MESOTHELIOMATOUS TUMORS IN SOUTH AFRICA: PATHOLOGY AND EXPERIMENTAL PATHOLOGY

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1 MESOTHELIOMATOUS TUMORS IN SOUTH AFRICA: PATHOLOGY AND EXPERIMENTAL PATHOLOGY Ian Webster Pneumoconiosis Research Unit, Council for Scientific and Industrial Research, and Asbestosis Research Project", Johannesburg, South Africa It is now more than five years since Wagner' first drew attention to the problem of pleural mesotheliomata in South Africa. He indicated that these tumors were probably associated with exposure to asbestos dust in the northern regions of the Cape Province of South Africa or with exposure to the asbestos produced there. By 1960, Wagner, Sleggs and Marchand' had found thirty-three such cases and in his thesis presented to the University of the Witwatersrand in 1962 Wagner? recorded seventy-eight cases of primary mesotheliomata of which three arose in the peritoneum. A total of one hundred and sixty-nine cases of primary mesotheliomata have now been diagnosed in South Africa. One hundred and' twenty-five of these have been examined in the Pneumoconiosis Research Unit, Johannesburg (TABLE 1 ). In only seven of the one hundred and twenty-five cases has a full postmortem been carried out at the Pneumoconiosis Research Unit or at the University of the Witwatersrand, and in the majority of the cases "confirmed at post-mortem" selected specimens were obtained from hospitals where there was no pathologist on the staff. The records of the additional thirty-six cases were submitted by the Universities of Cape Town, Pretoria and Natal and by the Bloemfontein Laboratories of the South African Institute for Medical Research. In these cases there was no evidence of a primary tumor elsewhere in the body and the diagnosis of primary mesothelioma was confirmed histologically. Pathology of Mesotheliomatous Tumors Localized fibrous mesotheliomatous tumors have been described by Stout and Murray," and Clagett, McDonald and Schmidt5 but these tumors are probably more accurately designated as fibromata of the pleura (see Price- Thomas and Drew"). If, however, such tumors can be classified as mesotheliomatous then multiple fibrous plaque formation especially of the parietal pleura and diaphragm could well be the diffuse simple counterpart of a malignant mesothelioma (FIGURES 1 and 2 ). Three such cases have been found in South Africa and all three showed the presence of asbestos *Sponsored by the State Department of Mines and the Asbestos Mining Industry of South Africa. 623

2 624 Annals New York Academy of Sciences bodies in smears made from the lungs and in one case there was evidence of asbestosis. McCaughey? has divided the diffuse mesotheliomatous tumors into those of epithelial, mesenchymal, mixed and anaplastic types. All of these types have been seen in this series, but in only an occasional case could the type be specified with accuracy, and features of all four types have been found in one specimen. The pathology of malignant mesotheliomatous tumors in this series is based mainly on the findings in forty-one cases where the diagnosis was confirmed at post-mortem. The tumors consist of cells of varying type, some small (FIGURE 31, others large (FIGURE 4), some spindle shaped (FIGURE 5), some varying in the nuclear cytoplasmic ratio, others regular. The cells are sometimes arranged in acina, sheets, or in a papillary formation (FIGURE 6), but are usually associated with a connective tissue stroma. In some cases the stroma appears to consist of reticulin fibers, loosely or compactly arranged, TABLE 1 CASW DIAGNOSED AS MESOTHELIOMA n = 125 but in many it is composed of dense collagen (FIGURE 7). Thus it is possible that the stroma may be part of the diffuse fibrous plaque formation and that the cellular part of the tumor may arise as a type of scar tumor either from clefts of mesothelial cells in the plaques or from metaplasia of the regional mesothelial cells. In sixteen of the cases diagnosed as mesotheliomata of the pleura at autopsy, and in which there was obliteration of the pleural space it has been impossible to exclude a primary multicentric bronchiolar carcinoma (FIC- URES 8 and 9). There is, however, some similarity between a peripheral alveolar cell carcinoma of the lung and a mesothelioma of the pleura in that distant hematogenous or lymphatic metastases are rare or, if found, are late manifestations of the tumor. Although numerous tumor emboli can be seen in the blood vessels and lymphatics in a case of mesothelioma, spread of the tumor is mainly by contiguity. The pericardium and peritoneum are most frequently involved (FIGURES 10 and ll), but extension of the tumor to the vertebral column has been found. Metastases to regional lymph nodes

3 Webster : Mesotheliomatous Tumors in South Africa 625 FIGURE 1. Fibrous plaques on the parietal pleura.

4 626 Annals New York Academy of Sciences FIGURE 2. Mesothelioma of the pleura.

