had lived for 50 years close to an asbestos factory, and had been employed in a drapery factory close by, where already many cases of pleural plaques had been detected. Only two cases of the five women showed a slight fibrosis of the lungs with asbestos particles, in one case asbestos particles alone could be observed, in- two cases there were noc signs of an asbestosis. In five cases, living or employment close to the asbestos factories alone point to an exposure to asbestos. Where groups (c) and (d) are concerned, it should be noted that it is surely striking that two men at the age of 59 and 62 show a pleural mesothelioma in connection with a silicosis, which so far, could not be observed for cases of silicosis within the range of the silicosis information centre Dresden. In one case, the diagnosis for a pleural mesothelioma was confirmed by a pathological-anatomical test. One of the men was employed in an ore-mine, one worked in the area of the Elbsandstone. In seven cases, however, five men and two women, not evidence could be found. One woman, however, worked in a shop in which asbestos had been used for the purpose if Insulation. But neither direct contact nor occupation at such a working facility could be confirmed. Here, the diagnosis of pleural mesothelioma is confirmed in four cases through a section. The age of the men was between 43 and 63 years, a median of 55.5 years. The ages of the women was 22 and 55 years. The group (e) consists of four women and four men. The diagnosis was established through X=Ray in one case, in seven cases through sections,but') there was no evidence for exposure to asbestos. HFM- 005088 8003 1173 4 The women were between 55.9 and 67.7 year old, a median of 60.6 years. The men ranged from 51.7 to 69.8 years in age, an arerage of 59.2 years. Based on the 27 cases of a diffuse malignant pleural mesoltheliomas, which have been seen in the pathological institute of the Medical School in Dresden, the pathology of this tumor is to be discussed in detail. Mesotheliomas are understood to be tumors that have their beginning in the covering cells (mesothelium, mesothelial cells) of the serous membranes (pleura, pericardium, peritoneum, tunica vaginalis coelum testis). In their developmental history, they go back to the cells that line the common body cavity, from which the pleura-pericardium-and abdominal cavities develop. These cells have the capacity to develop either in the direction of epithelium or of connecting tissue, which is the reason why the mesotheliomas are divided into carcimatose or sarcomatous forms - according to Giese. In the older literature, there are many synonyma for such tumors, as pleural endotheliosis, pleural sarcoma, perithelioma, tumor of the covering cells or pleuroma (Kerinnes and Glaser: Witte). In our cases, no organ Other than the pleura could be considered for the location of the primary tumor. The pleural mesothelioma was located on the right 18 times, and on the left nine times. They were exclusively diffuse malignant mesotheliomas, with the lungs being surrounded by tumor tissue in layers of up to several centimeters in thickness. In 12 cases, metastases existed in the lymph nodes, with the thoracal lymph nodes being almost invariably affected. Only in two cases there was lymphangitis of the lungs. In fifteen cases, there was a tumor infiltration into the neighbor ing organs (lungs, heart, chestwall, diaphram, mediastinum, spine, lymph nodes, liver). In the same number of cases a hematogenous metastasing of the organ (lungs, hearty liver, kidney, adrenal gland, pancreas, intestines, thyroid gland, spleen, spine, skin) was observed. Fifteen times a spreading of the tumors into another serous cavity (heart, peritoneum), especially the pericardium, could be seen. In two cases there was the impression of an isolated pericardium mesothelioma. Once the tumor had spread into the opposite pleural cavity, in which case the possibility of a doubl-sided pleural mesothelioma offers itself. Haematoma of the pleura, in part of a hemorrhic character, existed 14 times, but was not always followed by a compression atelactasis. A special localization of the tumor through certain lung sections could not be determined. The histological studies were based on the sections of tumor and lung tissue which had been prepared in the customary manner and had been dyed with hematoxylin-eosin. Formalin was used for the fixation. The sections were in