Document MoymkaJzK2KaB8KaQmrzROVjx

[Slumbers N 0.S IIJ \ August 23, 1967 PLAINTIFF'S EXHIBIT 7/^139^ Mr. J}\M. Barnhart National Insulation Manufacturers Association Uil Lexington Avenue New iork. Hew York 10017 SUBJECT* J.A.M.A. Article, Mesothelioma and Its Association With Asbestosis" A oopy of the attached article should be sent to Members of the Health and Safety Committee. It is a good review on mesothelioma. Sincerely, Lee B. Orant, M.D o 587 Mesothelioma and Its Association With Asbestosis Maxwell Borow, MD, Alfred Conston, MD, Lawrence L. Livornesc, MD,and S'orbed Schalel, MD Within a three-year period in a community hospital, exist. Since Godwin' in 1957 laid down strict cri 17 cases of mesothelioma, nine of the pleura and eight teria for the diagnosis of pleural tumors and Wins of the peritoneum, were found at surgery. Two of our low and Taylor* in 1960 for neritoneal tumors, the pitients contracted this malignancy with only environ diagnosis of these neoplasms has become more com mental exposure consisting of living in a community mon. The incidence of primary mesothelioma has adjacent to the asbestos mill. In the S2me hospital, there varied statistically from .02% to .2% of all autop has been a high incidence of bronchogenic carcinoma sies. with a ratio of one to two iri favor of the male. with asbestosis. A review of the autopsy material of the The first large series of cases of diffuse meso past decade brought to light only one additional case. thelioma was diagnosed histologically in 1957 at the It is our belief that the incidence of mesothelioma is Pneumoconiosis Research Unit at Johannesburg, increasing as is ii.. incidence of asbestosis, with the South Africa. In trying to explain this mysterious increasing application of this product in many different epidemic, Wagner et al/ noting that asbestos bodies industries. could be found in the lungs of some of their pa tients, obtained detailed life histories of these pa Primary tumors of the serosal surfaces are so rare that for years they were considered to be pathologic curiosities. The first reference to such mors can be found in a report by Von Rokitansky/ who in 1854 described primary tumors of the peri toneum whjch he called "colloid cancer." During the next 100 years, there were sporadic reports of similar types of tumors. However, this entity re mained so ill defined that there was much doubt as to its precise nature. Brown and Johnson' in 1951 considered these mesothelial tumors (mesothelio ma) to be the end result of an inflammatory pro cess, with organization of the exudate. Willis' in his pathologic text made the following statement: "To the present day accounts of supposedly primary serosal tumors continue to be descriptively inade quate and insufficiently critical, displaying a lack of awareness of the possible behavior of small unde tected carcinomas," and he also cautioned the read er to preserve an open mind regarding the exact histogenesis of these tumors. In 1954, Ackerman4 stated that it was the majority opinion that al though primary mesotheliomas are rare they do tients. By 1960, they were able to establish an as sociation with the Cape of Good Hope asbestos tu3fi3eldpsa,tieonr tsthwe itihndhuissttorilaogl icusaellyopf roavsebnesptolse,urianl 32 of meso theliomas. The mrioritv of these patients had not actually worked with asbestos but had lived in the vicinity of the mines and mills and some had left these areas of exposure as young children. The aver age period between exposure and develooment of the tumor was 20 to 40 years. By 1962, Wagner et al* had diagnosed a total of 87 pleural and two peritoneal mesotheliomas. In only two cases was it not possible to establish a history of exposure to the asbestos dust. Of these 87 cases, 12 had had industrial exposure and the remainder had had en vironmental exposure from living in the vicinity of the mills and dumps. This association between mesothelioma and asbestosis was made even more intriguing when, in 1955, Bonser et al* described a series of 72 autopsies on patients with asbestosis, in which four cases of peritoneal mesothelioma were found. Subsequently, Mancuso and Coulter'0 found five peritoneal mesotheliomas in autopsies on 1,495 asbestos workers, and Hourihane," upon reviewing From the departments of surgery and pathology, Somerset Hos pital. Somerville, NJ. Reprint requests to SIS Cburch St, Bound Brook, NJ 08805 (Dr. Borow). the necropsy files of the London Hospital from 1917 to 1962, found 34 cases of mesothelioma, 17 of the pleura and an equal number of the peri JAMA, Aug 21, 1967 Vol 201, No 8 93 588 