5 Webster : Mesotheliomatous Tumors in South Africa 627 FIGURE 3. A section of a mesothelioma consisting of small round cells. 96 x.

6 628 Annals New York Academy of Sciences FIGURE 4. A section of a mesothelioma consisting of large cells in an acinar arrangement. 60 X.

7 Webster : Mesotheliomatous Tumors in South Africa 629 FIGURE 5. A section of a mesothelioma showing spindle cells. 96 x.

8 630 Annals New York Academy of Sciences FIGURE 6. A section of a mesothelioma showing cystic spaces and vacuolated cells. 60 X.

9 Webster : Mesotheliomatous Tumors in South Africa 631 FIG~JRE 7. A section of a mesothelioma showing the presence of dense collagen and clefts in the collagen containing malignant cells. 60 x.

10 632 Annals New York Academy of Sciences FIGURE 8. A tumor with the macroscopic appearances of a mesothelioma, which on histological examination was a peripheral carcinoma of the lung which had spread to the pleura.

11 Webster : Mesotheliomatous Tumors in South Africa 633 FIGURE 9. A section taken from the specimen shown in FIGURE 8, demonstrating the peribronchiolar nature of the tumor nodules in the lung.

12 634 Annals New York Academy of Sciences FIGURE 10. Spread of a mesothelioma by contiguity to the mediastinal tissues.

13 Webster : Mesotheliomatous Tumors in South Africa 635 FIGURE 11. Spread of a mesothelioma by contiguity through the diaphragm onto the surface of the liver.

14 636 Annals New York Academy of Sciences FIGURE 12. A mesothelioma sometimes arising in the costophrenic angle.

15 Webster : Mesotheliomatous Tumors in South Africa 637 are not uncommon. After paracentesis or thoracotomy the tumor spreads into the thoracic wall presenting as a subcutaneous nodule (FIGURE 12). Winslow and TaylorX following on the work of Meyer and Chaffee" have stated that hyaluronic acid could be demonstrated in the stromal connective tissue of mesotheliomatous tumors. Wagner, Munday and Harington" considered, however, that the presence of hyaluronic acid in the stroma was not a specific property of mesotheliomatous tumors, but in the cells or cystic spaces of the tumor it was a more specific feature of a mesothelioma of the pleura. Considerable difficulty has been encountered in confirming this diagnostic feature, not only in formalin-fixed specimens but also in those fixed in formal alcohol acetic acid. In some cases presenting clinically as mesotheliomata, and in others where the histological features appeared to be consistent with those of this diagnosis, metachromatic staining reactions were not entirely prevented by the action of hyaluronidase of either type. As metaplastic mesothelial cells of the visceral and parietal pleura, although containing metachromatic material in the cytoplasm, did not contain hyaluronic acid, it does appear that a complex group of polysaccharides may be present in some of these tumors. Such a polysaccharide has been found in a metastatic tumor of the pleura, namely, a rhabdomyosarcoma. Harington, Wagner and Smith" also indicated that hyaluronic acid could be found in pleural effusions in certain cases of mesothelioma of the pleura. Although an occasional doubtful result has not been associated with a mesothelioma, the results of the investigations on two patients are of particular interest. The first, a woman of 57, presented with recurrent pleural effusions. On five occasions pleural fluid was removed and a biopsy specimen of the pleura taken. On each occasion, although the pleural fluid contained hyaluronic acid, no evidence of malignant neoplasia could be found on histological examination of the pleural tissue. A subsequent biopsy did, however, show features consistent with those of a mesothelioma and the clinician, C. A. Sleggs, the Medical Superintendent of the West End Hospital, Kimberley, considered the presentation of the case that of a typical mesothelioma of the pleura." The second case, also a patient who presented with recurrent pleural effusions, again showed the presence of hyaluronic acid in the pleural fluid and although malignant neoplastic cells were found in the pleural fluid and a malignant tumor developed in the paracentesis needle tract, two tumors of the lung were found on necropsy. One was a peripheral bronchiolar carcinoma and the other an adenocystic tumor. The metachromatic staining reaction of the material in the cystic spaces was not completely abolished by either bovine or streptococcal hyaluronidase. The presence of hyaluronic acid in the tumor or in the pleural fluid is thus a useful guide, but should not be used as an absolute criterion in the