part frozen cuts, in part parffin cuts. If the rough distinction into carcinomatous and sarcomatous forms is followed, the following results can be established: HFM - 005089 8003 1174 5 Among the pleural mesotheliomas, 15 sarcomatous forms were found and 11 carcinomatous forms, in one case there were no sections available. At a close study of the lung tissue, for the 27 diffuse malignant mesothel iomas of the pleura, 11 cases of lung fibrosis could be observed, mostly only to a slight degree, or asbestos particles were noticed. In eight cases, asbestos particles with interstitial lung fibrosis could be observed, with the fibrosis in six cases only being slightly developed. In two cases, a clear fibrosis was established. Three times, a more or less great quantity of asbestos particles could be traced in lungs, in part encapsuled in gigantic foreign substance cells, and not linked with a fibrosis. In no case were the asbestos particles found directly in the tumor tissue, but sometimes immediately subpleurally, (ill 1). Concerning the roentgenology of the pleura mesothelioma, it should be stated that there is no sign for a circumscribed tumor of the pleura. The diffuse form of the pleura mesothelioma, with which we are con cerned in our cases, on the other hand shows, at least in its further course, characteristic symptoms. The basal pleura has to be regarded as the main location of origin. A shadow, that is clearly limited towards the cranium and runs almost horizontally and cannot be separated from the diaphragm and which remains there even after the tapping of a hematoma, has to be part of the pleura. The x-ray examination should always be started by x-rays on various levels as well as by a careful transillumination. If these methods do not result in a final conclusion, a pleuroscopy and pleuroscopic biopsy should be In most cases, the tumor spreads in the beginning at the lateral thoraxwall in the area of the lower range. The x-ray then shows a clearly limited, quite frequently slightly Irregular shadow above the lower lateral thorax wall and the diaphragm (ill 2). This result looks entirely the same as a callosity in the pleura or a capsuled-in hematoma of a different genesis. For this beginning stage of a diffuse pleura mesothelioma - as for all results gained from x-rays, a careful collecting of the anmnesis and a general examination of the patient have to be performed. Behind the pidture of a callosity of the pleura, which cannot be linked with any other form of disease, a malignancy has to be suspected. If the callosity of the pleura shows already in the beginning phase the clear formation of an uvula towards the lung, the diagnosis can be made, at this stage also, quite easily by x-ray (ill 3). In the further course, which is in most cases fast and malignant, the tumor spreads first at the lateral thorax wall, and goes in most cases hand in hand with extensive hemorraghic hematomas. In this stage, the x-ray will show, sometimes only after the hematoma is tapped, the'wide shadow areas, which are characteristic for the diffuse pleural mesothelioma, and which frequently reach to the tip of the lung, and which are located at the lateral thorax wall. These shadows cannot be separated from the thorax well during trans illumination, and they show the typical shape, which is described in the literature as garland - or curtain shape, (ill 4-6) 8003 1175 HFM - 005090 6 In the final stages, the tumor spreads also into the pleura of the lower and upper mediastinum, and it shows at this location the same changes of the pleura that are close to the heart, it quickly spreads to the pericardium. Due to the unfortunate localization these patients arrive ad exitum before the tumor can spread to the are of thoracal pleura. These cases, which occur rarely, then create the impression of an isolated mesothelioma of the pericardium, as it was seen in a similar way in the two cases that were mentioned above. Discussion Today, there are no doubts anymore about the link of an asbestosis of the lungs and a carcinoma of the bronchi, which was also reflected in the insurance law. Thus, an asbestosis linked with a carcinoma of the bronchi is recognized as a job-related disease which entitles the worker to workman's compensation. In recent months, the reports about a linkage of diffuse malignant pleural mesotheliomas with lung asbestosis have beocome more frequent. Such tumors, which are otherwise very rare, were