MESOTHELIOMA AND AS8EST0SIS--BOROW ET AL toneum. All of these patients had pulmonary as' bestosis, even though in a few there was no his tory of exposure to the asbestos dust. In the same year, Enticknap and Smither'1 reported 11 cases of peritoneal mesothelioma in patients exposed to.asbestosis. In an attempt to determine whether mesothelio ma of the serosal surfaces had any relationship with asbestos exposure in the United States, Selikoff et a]" studied 307 consecutive deaths among asbestos insulation workers in Northeastern United States. They found ten deaths caused by mesothelioma, four pleural and six peritoneal mesotheliomas. In addition, these workers had an extremely high death rate attributed to cancer of the stomach, colon, and rectum. Of the 307 deaths, 40.4% were attributed to cancer, 5.5% to asbestosis, and 54.1% to other causes. In a second study where they re viewed 26 consecutive autopsies of patients with asbestosis, they found four mesotheliomas of the pleura and three of the peritoneum. One of us (M.B.) has had the unique experience of operating, within the past two years, on 11 patients who proved to have mesothelioma. Six of these were of the peritoneum and five of the pleura. These cases added to those diagnosed previously made a total of 17 cases of mesothelioma, of which eight were peritoneal and nine were pleural mesotheliomas. All 17 cases were diagnosed within the past three years. A review of the autopsy material at Somerset F''*pital, Somerville, NJ, from 1948 through 1965 did not disclose any additional cases of mesothelioma. This high concentration of what is considered to be a rare tumor can be explained by the close proximity of a major asbestos mill. Approximately 75% of all the asbestos fiber which is mined in North America is converted to commercial use in an industrial fa cility which is located only two miles from Somerset Hospital. The association between pulmonary cancer and asbestosis has been recognized at this institution for many years. The number of patients admitted with these conditions is difficult to determine, as in ear lier years many of them were diagnosed as pulmo nary fibrosis or silicosis. The only accurate statis tics could be obtained from the autopsy material of the past decade, 1955 to 1965, when 1,330 autop sies were performed. In this group, there were 22 cases of bronchogenic cancer with pulmonary asbes tosis, as well as the 17 cases of mesothelioma. An interesting observation is that, despite the fact there were large numbers of women also employed at this industrial facility and many contracted as bestosis, there is only one female with mesothelio ma in our series, and she never worked in the as bestos plant but lived nearby. This experience is in . contrast to other reported series, particularly those from South Africa where there was a significant number of females afflicted with mesothelioma. Newhouse and Thompson,14 in studying the occu pational histories of 83 patients with mesothelio ma, noted that 42 of these patients were female. We might attribute our absence of females involved with this disease due to a difference in occupational exposure between the male and female workers. However, other studies would not substantiate this, as there appears to be a high incidence of meso theliomas in people just living in the vicinity of the asbestos mines or industries. In Wagner's series from South Africa, more than half of the people had not been employed by the asbestos industry. These people had had environmental exposure due to liv ing in the vicinity of the mills and dumps. The sta tistics from the London Hospital, as reported by Newhouse and Thompson14 are very much the same, with one half of the patients having only an en vironmental exposure to asbestos. With this infor mation, one wonders why we have not seen similar circumstances in our community, especially since there is a large asbestos dump adjacent to a resi dential area. Another interesting observation in our series is the fact that 16 of the 17 patients with mesothelio ma were diagnosed within the past three years. A re view of the autopsy material for the previous decade brought to light only one additional case which initially had been misdiagnosed. Since the refine ment of the asbestos fiber has been one of the ma jor industries in this geographic area for over 60 years, it is difficult to explain why we are only now aware of this disease. One possible explanation is that in our group of patients, once the diagnosis was suspected, an intensified effort was made to obtain an autopsy when the patient died. However, prior to our recognition of this entity, patients with mesothelioma were most likely diagnosed as having a generalized carcinomatosis and little effort was made to obtain an autopsy when they did. Regard less whether this reasoning is correct or not, it is our distinct impression that there has been a defi nite increase in incidence of this malignancy within the last few years. 