16 638 Annals New York Academy of Sciences TABLE 2 PLEURAL BIOPSIES Report Not representative Nonspecific reaction Tuberculous pleurisy Possible mesothelioma Probable mesothelioma Other diagnoses I I Number n = 450 diagnosis of a mesothelioma of the pleura. It is of some assistance in the diagnosis of biopsy specimens of which 460 have been examined in the last few years. TABLE 2 shows the results of the examination of these biopsy specimens. The specimens classified as not representative consisted of parietal muscle and connective tissue only. It is submitted that the reasonably high incidence of the finding of tuberculous granulation tissue indicates that the laboratory technique is sufficiently satisfactory to demonstrate the pathology in the specimens submitted, if a pathological lesion were present. It is the practice in our laboratories to report on biopsy specimens as follows : (1) Where atypical mesothelial cells are found in groups or in the interstices of connective tissue, a report is issued indicating that a mesothelioma should be considered. This group is designated as possible mesothelioma in TABLE 2. (2) Where there is marked infiltration of the connective tissue or wellmarked atypical change in the mesothelial cells, it is reported that the pathology is consistent with that of a mesothelioma, probable mesothelioma in TABLE 2. TABLE 3 FINAL DIAGNOSIS IN 45 PATIENTS Probable mesothelioma (n = 26) Possible mesothelioma (n = 19) Mesotheliomatous tumors Clinically tuberculosis Metastatic carcinoma 23 Clinically mesothelioma 10 2 Mesotheliomatous tumor 1 1 Tuberculous pleurisy 6 Other diseases 2

17 Webster : Mesotheliomatous Tumors in South Africa 639 FIGURE 13. A biopsy specimen which was reported as a probable mesothelioma. The patient responded to antituberculous therapy.

18 640 Annals New York Academy of Sciences TABLE 4 EXFOLIATIVE CYTOLOGY - PLEURAL FLUID Report I I I I Carcinoma Unknown Negative (81) Doubtful (33) Positive (35) n = TABLE 3 shows the final diagnoses in patients from whom pleural biopsy specimens were examined and reported as either possible or probable mesotheliomata. That such a large percentage of the possible diagnoses were shown to be tuberculous is not disturbing as this diagnosis was given to suggest that further investigation and observation were necessary. The two cases in the probable mesothelioma group do cause concern as the histological features were indeed suggestive of such a diagnosis (FIGURE 13). These patients responded favorably to antituberculous therapy. A mesothelioma may yet develop but it is unlikely on the present clinical presentation. There is no doubt that the more definite histological features do allow of a diagnosis of malignancy to be made, but it may be difficult to distinguish between a mesothelioma and a metastatic bronchiolar or bronchogenic carcinoma. area Northern Cape (169) TABLE 5 COMPARISON OF SPEC1 MENS FROM TWO REGIONAL HOSPITALS I Mesotheliomatous tumors 1 Tuberculosis 1 Other 1 I I I Carcinoma u I I I I I I 4.7% 13.6% 65.m 16.7% 1 Southern Transvaal I I (466) 2.4% 0.2% 69.6% 27.8%

19 Webster : Mesotheliomatous Tumors in South Africa 641 In addition to these observations, consideration must be given to the use of exfoliative cytology as a means of diagnosis of mesothelioma and the final diagnoses of the patients in whom these examinations are carried out is shown in TABLE 4. Although the percentage of cases confirmed as mesotheliomatous tumors appears reasonable, it should be remembered that there is an awareness of the diagnosis of mesothelioma in South Africa, and possible cases are usually brought to our notice. The relatively large percentage of cases in which there is no knowledge of the final diagnosis is disturbing, especially when a number of these cases lived in the Kimberley District and were not on the comprehensive list of mesotheliomatous tumors submitted by C. A. SleggsI2 from that region, two months before this paper was written. However these peripheral tumors are designated, there is no doubt that the incidence is increased in the northern region of the Cape Province. This is well instanced in the summary of the pathological findings in specimens submitted from two State Tuberculosis Hospitals, one in the Northern Cape and the other in the Southern Transvaal. Although the percentage of cases of tuberculosis is similar in the specimens from the two hospitals, the incidence of mesotheliomatous tumors is significantly higher in the specimens from the Northern Cape (TABLE 5). Sleggs': considers that a plastic pleurisy develops in tuberculous patients in the Northern Cape, and with the interaction of dust a mesothelioma ensues. Certainly tuberculosis alone does not produce such tumors. If it did one would expect to find similar tumors in the cases from the Southern Transvaal where fibrous thickening of the pleura also occurs. The one patient with a mesotheliomatous tumor in the Southern Transvaal Hospital was an asbestos worker, and it is believed that asbestos pollution of the atmosphere of the Northern Cape asbestos fields was associated with the development of the tumor. Any discussion of the association of asbestosis with mesotheliomatous tumors of the pleura must take into account the cases in which sufficient material was examined to diagnose asbestosis, and of the forty-one cases in which this could be done, nine of the cases did not show any evidence of asbestosis even after a detailed and extensive histological examination. In South Africa legislation"' requires that, provided the relatives of a deceased miner consent, the attending medical officer must ensure that the respiratory organs are removed from the body and submitted to the Miners' Medical Bureau for examination. Three hundred and fifty records of such cases from the asbestos areas of South Africa have been analysed in order to determine whether there was a relationship between asbestosis and malignant disease of the respiratory organs, especially mesothelioma of the pleura. There is an increase in the numbers of cases of malignant neoplasia in