observed, most of all, after job-related exposure'. In recent times, Wagner and associates reported, as mentioned above, about 84 such tumors, for which also a non-job related risk has to be taknrinto consideration,. Jacob and Bohlig already pointed out that an Increased number of serosa tumors could be observed not in frequency in connection with an asbestosis. First reports of a pleural mesothelioma in connection with an asbestosis in Germany date back to Vedler. Unfortunately, this report did not study the cases - which are given in the chart as number 1-6. Possibly, the connection between the asbestos dust exposure could have been established even then, especially even in our cases this connection was only established in retrospect. Mesotheliomas after an exposure to asbestos are, in the overwhelming number of cases, located in the pleura, rarely in the peritoneum. In the area of the silicosis information center Dresden, several cases of peritoneal tumors were registered after an exposure to asbestos in a job-related context. There can be no precise information about the frequency of the meso thelioma in the pleura. It should be mentioned, though, that out of 21,541 sections within the period from 1950 to the first quarter of 1964, 27 cases were observed. Just as the pleural calcifications usually did not show a dimultaneous lung fibrosis, our studies show also that there is no connection between the degree of the changes in the lungs due to asbestosis and the occurrence of mesothelioma of the pleura. Only in two cases was there a clear asbestosis. Through anamnesis a connection with exposure to asbestos dust could be established in 16 cases. Beside the nine :that were exposed to the asbestos dust on the job, the nine cases from the neighborhood of asbestos factories can be, with great probability, traced back to an exposure of asbestos dust. The finding of asbestos particles in four cases can be taken as a sure proof such a non-job related asbestos risk. ' HFM - 005091 8003 1176 According to the literature, men are more prevalent for the pleura mesotheliomas without any traces of asbestos. The cases, for which an exposure to asbestos could not be proven - apart from the cases that go hand in hand with silicosis are nine men and six women. Therefore, our numbers seem to coincide with the findings of the literature. But, there was not in every case lung tissue, especially -tissue from the basal lung parts, available for a detailed study. In this context, the study by Thompson should be mentioned, who in describing seven cases of mesotheliomas, without a roentgenologic hint, could also macroscopically, at first, not find any lung asbestosis in the autopsies. Only the careful histological study of the basal lower lobe areas showed in six cases an asbestosis of the lungs with a sufficient number of asbestos particles. The sections from other parts of the lunbs did not show any asbestosis and generally speaking, no particles of asbestos either. The author points out especially, that in the majority of cases, the find of a basal asbestosis is overlooked. The more frequent occurrence of the pleural mesothelioma of the right side, which is stressed by some authors, can be confirmed by us. The literature lists as the duration of the development for a mesothelioma as 20*40 years or more. The patients of pleural mesotheliomas of our study, for which the retrospective anamnesis contained usable information have on the rtrerage, a 37.4 latency time from the beginning of the exposure to asbestos to the finding or their death. The shortest time was 23 years, the longest 45. Only women experienced job-related exposure. This circumstance can be explained with the fact that there are more women employed in the departments with a risk factor in the asbestos-processing industry. The time of latency from the beginning of the exposure to the occurrence of death for the patients that were at risk because of propinquity exposure was at approximately 42 years, that means, it is not notable higher than for job-related exposures. The median age of all deceased at 60.7 years in all groups, comes close to the report of Caughey (2- copy almost illegible) and associates who listed 53.5 years. Two (Illegible) mesotheliomas of the pleura were found in connection with a silicosis. It does not seem appropriate to deduct certain conclusions from that. Certain parallels should be pointed out. Thus Hurwitz and Lieben