1. Tubulopapillary type mesothelioma (case 1, slightly reduced from X120). 94 JAMA. Aug 21. 1967 Vol 201, No 8 2- Asbestosis of the lung (case 1, X120). Report of Cases Case 1.--A 52-year-o]d white man was admitted to the hospital with increasing constipation, an enlarged abdomen of one months duration, and an ill-defined abdominal pain. He had been retired with a medical disability from pulmo nary asbestosis after working 28 years at an asbestos mill. He suffered a myocardial infarction two years before ad mission. He smoked only occasionally. Physical examination revealed a slightly emphysematous chest with harsh breath sounds and abdominal distention. No intra-abdominal masses could be palpated at that time. Chest x-ray of the lungs demonstrated basilar fibrosis, bilaterally, interpreted as most likely due to asbestosis. An anteroposterior x-ray film, without contrast material, f the abdomen demonstrated a ground glass appearance jggestive of ascites. Some attenuation of the rectosignoid on the x-ray film taken after evacuation of the oarium ene-ma raised me possibility of a pelvic mass. A paracentesis yielded approximately 1,500 cc of straw-col ored fluid. Surgical exploration revealed the visceral and parietal serosal surfaces to be studded with fine papillary, almost granular-like, projections. A diagnosis of papilloma mesothelioma was made from a biopsy specimen (Fig'l). Following an intraperitoneal injection of gold AU-198, he remained symptom free and ascitic free for nine months. Fourteen months after surgery he died from a myocardial infarction. Autopsy examination revealed pleural cavities to be free of tumor. Pleural plaques were present at the bases and there were multiple adhesions. The lungs demonstrat ed bullae emphysema with an irregular delicate fibrosis throughout. The heart was enlarged with old'scarring and a fresh infarct. The peritoneal cavity yielded 1,000 cc of slightly mocoid yellowish fluid, and all the coelomic cav ity organs as well as the parietal peritoneum were cov ered with white hard nodules, varying from 5 mm to 5 cm in diameter and having a mucoid appearance on the cut surface. In many areas there was a tendency for these nodules to coalesce to form larger tumor masses. The tu mors did not penetrate for any appreciable distance be- 3. Serosal tumor encasing loops of bowel (case 2). 589 neafh the surface, and all olher organs were unremarkable. Microscopic examination demonstrated an extensive in terstitial fibrosis of the lungs with many asbestos bodies (Fig 2). The hypertrophied heart showed areas of fibrosis and acute necrosis. The tumor was characteristic of meso thelioma with cuboidal cells showing some pleomorphisra and superficial papillation. Case 2.--A 51-year-old white man was admitted to Som erset Hospital because of abdominal pain. For 25 years he was an employee at an asbestos refining plant. He smoked less than one pack of cigarettes per day. Results of physical examination were normal, and all laboratory studies were unrevealing. Chest x-ray showed a fibrotic infiltration of both lower lobes. An upper gastro intestinal roentgenographic series demonstrated duodeni tis and gastritis. He was discharged on a regimen for ul cer convalescence only to be readmitted seven months later with postprandial abdominal pain and a 10-lb weight loss. On palpation the abdomen appeared board-like, though there was no tenderness, and an extraluminal mass could be palpated through the anterior portion of the rectal wall. A barium enema demonstrated rigidity and narrowing of the sigmoid colon. At surgery, the abdominal cavity was found to be almost completely obliterated by large masses of neo plastic tissue which had enveloped the intra-abdominal or gans and was infiltrating the parietal peritoneum. A diag nosis of mesothelioma was made from a biopsy specimen. The patient died four months later. Pertinent findings at autopsy included numerous large plaques on the parietal pleura and congestion at the bases of both lungs. The peritoneal cavity was virtually obliterat ed by a large, yellowish-white hard tumor which was Com pletely encasing the abdominal organs (Fig 3). Except for this surface involvement, the organs were unremark able. Microscopic examination demonstrated bronchial pneu monia with a mild pulmonary fibrosis and many asbestos bodies. The tumor consisted of fusiform cells in a hyalinized stroma with papillary formation characteristic of mesothelioma (Fig 4). Case 3.