20 642 Annals New York Academy of Sciences cases with asbestosis, and the results suggest that although there is an increase in the number of cases with marked asbestosis compared with those with slight asbestosis, this does not apply to the cases of mesotheliomata. Although the age distribution in the three groups is similar, this may not be valid as it is doubtful whether the ages given are always accurate. Before discussing the points for and against asbestos exposure as the causative agent in producing mesotheliomatous tumors, it must be noted that there is increasing evidence to suggest that these mesotheliomatous tumors occur in families, a view which is supported by both Sleggs" and Marchand.I4 The following points favor the association of asbestos exposure with the development of mesotheliomatous tumors : There is an increased incidence of malignancy of the chest in people with asbestosis. The mortality from malignant tumors of the lung in the asbestos districts is three times higher than one would expect.i5 Asbestos dust is found in the atmosphere of areas in the Northern Cape. Of the nine patients (TABLE 6) in whom mesotheliomatous tumors were found without evidence of asbestosis, six were associated in some way with the Northern Cape. However, the following factors tend to suggest that some other factor, either alone or in association with asbestos should be considered : Some of the patients with mesotheliomatous tumors have visited the Northern Cape for a few days only. No evidence of asbestosis has been found in a number of cases of mesotheliomata. The relatively high percentage of cases showing asbestos bodies in smears made from their lungs in the post-mortem survey carried out by Thomson*a in Cape Town has been confirmed in a similar series in Johannesburg where 47 per cent of the cases showed asbestos-like bodies in such smears.'? This indicates that a large TABLE 6 ASBESTOSIS AND MESOTHELIOMATOUS TUMORS Asbestosis 32 Mesotheliomatous tumors 41 I No asbestosis 9

21 Webster : Mesotheliomatous Tumors in South Africa 643 proportion of the population in South Africa has been exposed to asbestos dust and yet only 169 cases of mesotheliomatous tumors have been found. (4) A number of cases diagnosed as mesotheliomata have been exposed to manganese dust only, while others have had longer service on manganese mines than on asbestos mines. (5) Tuberculosis has been found in close relatives of those patients with peripheral tumors diagnosed as mesotheliomata. (6) Although the chemical composition of the Cape blue and Transvaal blue asbestos is similar, no case of mesothelioma of the pleura has been found in people exposed to Transvaal blue asbestos dust. Cases TABLE 7 RELATIONSHIP BETWEEN ASBESTOSIS AND MALIGNANCY Asbestosis None % Slight Wo Marked % 64 2 Malignancy Carcinoma Mesothelioma I I I I 97.0% 3.0% - 3.0% % 4.0% 4.0% 8.0% % 9.0% 5.0% 14.0% - n = 350 of bronchogenic carcinomata and bronchiolar carcinomata have been reported in this group. From an analysis of the autopsy records of people who had worked with amosite asbestos, two out of nine Whites and four out of 60 Bantu died of carcinoma of the lung. This incidence is higher than expected in South Africa,IR but the number of cases is small. Although one of the carcinomata was of the peripheral bronchiolar type no mesotheliomatous tumor has been found in the people exposed to amosite. Experiment a1 Pat ho 1 o g y As yet animal experimentation has not produced a solution of the problems outlined above. Asbestosis can be produced in monkeys, guinea pigs, rabbits, and rats by exposing these animals to a dust cloud of asbestos.

22 644 Annals New York Academy of Sciences FIGURE 14. An adenomatous tumor in the lungs of a guinea pig exposed to crocidolite asbestos which probably has malignant characteristics. 60 x.