and McBride found calcifications of the pleura also in connection with silicosis. Stephanopoulos found the same after exposure to marble dust. But we could not so far in our area, observe calcifications of the pleura after exposure to such silicone dusts. The question about the cause of the mesotheliomas of the pleura with asbestosis raises the basic problem of the oncogenesis overall. A mechanical as well as a chemical affect of the asbestos would be conceivable, also in those cases where no lung reaction in the sense of an asbestosis could be observed. The theory by Kiviluoto should be especially mentioned. He sees the capacities to sink and float of the fibers of different lengths as the cause, which was confirmed by Anspach, based on his comparative studies of the frequency of HFM- 005092 8003 1177 U____ asbestosis and pleural plaques with the local situation of the in dividual asbestos firms. It seems that the lighter, shorter, more easily flying fibers can pass the lungs without reaction, as per the tests by Vorwald and Associates, and can cause plaques and pleura mesotheliomas in the sense of Kiviluoto's theory. Leicher places the main responsibility for the occurrence of tumors in asbestosis on the mechanical lesions of the tissue. The long latency times could be explained with the continuous slight mechanical effect. Animal tests confirm the oncogenic effect of the asbestos. There were several occurrences where through intra-pleural application of sus pension of asbestos dust pleural mesotheliomas were created. (Wagner) The stddies and reports in the literature allow the conclusion that job-related cancer of the asbestos workers. It seems justified to include this tumor, with existing asbestosis, in the compensation obligation according to number 28 of our regulations about information and compensation obligations for job-related diseases from November 14, 1957. The conditions do not yet seem to be given under which it would be recognized as a job-related disease, for those cases where, after exposure, no lung fibro&is or only asbestos particles could be proven. We think, further, that extensive studies and discussions are necessary, the same for the problem of the bronchial carcinoma and asbestos exposure without lung fibrosis in the sense of only a slight asbestosis. In any case, Bohlig is justified in pointing out that the existence of pleural reactions without lung fibrosis opens new ideas about the pathogenesis of the asbestosis and about the discussion of the job-related cancer of the asbestos workers, and opens new perspectives which may even appear somewhat heretic. Furthermore, the risk through emission in the neighboring environment of the asbestos factories has gained further relevance. Summary. _ . Out of 44 cases of diffuse malignant pleural mesotheliomas, 35 were studied in a detailed analysis. In 18 cases an exposure to asbestos could be proven, either job-related or outside the job. In eleven cases, fibrotic reactions of the lungs and asbestos particles were found in the sections. HFM- 005093 8003 1178 CHART t OBSERVED PLEURA MESOTHELIOMA 1946-1951 w inder 'All - OCp P (O4 9> oO. X o p0 ai .OPO1 GO 0 a pCoO J0Q) 0 60 9Oo oo n O*4' oI 0O ani 00) o o 0 pa p 9O) O O' 0 0 c u s d p 0 ppp *9 > 0x C p 00 9 COM' PU i <p 0 *4 9 CM c 0 O' *< a1 o X p o tp X > 0 -4 TJ c N* n O' 1 O> n0 O' p > o P *o CO O O' H d5 p Op P 4> <2 H o> 4)0 0 o Jr 5 -> P 0 m d O' *4 fH cm a O' P H6 9 a. 9a s eq O' a cm cm CM O' COM' O' O' 4 1 1 fPI rPI HO' P CM CD CM 00p O*4 oI O' O' O' O' CM P P P ^ O' a P <3 O' H y-*s O' CO CM o cm CM o OO o d dd d 1*--s. P cm <0 cm in cm n NnO4 o o o ooo d d d aCc a CO M CoO 2 g 5 Si e o d T3 O O X P Cz3 J0S g 45 to CO p 8 c o p 0 ^4 p 1 X o to d 09 p P o pX pP p 0 <P o. o 00 o p p0 0o p ,o X 0p 0 0 43 0 0 oO. d o P 0 0 9O 0 o d * P 45 t P P 0 0 P a O p 0 o 0 0 HFM - 005094 8003 1179 ZT''_:c.;rs-.ys- X1 HFM- 005095 HFM- 005096 W JUIW I V ^ ) |- .U ||.M U |U || -J( * * H 4 VU | f lit* to 3k. *- i 1 rm Mto fwM u4rfT<4 ft R..K. fl ur. ~ f 1- f/a toa> 1991 XI F,ll. *"/,, 1993 91 *,*. - 11199 3* P,X h j>/,, 199} 39 K..K. - 199} 91 II. 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Iltl-S infs |iii fe ,, 2* *;5 et is Jlijls |111 6ii=]4!* ai llSt E J I-f = J 1* =111*4142 *1 6K- 5tti li?l-iZ*"111-4* sir 'i4|J .fJf{c 2il" ii 0;!$* iihrsninsii*J | r e z.~ Ik e c Sfc e X ; E D ii^ii ciji Ell,* 5- S*. b|I9 1e it$n a! ii ft ?** i] i|ii es niuKi -- HFM- 005102 8003 1187