--A 47-year-old w-hile man was admitted to the hospital with a nonproductive cough and ill-defined dis comfort in the right lower lobe of the lung. The initial chest x-ray film was normal, but a second one taken two days before admission demonstrated a small pleural effu sion in the right costophrenic angle. Though he had been an insurance agent and more recently a liquor salesman, he had worked as a stock boy in an asbestos refining plant for 18 months, 24 years ago. Physical examination and complete work-up were unre vealing, including scalene node and two needle pleura] biopsies. Thoracocentesis yielded 100 cc of straw-colored fluid with some mesothclial cells. At exploratory thoraco tomy the patient was found to have a greatly thickened parietal and visceral pleura with encasement of a partial ly atelectatic lung. In certain areas the parietal and vis ceral pleura were intimately adherent to -one another, and could not be separated. There was no nodularity of the serosal surfaces. A diagnosis of pulmonary asbestosis and mesothelioma was made from a biopsy specimen. Postoperatively he re ceived steroids and cobalt radiatioif with a poor response, and he died ten months later with bilateral pleural in volvement. Clinical Feature* Our patients with peritoneal mesothelioma pre sented themselves in one of two ways. Four had as cites of unknown origin and the other three com plained of vague abdominal pain and weight loss. In this latter group an ill-defined mass was usually palpated either through the abdominal wall or on rectal examination. Laboratory work-up and roent genographic examination of the gastrointestinal JAMA, Aug 21, 1967 Vol 2dl, N<J 8 95 590 MESOTHELIOMA AND ASBESTOSIS-BOROW ET AL tract were unrevealing. The diagnosis was made either by surgery or peritoneoscopy and biopsy. Those patients with ascites were found to have small papillary projections studding the visceral and parietal peritoneum. The ascitic fluid varied from a clear syrupy to a thin straw-colored consis tency. Those patients with the palpable masses were found on exploration to have complete ob literation of the peritoneal cavity by large tumor masses which were occupying most of the coelomic cavity and invading the parietal peritoneum. We believe that this picture is but the end stage of the disease, while those patients with ascites repre sent an earlier stage. This is substantiated by the finding of papillary projections at surgery in several of our patients who having presented with ascites and in whom obliteration of the peritoneal cavity with large tumor masses developed later, as seen at autopsy. Patients with pleural mesotheliomas all present ed with varying degrees of chest pain and pleural effusion. A work-up was likewise unrewarding with the exception of positive findings from a pleural biopsy in one patient. The fluid in the pleural cavi ty varied from a gross bloody effusion to straw-col ored fluid, and the tumor involvement varied from papillary projections on the parietal and visceral pleura to a generalized thickened pleura. In areas the visc::<J and parietal pleura were intimitely ad herent and could be separated only with difficulty. Treatment with cobalt radiation therapy, radio active gold and chromium, and chemotherapy, used alone or in combination, had little effect on the course of this disease. Fifty percent of the patients suffering either from pleural or peritoneal meso thelioma died within one year and the remainder by the second year. Criteria for Diagnosis Although it is now accepted that mesothelial tumors of the serosal surfaces do exist and possess a number of characteristics which justify their seg regation as an entity, the criteria for the identifica tion of these tumors are still largely imprecise. The currently accepted criteria for the diagnosis of these tumors are that: (1) The diagnosis should be ap plied to those groups'which show an unequivocal predilection to spread along the serosal membranes, with either none or only a shallow invasion of the underlying organs. (2) AU other sources for the tu mor have been excluded. (3) If metastases are pres ent, they should be limited to the regional lymph nodes, rarely occurring in liver, bone, and lung. Special staining or histologic techniques may aid in a diagnosis of this disease. Wagner et al" have suggested that metachromatic staining (removable by exposure to hyaluronidase) within a tumor is strong evidence for the diagnosis of mesothelioma in a patient. Pathologic Characteristics.