23 Webster : Mesotheliomatous Tumors in South Africa 645 When J. C. Wagner was working in our laboratories he found a mesotheliomatous tumor in one of the animals so exposed, but such a tumor has not been found in any of the other animals exposed to asbestos. Donkeys, baboons and field rodents do develop asbestosis! from exposure to the dust around and about the asbestos mills, but in none of these has a mesotheliomatous tumor been found. Relatively large numbers of these field rodents were trapped and housed in our laboratories in order to prolong their life span. It was considered that, should a mesotheliomatous tumor develop in these animals, it would be more easily demonstrated in older animals. In 1959 J. C. Wagner inoculated some animals intrapleurally with different dusts. However, the results of this experiment were disappointing. Of 177 inoculated with crocidolite asbestos, six developed mesotheliomatous tumors, but such tumors were also found occasionally in animals inoculated with chrysotile, silica and carbon. In a recent experiment in which guinea pigs were exposed to a high concentration of asbestos dust for 40 minutes a week, some of the animals have developed multicentric bronchiolar carcinomata (FIGURE 14). In the experiment, groups of animals were given 1, 5, 10, 15, 20, and 25 exposures and the tumors appear to develop in those given the greater number of exposures. Conclusions Although the association of peripheral tumors of the respiratory tract appears to be related to the inhalation of asbestos, particularly crocidolite, there are sufficient points against this to suggest that the situation is reviewed continually and that other possible factors cannot yet be excluded. Although the exact classification of these peripheral tumors is difficult, this does not detract from the high incidence of such tumors in certain areas of South Africa where asbestos is mined, milled or processed. Acknowledgments I should like to express my appreciation to Dr. L. G. Walters, the Director of the Pneumoconiosis Research Unit, for the facilities to carry out this work and for his assistance in preparing the manuscript. Professor B. J. P. Becker, Professor J. F. Murray and Dr. A. G. OettlC have given most helpful criticism and advice. It is a great pleasure to acknowledge the assistance of the technical staff of the pathology laboratories of the Pneumoconiosis Research Unit. The records of cases examined for the Miners Medical Bureau are produced by permission of the Director of the Miners Medical Bureau, Dr. G. K. Sluis-Cremer. References 1. WAGNER, J. C Some pathological aspects of asbestosis in the Union of South Africa. In Proceedings of the Pneumoconiosis Conference. JO-

24 646 Annals New York Academy of Sciences hannesburg, A. J. Orenstein, Ed. J. & A. Churchill, Ltd. London, England. WAGNER, J. C., C. A. SLEWS & PAUL MARCHAND Diffuse pleural mesothelioma and asbestos exposure in the North Western Cape Province. Brit. J. Ind. Med. 17: 260. WAGNER, J. C The Pathology of Asbestosis in South Africa. Thesis presented for the degree of Doctor of Medicine, University of the Witwatersrand. Republic of South Africa. STOUT, A. P. & M. R. MURRAY Localized pleural mesothelioma: investigation of its characteristics and histogenesis by method of tissue culture. Arch. Path. 34: 951. CLAGETT, 0. T., J. R. MCDONALD & H. W. SCHMIDT Localized fibrous mesothelioma of the pleura. J. Thorac. Cardiovasc. Surg. 24: 213. PRICE-THOMAS, C. & C. E. DREW Fibroma of the visceral pleura. Thorax 8: 180. MCCAUCHEY, W. T. E Primary tumours of the pleura. J. Path. Bacteriol. 76: 517. WINSLOW, D. J. & H. B. TAYLOR Malignant peritoneal mesotheliomas. Cancer 13: 127. MEYER, K. & E. CHAFFEE Hyaluronic acid in pleural fluid associated with malimant tumor involving pleura and peritoneum. Proc. Soc. Exptl HARINGTON, J. S., J. C. WAGNER & MARIANNE SMITH The detection of hyaluronic acid in pleural fluids of cases with diffuse pleural meso-.theliomas. Brit. J. Exp. Path. 44: 81. SLEWS, C. A. Personal communication. REPUBLIC OF SOUTH AFRICA Pneumoconiosis Compensation Act, No. 64. MARCHAND, PAUL. Personal communication. OETTL~, A. G Cancer in Africa, especially in regions south of the Sahara. J. Nat. Cancer. Inst. (in press) THOMSON, J. G., 0. C. KASCHULA & R. R. MACDONALD Asbestos as a modern urban hazard. South African Med. J. 37: 77. CHATGIDAKIS, C. B. & I. WEBSTER. To be published. OETTL~, A. G. Personal communication. WEBSTER, I Asbestosis in non-experimental animals in South Africa. Nature 197: 506. :t.