--In the earlier stages, the tumor is made up of many small, rounded, firm ' nodules on the visceral and parietal surfaces. Later, 96 JAMA, Aug 21, 1967 Vol 201, No 8 there is a coalescence of these, nodules, so that the terminal state usually consists of solid, broad, thick bands which encompass the viscera and fix them within a dense mass. Often the delineation between parietal and visceral peritoneum is lost, so that the usual autopsy dissection is impossible due to this encasement. The tumor is generally white and firm and may have a mucinous appearance on the cut surface. Histologic Characteristics.--We have seen two major histologic types of mesothelioma. The most common variety is the epithelial form where there are cuboidal or polyhedral cells producing a tubulopapillary appearance or a solid group of cells with out a clear tubular formation. Usually there is a fair ly uniform cellular structure, but occasionally bizarre nucleated cells can be seen. Pathologic mito tic cells are rarely found, but doubly nucleated and multinucleated tumor cells are often seen. The other variety is the mesenchymal or fibrous type of mesothelioma in which spindle cells are arranged in an almost fascicular pattern within a stroma of abundant hyaline collagen. Occasionally the cells may be arranged loosely in indistinct fasciculi or may occur in solid nests. The most striking histologic characteristic of mesothelioma is the structural variation which may occur from area to area within the same tumor, so that in one area the growth may have epithelial structure, while in another a purely mesenchymal appearance or in between combina tions. Pathogenesis The mode of action of asbestos in producing neo plasia is at present poorly understood. Furthermore, a puzzling feature has been the presence of meso thelioma in one mining area, while in another min ing area a few miles distant, the disease has as yet to be identified. There are two major mining dis tricts in the Republic of South Africa. In the north west Cape of Good Hope province, crocidolite is the fiber mined, whereas in the Transvaal asbestos field, both crocidolite and more importantly amosite are mined. Up to the present time there has been a .4 Spindle cell type mesothelioma (case 2, X60). ' # *. -J MESOTHELIOMA AND ASBESTOSIS--BOROW ET AL 591 high prevalence of mesothelioma of the pleura and peritoneum in northwest Cape of Good Hope. On the other hand no case as yet has been reported from the Transvaal asbestos area or its surround ings. Sluis-Cremer'* has studied the geographical and environmental differences in these two areas and has come to the conclusion that none of the fac tors examined explained satisfactorily the absence of mesothelioma in the Transvaal region. Other than for the mineralogic difference between the two areas, he found no variation in the intensity or length of production of these fields or in the extent of the environmental pollution and incidence of pul monary asbestosis. In North America, chrysotile is the main fiber mined although crocidolite and amosite are present in lesser amounts. Both pleura and peritoneal mesothelioma have been found in work ers exposed to these fibers. Wagner" in 1962 induced mesothelioma by inocu lating various dusts into the pleural cavity of rats. Pleural tumors developed in those inoculated with crocidolite, chrysotile, and a finely divided silicon powder (99.9% silicon dioxide). Recently Skidmore and Wagner" showed that crocidolite, chrysotile, silica powder, and to a lesser extent, amosite, all induced pleural mesotheliomata in guinea pigs after interpleural injection. Peacock and Peacock" in duced malignant tumors in fowls with crocidolite and amosite. A number of hypotheses to explain the pathogenesis of this disease have been proposed, but none of them have been widely accepted. The first theory was that of physical irritation due to the presence of asbestos fibers deposited in the ter minal lymphatics of the serosal surfaces or due to the migration of the asbestos fiber from the lung following inhalation or from the gut as a result of ingestion. Fibers have been demonstrated in a num ber of tissues, including parietal pleura, gastric mu cosa, and spleen, but there have been no reports of fibers in the peritoneal surfaces. Another concept is the auto-immune theory in which the presence of asbestos bodies in the lung is said to elicit the production of an abnormal globu lin. Up to the present time, there is little positive evidence for this concept. The serum of patients with either asbestosis or neoplasia shows only a slightly raised titer for the rheumatoid factor, and immunotf-uorescent staining has not shown evidence of an antigen-antibody aggregate. Recently, Harington and Roe10 suggested that the carcinogenicity of asbestos may be related to the presence of nat ural and contaminated oils associated with the as bestos fiber or to certain carcinogenic metals or metal complexes in the fibers. They found that crocidolite and amosite contained appreciable amounts of natural oils. Furthermore, all the as bestos fibers, including chrysotile, may contain sec ondary oils as a result of an addition of oil to the asbestos during the processing or as a result of con tamination. Furthermore, almost universally, the asbestos is transported and stored in jute bags and the oil from the jute fiber is absorbed to a great ex tent by all three types of asbestos fiber. Both chrysotile and amosite have a significant ferrous content, particularly of certain macromolecular complexes of iron, such as iron-dextran which is known to be highly carcinogenic in animals. The iron content of chrysotile is much lower than the other two fibers. It is proposed by Harington and Roe50 that the carcinogenic agent or agents may not be the fiber themselves but either w.u natural oil or secondary oils which are present on the fiber and or possibly the iron complex. The authors are currently performing biologic tests for the carcino genicity of these materials. However, these studies were in a preliminary form at the time of the report. Generic end Trade Names of Drug Gold Au 198-Aurcoloid-198, Aurtolopt-Au 198, Aurcotcan-198, Radiofold Colloidal Au 198, Aureotope. References 1. Rokitansky, C. Von: Manuel of Path. Anat. Sydenham Soc. Trans., London p 265, 1854. 2. Brown, WJ., end Johnson, L.C.: Post Inflammatory "Tu mors" of Pleura: 3 cases of Pleural Fibroma of Interlobar Fissure, Milit Surg 109:415-425 (Oct) 1951. 3. Willis, R A.: Pathology of Tumors, Washington, DC: Butterworth Inc., 1960, p 185. 4. Ackerman, L.V.: Altai of Tumor Pathology, Washington. DC: Armed Forces Institute of Pathology, section 6, part 23, 1956, p 100. _ 5. Godwin, M.C.: Diffuse Mesotheliomas With Comment in Their Relation to Localized Fibrous Mesotheliomas, Cancer 10: 298-319 (March-April) 1957. 6. Winslow, D.J., and Taylor, H.B.: Malignant Peritoneal Mesotheliomas, Cancer 13:127-136 (Jan-Feb) 1960. 7. Wagner, J.C.; Sleggs. CA.; and Marchaod, P.: Diffuse Pleu ral Mesothelioma and Asbestosis Exposure in North Western Cape Province, Bril J Indutlr Med 17:260-271 (Oct) 1960. 8. Wagner, J.C.: Epidemiology of Diffuse Mesothelial Tumors: Evidence of an Association From Studies in South Africa and Jnited Kingdom. Ann NY Acad Sd 132:575-578 (Dec 31) 1965. 9. Bcnser, G.M.; Faulds, J.S.; and Stewart, MJ.: Occupational Jancer cf Urinary Bladder in Dyestuffs Operatives and of Lung in Asbestos Textile Workers and Iron Ore Mines, Amer J Clin Path 25:126-134 (Feb) 1955. 10. Mancuso. T.F., and Coulter, E.J.: Methodology in Industrial Health Studies. Arch Emiron Health 6:210-226 (Feb) 1963. 11. Hourihane, D.O.: The Pathology of Mesotheliomata and an Analysis of Their Association With Asbestos Exposure, Thorax 19:268-278 (May) 1964. 12. Enticknap, J.B., and Smitber, W.P.J.: Peritoneal Tumors in Asbestosis, Brit J Indutlr Med 21:20-31 (Jan) 1964. 13. Selikoff, I.J.; Churg, J.; and Hammond, F.C.: Relations Between Exposure to Asbestos and Mesothelioma, New Eng J Med 272:560-565 (March) 1965. 14. Newhouse, M.L., and Thompson, `H.: Epidemiology of Mesothelial Tumors io the London Area, Ann NY Acad Sci 132: 579-588 (Dec 31) 1965. 15. Wagner, J.C.; Munday, D.E.; and Harington, J.S.: Histo- chemica! Demonstration of Hyaluronic Acid in Pleural Meso theliomas. J Path Bad 84:73-78 (July) 1962. 16. Sluis-Cremer, G.K.: Asbestosis in South Africa, Certain Geographical and Environmental Considerations, Ann NY Acad Sci 132:215-234 (Dec 31) 1965. 17. Wagner, J.C.: Experimental Production of Mesothelial Tu mours of the Pleura by Implantation of Dusts in Laboratory Animals. Nature 196:180-181 (Oct 13) 1962. 18. Wagner, J.C., and Skidmore. J.W.: Asbestos Dust Deposi tion and Retention in Rats. Ann NY Acad Sci 132:77-86 (Dec 31). 1965. 19. Peacock. A., and Peacock, PJL: Aibeitoe Induced Tumort in Fowls, abstracts. Fifth Annual Meeting British Association for Cancer. Scotland: R. S. Edinburgh, 1964. 20. Harington. JS., and Roe, FJ.C.: Studies of Carcinogenesis of Asbestos Fibers and Their Natural Oils, Ann NY Acad Sci 132: 439-450 (Dec 31) 1965. JAMA. Aug 21, 1967 Vol 201, No 8 97